Dan Keller 0:08

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research, the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow. No two cases of Parkinson's disease are exactly alike. Throughout this podcast series, we've talked about biomarkers—those identifiable and measurable traits that a person carries or exhibits. One of those is a person's genetics. People with PD may experience different symptoms at different times and may vary in how the disease progresses. These are the outward signs that they experience. But beneath the surface, are there genetic makeups which contribute to a person's risk for PD, how the disease presents, and the course that it may follow? To explore these genetic factors, the Parkinson's Foundation has initiated the largest and most comprehensive genetic study in PD, aiming to assess these factors in 15,000 people with the disease. I spoke with Dr. Jim Beck, the Chief Scientific Officer of the foundation, about this initiative called PD GENEration: Mapping the Future of Parkinson's Disease. He says that while only a minority of people will have identifiable genetic risks for their disease, the study should shed light on mechanisms of the disease that may be applicable to the entire PD population and may lead to better treatments. We spoke about the three main goals of the PD GENEration study.

Dr. Jim Beck 2:10

One of them is a very pragmatic goal, and that is to accelerate clinical trials which are coming. The other is to be able to bring precision medicine to Parkinson's disease, meaning being able to utilize genetic information to make informed decisions about the care of people with Parkinson's disease. And the third one is to really empower people with PD to know more about their disease, to be able to make informed decisions about what it means to have Parkinson's disease, and so that they can take control of their lives. What's it looking at, and how it's [a] genetics initiative? So we're going to be looking at genes. And for your listeners who may or may not [know] what genes are—genes are recipes for making proteins in the body, much like a recipe you'd have to make cake. And these recipes sometimes have errors in them. And it's much like... I like to make pound cake; it was my mother's dessert she'd always make for me, and so I still make it. And sometimes I try different things, and I bought a fancy flour I saw at a grocery store, and my cake was awful. One time I didn't put enough vanilla into it, and it was fine, but, you know, it was okay. So one was a deleterious mutation, which led to something bad. The other was a risk factor or slight change or variants in the recipe that could have been bad or could have been good. And so you see that same thing with genes for people. And so what we want to do is look at genes which affect Parkinson's disease. Some of these genes, when they're mutated, cause Parkinson's disease—we have lots of confidence. Other ones are like these variants in the recipe, and they are associated with a greater risk for Parkinson's disease—not always getting Parkinson's disease, mind you, but a greater risk. And the two we're going to be looking at are LRRK2, which stands for leucine-rich repeat kinase 2, and GBA1, which is a gene which makes a protein that's involved in Gaucher's disease. Where you have two copies of GBA mutation, a person gets Gaucher's disease; one copy, they have an increased risk of developing Parkinson's disease. And we want to be able to test people for these genes and be able to provide that information back to them.

Dan Keller 4:13

Where does it stand now? How far along is it? When do you see it producing useful results?

Dr. Jim Beck 4:17

We just announced this initiative, and we're collaborating with the community—both the scientific and the PD community—to ensure that what we're doing is going to have impact in their lives. So what we want to do is not just simply offer genetic testing to people with Parkinson's disease. That's something that people can do to a certain extent already. What we want to do is offer it within a clinical setting, because we think what has been a missing part of the equation is including a person's physician as well as a genetic counselor to be able to provide that interpretation to what the results mean. Used to be, you could go get over-the-counter testing; you spit into a tube, and you get your report back, and it would say whether you had a PD gene. But what people didn't realize, because they didn't have a counselor there with which to guide them, is that they only looked at one variant of one gene when there are over two dozen genes which could be impacting for Parkinson's disease. And as a result, they would say, "Oh, I don't have this variance in this one gene. I don't have a genetic form of Parkinson's disease." It's like going to the mechanic and having them, you know, take a look at your car because it's not running right. And they just look at the gas cap. "Yeah, gas cap's working fine, problem solved," when, in fact, that there's some other issue which might be causing their PD. The other thing is that because we want to look at these two different genes—LRRK2 and GBA—genetic testing for them, if you wanted to do that on your own privately, is not easily accomplished. The LRRK2 gene—you can go to some places, direct-to-consumer, or even get it ordered; they can provide some limited testing. GBA is much more difficult, because we need to get the full gene sequence. It's kind of like with LRRK2, you can kind of go by the CliffNotes and just look at a couple bullet points to find out whether you're affected, but with the GBA, you have to go through page after page, line by line, in order to really understand whether there's a variation in that gene which could lead to Parkinson's disease. And so you could do that, but you'd have to go to two different providers, two different genetic testing places to do that. And we want to consolidate that into one place to be able to offer it for free for people with Parkinson's disease, and then be able to incorporate that as part of a larger study that we have, our Parkinson's Outcomes Project, which has the largest natural history study of people with Parkinson's disease. What we want to do, ultimately, is to link someone's genetic status with their clinical status. It's the scientific way you say genotype and phenotype. And so we want to understand how someone's genes influence their course for Parkinson's disease. How can we utilize that information to improve their care?

