Episode #3: Prevention and Early Intervention in Parkinson's Disease with Dr. Ray Dorsey

Edited Transcript of Foresight Medicine Episode #3 on Prevention and Early Intervention in Parkinson’s Disease with Dr. Ray DorseyRobert Rogers: I’m Robert Rogers, host of the Foresight Medicine Podcast at the Foresight Medicine Substack, where we are envisioning the future of preventive healthcare as a systematic and whole-body framework for leveraging new technologies to maintain health for as long as possible. In this podcast series, I interview leading experts at the forefront of prevention and early intervention across medical specialties. Today, we will be discussing Parkinson’s disease.I am very honored to have as our guest Dr. Ray Dorsey. Dr. Dorsey is Director of the Center for the Brain and Environment at the Atria Health and Research Institute, and part-time professor of neurology at the University of Rochester Medical Center. He is a leading Parkinson’s clinician and researcher with numerous very impactful publications that span the fields of epidemiology, clinical trials of Parkinson’s, as well as Huntington’s disease, and he has pioneered new models of care delivery and clinical trial implementation for neurological diseases. He has shaped our understanding of the growing global burden of Parkinson’s disease, including the concept of a Parkinson’s pandemic and has been a prominent voice in highlighting the role of environmental exposures as targets for prevention. He’s the co-author of two highly acclaimed books on these subjects, Ending Parkinson’s Disease and The Parkinson’s Plan, A New Path to Prevention and Treatment.Listeners should note that we are recording this on Tuesday, March 24th, 2026, and this conversation is for general information purposes only and does not constitute individual medical advice. Ray, welcome. I’m really excited for our conversation. Thank you so much for joining me today.Ray Dorsey: Many thanks for having me, Robert. Delighted to be with you.Robert Rogers: Great. So, in the next 40 minutes or so, I want to cover a lot of ground about the frontiers of prevention and early intervention and detection in Parkinson’s disease, but I’d like to spend the first few minutes laying a little bit of a foundation for our listeners, both about Parkinson’s disease, but also just briefly about you. The question I always start off with is, what drew you to study and take care of patients with Parkinson’s?Ray Dorsey: So both my parents were psychiatrists, so I like to say I rebelled and I became a neurologist. And, during the course of my medical training, as you know, you spend time in different settings, and once we made it to the clinics. I had a wonderful grandmother, and I enjoy being around older people, and got to care for people with Parkinson’s disease, it’s very clinical in its orientation, a lot of it’s based on listening and observation, and you can make people better. And so, I thought that would be a great combination and something that mastered a lot of my interests, and I think I chose wisely.Robert Rogers: I would certainly say so, based on the impact you’re having in the field. We’re going to talk about preventing Parkinson’s, but I want us to make sure we understand what is this terrible disease that we care about preventing in the first place. So, say a patient comes into your office for the first time, and sadly you have to deliver them the news that, yes, they indeed do have Parkinson’s. How do you explain, based on what our current textbook model or understanding is of what is Parkinson’s disease? What is its pathophysiology, its symptoms, and its prognosis?Ray Dorsey: Classically, Parkinson’s disease is a neurological disorder that produces at least two of the following four symptoms. One is a tremor, usually in the hands, usually asymmetric, usually at rest. Second is, slowness of movement takes people longer to do almost everything. Third is stiffness or rigidity, and fourth is difficulties with a balance or a gait.When Dr. Parkinson first described the condition in 1817, he said, I’m describing something that’s not been classified in the medical literature, something that’s not in the medical textbooks of the time, he described 6 individuals with this disease based on just casually observing half the people on the streets of London. Two centuries later, it’s estimated that 6 million people had the disease. So you went from something affecting 6 people on the streets of London that wasn’t part of the medical textbooks to one that’s the world’s fastest-growing disease affecting 6 million people around the world. And it begs the question, why?And we know that our genes don’t change that much in that period of time. We know