Dan Keller 6:41

You named two genes out of this multitude of them. For example, these two genes—do they lead down the same Parkinson's disease road, or is there some difference? What would it matter to a patient whether they have Parkinson's disease because of this or because of that?

Dr. Jim Beck 6:55

Yeah, that's a really good question. And I think the first thing to keep in mind is that most people won't have a genetic form that we can easily identify at this point for their Parkinson's disease. We're only talking about genes which affect probably 10% of people with PD. And in fact, most people—it's only maybe 15 to 20% of all cases of PD have a genetic form of PD. So within this limited range, people with LRRK2 PD or GBA PD—and this goes back to something just even a couple years ago—if you were to get genetically tested, trying to understand a genetic cause to your PD, and you went to your physician and you said, "Hey, I've got LRRK2 mutation, I've got LRRK2 PD," or "I've got GBA variants and GBA PD, how's that going to affect my treatment?" They kind of shrug their shoulders and say, "Not really. It's not going to affect your treatment at all," because their doctor, like most movement disorder specialists or neurologists, are treating for symptoms. And so knowing the genetic status didn't affect the treatment of symptoms. But fast-forward a couple years now, we now have an understanding that someone who has LRRK2 PD, on average, has a slower time course to their Parkinson's disease. And we also understand that someone with GBA version of PD has a slightly more aggressive form of Parkinson's disease, and it progresses more quickly than LRRK2 PD—more quickly than the average case of PD. And so what's the impact of that? The impact of that is that, you know, as part of this initiative—you know, how we want to improve care—is that if someone were to go through our genetic testing initiative and find out they had LRRK2 PD and were experiencing motor complications to their Parkinson's disease, their neurologist would probably say, "Hey, you know what? The likelihood is you're not going to have any cognitive involvement. Your PD is going to progress slowly. Maybe we should be more aggressive and consider something like deep brain stimulation as a potential therapy for your complications." Whereas someone [who] had GBA PD, which has a faster progression, typically with some cognitive involvement—so people with GBA PD often have some cognitive impairment as a result of their disease—their neurologist might say, "You know what? Let's hold on a second. Let's really carefully evaluate the situation here, because we know that deep brain stimulation can cause cognitive impairment on its own. We don't need to make a bad case worse. So let's see about what our options are and how we can improve your situation before we go to deep brain stimulation." So that's one very practical way with which we could see how understanding someone's disease status could be useful for their care.

Dan Keller 9:25

Given the variety of different genes that may be involved, do you think that 5 to 10% number you gave today will hold, or is it just that you haven't discovered all the genes that are affecting it and many more—a higher percentage—could be genetically related?

Dr. Jim Beck 9:44

Yeah, that's a really good point. So by and large, most people who come through our genetic initiative are going to come up empty-handed if they're looking for a gene to cause their PD, simply because we may not know what that gene is as of yet. So that leads to two questions: you know, what do we [want] to do with that DNA, and then how is that going to impact the broader range of people who have idiopathic PD? You know, the PD we don't know why they developed it. So what we plan to do is bank all the DNA that people contribute because they've given their time and their efforts. And this is a valuable collection. We want to make it available to researchers—researchers who don't look at just a handful of genes that are actionable right now, but they look at 30, 50, 150 genes to try to get a better sense of what might be causing Parkinson's disease. The example, Dan, that I give to many people is that we understand there's a clear genetic correlation to something as simple as height. You look at a family—the parents are really tall; you're not going to be surprised to learn that the children are going to be tall. And the vice versa happens, too—the flip side where a family of short stature are probably going to have children which are short as well. But I ask people, "How many genes are involved with height?" And, "Is there one height gene? Is there two height genes?" I show up five fingers, 10 fingers, and I say, "Is there 30 genes involved in height?" And people are flabbergasted to recognize that there's over 100 genes involved in determining someone's final height. And each gene contributes about a third of an inch to that overall height. And so these 100 genes play a role in determining someone's height. So there might be 100 or more genes to determine someone's risk for developing Parkinson's disease. One thing that I think would be really cool, it could happen—and this is, you know, we're not there yet, but that's why we want to make this DNA available for research—is that scientists might figure out a genetic risk score for someone with Parkinson's based upon this dataset that we have. And so that means when someone is in their 40s and they go in as part of a physical or even earlier, when this type of precision medicine becomes kind of the standard part of medical care, they run the genetic tests on someone and determine that this person has a higher risk for developing Parkinson's disease. And as a result of this initiative, we hope to be able to facilitate and accelerate the development of drugs which might halt Parkinson's disease. And so those drugs might then, in turn, be utilized for these people who have a higher risk score for developing Parkinson's, or at the very least, the clinician's going to say, "You know, we need to keep an eye on you so we can intervene when you show that first sign of symptoms." So that's something that's really interesting. Have we missed anything interesting or important? Yeah, yeah, yeah. One question that I often hear from people is, why are we focusing a lot of resources on, in essence, 10% of the people with Parkinson's disease? What about these other 90%? Wouldn't you be better served trying to understand what's going wrong with these other 90%? And so I often like to tell a story about two people who many folks know, and that is Winston Churchill and Jim Fixx. Winston Churchill was a man of short stature who drank a lot, smoked a lot, who ate a lot, who had some stress in his life, and yet he lived to be 90 years of age. Jim Fixx, on the other hand, was a man who wasn't particularly healthy early in life but really turned it around, became a big believer in exercise, and in fact, converted many people in the United States to become really into running, and started Runner's World magazine. He died at the age of 52, I believe, of a massive coronary while running in Vermont. What's the difference between these two men? Well, genes. Genes is the difference. And so in Jim Fixx's case, he was likely a person with a mutation in a gene that led to high levels of cholesterol called familial hypercholesterolemia. And scientists understanding mutations in that gene led to better understanding of how cholesterol is regulated in the body, and then could develop a drug called statins. And so I ask people, "How many people here know," and your listeners, "how many people know anyone who actually has a mutation that leads to familial hypercholesterolemia?" Most people say they don't know anyone. But when I ask them, "How many people do you know are taking a drug, statins?" And most people know somebody who's taken a statin. And so I think that's where we're going with Parkinson's disease, I hope, is to be able to identify certain individuals who are rare and have a risk for developing Parkinson's disease, utilizing that knowledge, being able to potentially impact their Parkinson's disease, and then hopefully be able to go broader, broader, and be able to help a larger population of people with PD. Because people with LRRK2 mutation—LRRK2 is an enzyme that gets overactive when they have that mutated gene. But there are people who don't have a mutation in LRRK2 yet still make too much of that enzyme, and they have Parkinson's disease. And there are people who don't have a variant in their GBA gene and still have low levels of the enzyme, that glucocerebrosidase, that gets made by the GBA gene. Much like someone who might have a mutation in that gene would have low levels of that enzyme—not as low, but they also have Parkinson's disease. So therapies which can be utilized to either rein in LRRK2 or boost the levels of GBA might affect a broader range of people with Parkinson's disease. And what's really interesting, too, is that—and this goes beyond the 10%, the 90% story—but it goes on to the fact that there's a whole host of people who have yet to be diagnosed with Parkinson's disease, yet are at risk. And so identifying those who might have a genetic mutation that could be causative to develop their PD, we might, hopefully again, accelerate clinical research to the point where we have a drug which could be used prophylactically, which basically means that, again, when someone turns 50, they go in for their colonoscopy, they may get the genetic test to understand that they're at risk for PD. And then their physician says, "You know what? You might be worried about PD one day. I'm going to prescribe this medication which we hope will prevent you from ever experiencing the symptoms." Our goal as a foundation is a world without Parkinson's disease, and that is one way with which we hope to achieve it.