that it’s growing faster than aging alone can explain, and growing far faster than other age-related diseases, like stroke and Alzheimer’s disease, they really lead you to the conclusion that Parkinson’s disease is being fueled by… not by changes in our DNA, not by things that are going inside of us, but things that are going outside of us in our environment. Chemicals in our food, including certain pesticides, water, including dry cleaning and degreasing chemicals. And outdoor air pollution are likely responsible for the astronomical rise of this disease.Robert Rogers: That’s super interesting about how, you know, it was only 200 years ago that the disease became prominent enough to really make it onto the radar, and here we are with a Parkinson’s pandemic. And I’d like to double-click on that, and maybe just take us a little bit deeper into how how we go about studying and identifying what it is in the environment that is driving the increase in Parkinson’s disease.Ray Dorsey: Yeah, so it’s, it’s, it’s hard, So, since you’re a pulmonologist, do you know how they determined that smoking was linked to lung cancer?Robert Rogers: You, you, go, go ahead, you’ll, you’ll teach, you’ll teach me and our audience.Ray Dorsey: In the late 1800s in Europe, lung cancer starts emerging, and lung cancer was extraordinarily rare. And the German pathologists, being German, said, did we miss this? So they went back to their cadavers and, you know, looked at the lungs more carefully and see if they were missing occult or hidden malignancies, and there wasn’t any. And they were wondering what was causing it. In the U.S, it was so rare in 1900. That was considered a once-in-a-lifetime oddity. All that doctors and medical students would gather around when they saw a case of lung cancer, thinking they would never see one again. But lung cancer kept getting more and more common in the early 1900s, and in Britain, they were wondering what was going on. Some people thought, was this a delayed effect of exposure to gases from World War I? Other people, including a physician, Richard Dahl, thought it was due to asphalt that was being, poured to pave the way for roads in early 20th century England, and then some people thought it was due to these new things, cigarettes, that had been recently introduced into Europe and then the US around 1900.And so Richard Dahl and his friend Bradford Hill, a statistician did something called the British Doctor Study. They mailed postcards to all the British physicians, I think they might have been all men, and asked them, do you smoke? Yes or no? And if you smoke, how much do you smoke? And then they, sat around and waited. They waited for all the doctors to die. And then they looked at those who died from lung cancer and those who died from other causes, and it turned out that those who died from lung cancer were 30 times more likely to smoke cigarettes than those who, than people who didn’t. Ergo, smoking is as strongly as associated with, lung cancer.But Bradford Hill was bothered by this. He said, boy, I have an association, how do I know it’s a causation? Maybe all smokers really enjoy drinking coffee, and maybe it’s coffee that’s causing lung cancer. So, Bradford Hill put forth nine criteria by which you could go from an association to a causation. I can’t give you them all, but one is, like, the strength of a relationship. Is this a small, small thing or a large effect size? Is this been replicated? Does the exposure happen before the disease? Do people smoke the cigarette before they get lung cancer as opposed to getting lung cancer, which might make them more prone to smoke. Is there a dose-response relationship? Is the more exposure to the toxicant, the chemical, the exposure, more cigarette smoking associated with a greater risk of the disease? Is this biologically plausible? Does this make sense? Are there animal models that are consistent with this? Can we, reason by means of analogy? You go through all those criteria, and smoking, you know, checks a lot of those boxes.Well, it turns out that my colleagues have applied those same criteria to some of the environmental risk factors linked to Parkinson’s disease. Chief among them is a weed killer called Paraquat.Over 70 countries have banned it because it’s been used to commit homicide and suicide, and it’s associated with a 150% increased risk of Parkinson’s disease among farmers who use it, associated with a 100% increased risk of Parkinson’s among people who simply live or work near where it’s sprayed, and in the laboratory reproduces the features of the disease.You’re starting to check off a lot of the Bradford Hill criteria, and they pointed out that it largely did check off these. So I think