Dan Keller 15:50

I hope you succeed. Very good. Thank you. For more information on PD GENEration, go to our website at parkinson.org/PDGENEration, where you'll find more information about the initiative. Learn about the power of genetic testing in achieving precision medicine for individual patients, why you might consider participating, and how you can. Be sure to search our PD Library at parkinson.org/library to find more resources on genetics, including fact sheets and an archived Expert Briefing by Dr. Roger Barker that looks ahead at what's in the PD pipeline, focusing on gene and cell therapies. And be sure to go back and listen to Podcast Number 7, where I talked with Dr. David Simon about how modern genetics can help guide the development of new drugs to preserve nerve cells with a goal of keeping Parkinson's from progressing. If you want to find out how you may be able to participate in the PD GENEration genetic study, you can also call our toll-free helpline. Our PD information specialists can answer questions and provide information about this topic or anything else having to do with Parkinson's. You can reach them at 1-800-4PD-INFO. For questions about the topics discussed today, or if you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO. That's 1-800-473-4636. Thank you for listening.

James Beck, PhD, has led the scientific affairs of the Parkinson's Foundation since 2008. Dr. Beck oversees the foundation’s research strategy and programs, including management of grants that support research centers, individual investigators, fellows and collaborative projects. In his role, he has changed the parameters of investigator-initiated grants programs to provide additional funding and multi-year support to Parkinson’s-focused scientists; expanded funding for early-career Parkinson’s researchers, established Conference Awards and instituted the inclusion of Parkinson's Foundation’s Research Advocates in the foundation's own programs. Dr. Beck is a member of the Forum on Regenerative Medicine of the National Academies of Sciences and the Udall Center Coordinating Committee.

Dr. Beck is currently an Adjunct Associate Professor in the Department of Neuroscience and Physiology at the New York University School of Medicine. Previously, he taught at Long Island University as Assistant Professor in the Biology Department. Additionally, Dr. Beck was a recipient of National Institutes of Health (NIH) funding and has been published in journals, such as the Journal of Neuroscience, Journal of Neurophysiology and Journal of Comparative Neurology. His research focused on the neural control of vertebrate motor systems and behavior.

Dr. Beck holds a BS from Duke University and a PhD from the University of Washington, Seattle. He completed his postdoctoral training at the New York University School of Medicine. Dr. Beck frequently comments in the media about the implications of the latest Parkinson's science headlines.

Dan Keller 0:00

Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research, the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow. The treatment of Parkinson's disease has come a long way, mainly beginning in the 1960s with the introduction of L-dopa therapy to a better and more diverse selection of drugs today to deep brain stimulation, among other therapies, but disease-modifying therapies, ones that can slow down or halt the progression of PD, are still elusive. Dr. Alberto Espay of the University of Cincinnati says what's needed is a new way of thinking about PD, one which depends on more precision in defining the underlying biology of the origins of each individual's disease. He proposes a search for biomarkers, those measurable physical or chemical characteristics within people that will better define different variants of PD so that more precise treatments can be targeted to them. In this regard, he compares Parkinson's research today to where the cancer field was 30 years ago. What's the current approach and the traditional approach to Parkinson's disease?

Dr. Alberto Espay 1:51

Essentially, we diagnose Parkinson's as a process of clinical evaluation. We take a story, we examine a patient, and after that process, we then determine the extent to which these features meet criteria, and if they do, we say, "This is Parkinson's." So we refer to this as a clinical diagnosis of Parkinson's disease. We further go on to say to patients that we do not have a test that can confirm our diagnosis, but we reassure them that we're experts and that we have clinical criteria and that that essentially should reassure them that we are right in terms of what we mean when we say Parkinson's disease.

Dan Keller 2:41

Once someone has a diagnosis, a label of Parkinson's disease, is the approach then sort of singular? Parkinson's is Parkinson's; people vary, and there's differences in how they're treated. But essentially, is the idea now it's rather singular?

Dr. Alberto Espay 2:57

Well, this is the very interesting phase of cognitive dissonance that we have in our fields. And by that, I mean that as we make the diagnosis of Parkinson's to a patient, we emphasize that there are many ways in which Parkinson's can present, and also many different slopes of progression, with very good kinds of Parkinson's as well as very bad kinds of Parkinson's—benign and perhaps malignant forms and anything in between. But we address your patient by saying, still we consider Parkinson's a single, if heterogeneous disease, and I think that is sending two conflicting messages to patients. On the one hand, we say this is a disease because we can make a firm clinical diagnosis based on our examination features, but then we're saying, but there are different kinds of Parkinson's, because we know people can have tremor or no tremor, difficulties with memory or not, they can have autonomic dysfunction, which means constipation, orthostatic hypotension and the like, or not. And yet we say at the end of the day, we're still talking about a single Parkinson's disease. That model has been really wonderful as far as treating the symptoms of Parkinson's, because symptoms are common denominators. But it hasn't really worked out well at all when we try to think of strategies to slow down the disease, or what we call disease-modifying treatments.

Dan Keller 4:35

So what's a better way of looking at it, and what technologies or features would you use to distinguish different forms of the disease?

Dr. Alberto Espay 4:46

Here is where the most difficult part of this period is. In our field, we have a variety of technologies that now we can use to start probing into behaviors of different kinds, because we think that if we can characterize patients well, we can determine different types of Parkinson's. The concept behind that is that if we can tell that somebody is different from another person in terms of features, we would predict that what we say is different has behind it a biology—that if we can say somebody has tremor and somebody does not have tremor, that these two are different biological constructs, which may or may not be the case. What the ongoing biomarker discovery cohorts are proving is that there is actually very little consistency of our grouping, meaning when we classify patients into whatever type we can think of them and compare them to other types, both within as well as between cohorts. So we're beginning to reckon that perhaps just because we think that we can create labels clinically does not mean that there is a biology behind each of them. So clinical features are not in any way predictive of what biology is. And so the way that we would have to tackle this is to start thinking the way other fields of medicine have: to begin from biology, from the abnormalities of biology, and then working backwards into the phenotypes. It's not that we say, "Here's the truth. The truth is my diagnosis of Parkinson's. Let's see what correlates with that truth." But rather, to do the opposite type of thinking, which is an analysis, which is: let's study aging. Let's measure as many biological abnormalities as we can measure and determine where are the outliers and who these people are, particularly for the kinds of outliers that may be quite relevant because we may already have therapies for them.

Dan Keller 7:15

So how do you dig down using present technologies, new knowledge that's already existing? How do you dig down to say these are the features or the markers of the biology, which then give the symptoms? It seems like, up till now, you're saying based on these symptoms we deduce there's this underlying biology. Really, you want to get at the biology first. So what do you look at? I take it you'd be looking at biomarkers, but I guess first of all, what do you consider a biomarker?

Dr. Alberto Espay 7:45

A biomarker is defined as an abnormality in the biology that is telling us something about the disease, and particularly about a disease event that's relevant to a progression. Or there are different kinds of biomarkers: there are biomarkers of disease state, there are biomarkers of progression, there are biomarkers of response to therapy. So it depends on what you're looking for. But the important concept here, in terms of this critical need, is that we have been developing biomarkers on the basis of what it is that we think we need. So in other words, we have a group of patients that have tremor, for instance, and we say, well, let's measure as much as we can about them, and then compare them with people who are healthy controls age-matched but do not have what we call Parkinson's, and then we find differences between them—which, of course, is a big deal of overlap, and those differences are not helpful. So to get to where we need to get, we would have to have an agnostic, non-hypothesis-driven approach, meaning we don't know what abnormal aging is, and we would have to then have much larger aging populations measuring as much as we can on them. And the key problem here, in addition to many others, is that we don't even know what we don't know. So there are things that we can measure we think are important, but perhaps the more relevant things in the future are things that we don't yet know how to measure. But we would then say, for instance, we have a therapy that works by a given mechanism of action. We already have thought the therapy doesn't work because we studied it in Parkinson's disease, not otherwise specified. Well, we could potentially think of a way to assay that particular mechanism or the biology of that mechanism in humans that are aging. Some of them might have something that we can call Parkinson's or a combination of other conditions, and then select them precisely, looking at the possibility that they could benefit from therapies that we have given for dead. Biomarkers are important if we can use the measurements and then determine what is it that this person has? That's not what we're doing, unfortunately, with the ongoing biomarker discovery programs at this time.

Dan Keller 10:16

So it sounds like a biomarker is a very broad term. It could be tremor, it could be a blood test, it could be brain waves. It could be how much tremor someone has. If you consider Parkinson's as sort of a singular group of diseases, but certain ones, certain subtypes, might respond to a drug, but you try that drug in everybody, the effect might get diluted out if only 20% have a response. And you've got 100% of people in a group and 80% of them don't show anything, your average is you're not getting a response, whereas 20% of those people might have done well. It sounds like you have to find those things that define the group that might respond.