we have lots and lots of evidence for some of these toxicants. For some, we have much less, and quite frankly, I think the fact that we have much less is an indictment of science, indictment of scientists, and indictment of funders.I’ve never been on rounds where we saw a patient who had lung cancer who smoked, where we talked about the genetics, the genetic… underlying genetic predisposition that led this smoker to get lung cancer. Have you ever had that? Nope. No. But we spend a tremendous amount of time in Parkinson’s disease trying to find out what the genetic underpinnings of the disease are, when, quite frankly, it’s just not a very heritable disease. We’ve known this for 100 years, that Only 15% of people with Parkinson’s disease have a family history of the disease. We’ve known from twin studies for 25 years that the rates of Parkinson’s are similar among identical twins and fraternal twins, suggesting that genetic factors aren’t, that important to the disease. It’s predominantly due to the environment.And then we had two studies done in 2024 that told us that of people with Parkinson’s, that less than 15% of them in the U.S, in North America, South America, and Europe, and the Middle East, less than 15% of people carry a genetic cause or genetic risk factor for the disease. The vast majority of people around the world and the vast majority of people in the United States who have Parkinson’s have little, if anything, to dowith genetic causes or genetic risk factors, the principal causes are not in our DNA. They are outside in our environment, and to our discredit, we have failed to rigorously assess many of these environmental causes.Robert Rogers: Yeah, and I want to, pick up that thread, but since you brought up a really interesting, side note, which is, how was it that the link between smoking and lung cancer was proven as causal? An interesting piece, I think, of epidemiological trivia is that smoking raises your risk of almost every disease that you can think of, except Parkinson’s, where there’s a pretty strong epidemiologic association that it decreases the risk. Maybe you’ll comment on that. And I bring that up not to discuss that epidemiologic association, or even… and of course, not to in any way encourage people to smoke related to Parkinson’s disease, but just to say that defining the specific contaminants in our environment that cause disease is very, very challenging, because there are so, so many toxins in our environment, and a decent proportion of them are actually in cigarette smoke, but presumably, the ones that are driving the incidence of Parkinson’s disease are not the ones found in cigarettes, so identifying what those ones are really is challenging, and like you said, calls for a very large research effort, which it sounds like you think we have to devote more resources to.Ray Dorsey: Yeah, so, we gotta do smoking and lung and Parkinson’s disease.Robert Rogers: Yeah, let’s do it.Ray Dorsey: Study after study has shown that there’s a 40% decreased risk of smoking… of Parkinson’s disease among smokers, so no one should smoke cigarettes. So why is that? Two hypotheses. My colleague Dr. Jeff Bronstein at UCLA, thinks it might be reverse causation. So I said the exposure has to happen before the disease occurs. You have to smoke the cigarettes before you get lung cancer. You can’t get lung cancer and then smoke cigarettes. He thinks it might be the other way around. He thinks that people, we know that pathology of Parkinson’s disease begins years, decades before the disease manifests. He says if you decrease the amount of dopamine-producing neurons in the reward centers in the brain, it might be easier to quit smoking. So it might be that people with prodromal, subclinical, pre-Parkinson’s disease find it easier to stop smoking, and therefore, people with early, Parkinson’s before they are diagnosed are less likely to smoke. So it could be the other way around, that early Parkinson’s disease makes you less likely to smoke.My colleague, Dr. Michael Schwarzschild, thinks this is another thing. He thinks that there are actually, contaminants, chemicals, and cigarette smoke that might, decrease your risk for Parkinson’s disease. Among these things are chemicals that decrease the amount of activity of an enzyme called monoamine oxidase, which is responsible for breaking down dopamine, and that if you slow the breakdown of dopamine, you decrease your risk of developing Parkinson’s disease. So he’s spending a lot of time and energy trying to determine are there, chemicals in cigarette smoke that could be actually beneficial or slow, decrease your risk of developing, Parkinson’s disease?Robert Rogers: And we established that we have strong reason