Dr. Alberto Espay 11:01

That's exactly right. We have many, many years of very interesting molecules that, in animal models, have given us hope for a cure. What we have then done is to say, "Well, if we have been able to cure mice, that is a model of Parkinson's, we should now give it to people with Parkinson's disease." But what we have missed is to determine who among those we call Parkinson's would actually be the best recipients for that particular intervention. So as you're saying, there could have been in every single one of the over 20 studies done of different medications individuals that probably benefited tremendously from the intervention, but they got diluted in an ocean of those that would have no way of responding because they did not have the underlying biology to respond to that mechanistically speaking. So in the future, it's not sufficient to say we have a therapy that, in animal models, has shown to be very helpful, and therefore we should just go on with trials. The answer to the question, "Should we try them in Parkinson's?" is not going to be just early Parkinson's, or even what we call prodromal Parkinson's—people who don't have motor features but have a constellation of non-motor aspects that may render them at risk for developing Parkinson's. But in fact, it should go even beyond that by saying: what is it about the people we want to target that would tell us they have stand a chance of responding? And if we don't have that biomarker, we should really not do the clinical trials. It's tough to think that we should stop, and I'm not suggesting that we should stop altogether, but that we should be very, very cautious of any endeavors in clinical trials where we aren't sophisticated enough to recognize that there is a biology that we should be looking for in any of the therapies. Because it is very unlikely that any therapy will ever work for the vast majority of people we call Parkinson's as far as disease modification. And it's important to always remember that this conversation is making sense only if we think about disease-modifying therapies or therapies with putative neuroprotective potential, not therapies for symptomatic improvement, which, of course, we've done really well on that. But then those are therapies that do act at common denominators—dopamine deficiency, norepinephrine deficiency, other neurotransmitters and so forth—that do happen to be affected, no matter what the biology is, in the individuals across every single subtype of Parkinson's.

Dan Keller 13:46

There seem to be two aspects here. One is modifying the course of the disease. The other would be neuroprotection and essentially stopping the disease. How close are you to having biomarkers for either of those things? Where does the field stand now, and what's the ideal where we're going?

Dr. Alberto Espay 14:05

So the field is at a turning point of sorts. We think we're getting closer to a biomarker of disease or a biomarker of progression, but in reality, we cannot be if we accept that Parkinson's is more than one disease. So this is going back to the concept of cognitive dissonance. I think if you poll a room of 100 experts on Parkinson's and ask the question, "Is Parkinson's one or many diseases?" all of them will raise their hand in support of the many diseases concept. The question you just asked me, "How close are we to finding a biomarker of progression of disease in Parkinson's?"—then you can still have many, many hands raised. People are very optimistic. We're about there. And it is problematic, right? It is dissonant to think that way. In fact, if you read the review papers on biomarkers, the first paragraph starts by saying, "A major challenge in the field is that there are many diseases likely subsumed within that thing we call Parkinson's disease, and that's problematic for the development of biomarkers." The very next paragraph starts by saying, "But let us now summarize the progress made in terms of efforts toward finding a biomarker for Parkinson's disease." Wait a minute—there is a problem there, right? And so it's really, really quite problematic. This era will eventually end, I hope, once we've hit the wall one too many times. We have been there. I think in terms of clinical trials, it's quite interesting that oncology, as a field, had quite an experience, right? They went through the same thought that we have, that cancer was a bad disease, breast cancer was a bad disease of the breast. But when they had their first trial, their first and only trial that compared radical mastectomy to breast-preserving surgery, demonstrated that there were no differences in long-term outcome, they did not do what we neurologists do, which is explain the failure as a problem with the clinical trial design. They did not say the radical mastectomy arm was too conservative, the conservative arm was too radical, the sensitivity of the measurements was poor, and importantly, the patients were just a bit too advanced such that the ability for the radical arm to prevail over the conservative arm was lost. That's what we do. We, unlike oncologists, explain our failures by saying those are artifacts of the clinical trial design. Oncologists have a negative trial, and they say, "All right, we need to reconsider what we were thinking." And it's a major, fundamental change that we need to do. We need to essentially embrace the divergence of thought, the divergence of biology that all cancers have in the mirror-image field of neurodegeneration. Just like there are many pathways for abnormal cell proliferation, there are many pathways to abnormal cell degeneration or aging, and therefore we should really not think that the brain is excepted from the kinds of principles in biology that oncology has embraced.

Dan Keller 17:15

Unfortunately, it makes the picture even more complicated. Using the oncology analogy, they have found biomarkers. A cell has this molecule on it, and that one and that one, so the cell with A, B, and X is different from the cell with B, C, and Y, and every cancer then becomes a rare disease. The more biomarkers you have and the more you slice and dice, the more different types you'll get. Do you envision this for Parkinson's?

Dr. Alberto Espay 17:43

Yes, it has to happen. When an oncologist sees a patient with breast cancer, he or she has no idea what that means. That patient has to be genotyped; the gene mutations have to be looked for. They have to look for sensitivity to receptors of estrogen and progesterone, the types of tissue affected and how the abnormality is distributed, and then and only then the oncologist knows what disease that is, and then only then the treatment is determined. We instead say, "Trust me, you have Parkinson's disease. Here's your treatment." We have no layer of sophistication, in any way remotely to what oncologists do. Now in 1981, when this major trial that I just mentioned was published, oncologists had no way of predicting that. Now, thirty plus years later, 75% of all breast cancers fall into eight very different molecular subtypes of disease, each of which is managed by a different cocktail of therapies, and only 25% of all breast cancers we have no idea what they are—they are negative to any kind of a study we do, but it's taken them decades. And so yes, it has to happen in Parkinson's. I hope that the neurologist of the future will be like the oncologist of the present, when we will then say, "You have Parkinson's," we will then follow that up by saying, "but we don't know what that means in you. Let's do the testing that we can do to try to understand your biology." But we can only get there if we start investing societally in a completely different model of biomarker development. We would have to really study aging, including healthy aging, and study people who have Parkinson's—but in fact, people that have something that looks like Parkinson's, but perhaps we wouldn't call it such. So expand the criteria; not to assume that let's just make sure that we only include individuals with the diagnosis of Parkinson's and nobody else. No, we have to be very inclusive and then include people with Alzheimer's, and then include people with a variety of other conditions, neurodegenerative as well as non-neurodegenerative, right? But then look at the whole population backwards, not from what we think we know, which is our labels, but rather from what we don't know but are interested in understanding the nature of, which is the biology, and then work our way back. It's tough. It's the hardest thing to do, and it will be incredibly more expensive than any investment we have so far made.

Dan Keller 20:22

Very good. I appreciate it. Thank you. To learn more about biomarkers, search our website at parkinson.org/biomarkers. You'll find a blog entry called "What's Hot in PD: The Importance of Imaging Biomarkers to Diagnose and Track Parkinson's Disease Progression." Also, Episode 54 of this podcast series, called "Understanding Brain Imaging in Parkinson's Disease," discusses that technology as a useful biomarker; and Episode 34, "New Pathways and Drug Development," gives insights into PD mechanisms and drug development. There's also a primer on preclinical studies and clinical trials that you can find by searching parkinson.org/clinical-trials, where you will also find many more resources on research. As always, our PD information specialists are available on our helpline. They can answer questions and provide information about this topic or anything else having to do with Parkinson's. You can reach them at 1-800-4PD-INFO. If you have any questions about the topics discussed today, or if you want to leave feedback on this podcast or any other subject, you can do it at parkinson.org/feedback. If you enjoyed this podcast, be sure to subscribe, rate, and review the series on Apple Podcasts or wherever you stream your podcasts. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series every other week. Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO. That's 1-800-473-4636. Thank you for listening.

Dr. Alberto Espay is professor and endowed chair of the University of Cincinnati James J. and Joan A. Gardner Family Center for Parkinson’s Disease and Movement Disorders. He trained in neurology at Indiana University as well as in clinical and electrophysiology of movement disorders at the University of Toronto, where he obtained a master’s degree in clinical epidemiology and healthcare research.

Dr. Espay served as chair of the Movement Disorders Section of the American Academy of Neurology; associate editor of Movement Disorders, the official journal of the International Parkinson and Movement Disorder Society (MDS); and in the executive committee of the Parkinson Study Group. He currently serves as chair of the MDS Task Force on Technology and as secretary-elect of the MDS Pan-American Section. Dr. Espay is also an honorary member of the Mexican Academy of Neurology and has received numerous awards, including the Cincinnati Business Courier’s Health Care Hero award, the Patients’ Choice award, the Compassionate Doctor award, and the Spanish Society of Neurology’s Cotzias award.

Dr. Espay has published more than 200 peer-reviewed research articles, 25 book chapters and five books. His research efforts have focused on the measurement of motor and behavioral phenomena in—and clinical trials for—Parkinson’s disease as well as in the understanding and management of functional movement disorders. With his colleagues at the Gardner Center, he recently launched a novel biomarker development program for neurodegenerative diseases with the aim of identifying small but biologically suitable subgroups most likely to respond to therapies already available for repurposing.