to believe that it’s changes in our environment that are changing… that are driving the increase in Parkinson’s. Challenging to identify all of the specific environmental contaminants. One that you mentioned that there’s very strong evidence for is Paraquat. There’s another one that you’ve written quite powerfully about, it goes by the abbreviation TCE or trichloroethylene. And maybe that, maybe just… I don’t want us to elaborate on every single environmental risk factor out there, but that seems to be one that, along with Paraquat, you’ve paid particular attention to. Maybe just tell us a little bit more about that association.Ray Dorsey: Here’s trichloroethylene, I know your listeners can’t see it, but, it’s a molecule. Your listeners, a little flashback to chemistry. Water’s made up of three atoms, two hydrogens, and 1 oxygen, H2O. Trichlorethylene is made up of a whopping 6 atoms, 2 carbon atoms, in black in this model, 1 hydrogen atom, and 3 chlorine atoms, hence its name, tri. chloroethylene. It’s got a cousin named perchloroethylene, or tetrachloroethylene, that’s got one additional chlorine atom, hence the prefix tetra, meaning four. If you’ve ever dry-cleaned your clothes, you’ve likely been exposed to tetrachloroethylene, also known as perchloroethylene, or PERC.My colleagues, Dr. Caroline Tanner and Sam Goldman, now at UCSF, showed that hobby or occupational exposure to these chemicals is associated with a 500% increased risk of Parkinson’s disease. These are also the principal contaminants at the marine-based Camp Lejeune, which many of your listenersmay be wondering why they hear all these advertisements about Camp Lejeune, because Trichloroethylene’s known to cause cancer, perchloroethylene likely causes cancer, so these, carcinogens are likely carcinogens that cause a lot of disease at this marine base for 25 years, and for the latter years, the Marine Corps knew that cancer-causing chemicals were in the drinking water at a marine base and did nothing. They knowingly let the best and brightest of Americans be exposed to cancer-causing chemicals in the water that they were drinking.And they studied Marines who served there, and they found that Marines who served there had a 70% increased risk of developing Parkinson’s disease. A few things that are really important to recognize is that these Marines were young, their average age was 20, some were teenagers. They were healthy, you know, it’s hard to be a Marine if you’re not healthy. And they were only there for a short period of time, on average just over 2 years, yet 34 years later, they had a 70% increased risk of developing Parkinson’s disease.I think it tells us a few things that are very similar to smoking, that the seeds of, to lung cancer, the seeds of lung cancer, the seeds of Parkinson’s disease, the seeds of Alzheimer’s disease are planted at a young age. You don’t get lung cancer at age 60 because you started smoking at 58. You get lung cancer at age 60 because you were likely smoking when you were 18 or you were 20. Second, that there’s a long lag, so the pathology that underlies lung cancer accrues over years or decades. You keep accruing mutations and the like, and the tumor gets bigger and bigger until it produces symptoms or comes to the attention of doctors, like on an x-ray or something like that.Same thing happens with Parkinson’s disease. It takes a while for the pathology to spread, to get to the part of the brain that classically causes tremor, to kill off enough nerve cells. 60% of the nerve cells are killed off by the time you are diagnosed with the disease.Robert Rogers: you know, I think you’ve laid out in many forms a very compelling case that to make a real dent in this Parkinson’s pandemic and prevent many future cases, we do need to make several changes at the level of public health research and then public health policy and implementation around environmental science. But I am curious. Is there anything that you think a physician can do within the context of the doctor-patient relationship to help patients avoid these exposures that increase their risk of Parkinson’s?Ray Dorsey: Listen, if you’re diagnosed with any condition, one of your first questions should be, why did I get this disease? Diseases have causes. If you want to cure a disease, the prerequisite to curing a disease is to know what its cause is. I can’t think of a medical condition that we can cure where we don’t know its cause. Maybe you’ll help me out. That’s your homework assignment while I speak. I name a medical condition we can cure where we don’t know its cause.Once you know a cause, you can prevent it, you can slow it, you can get better treatments, and you can cure it. So now, since having this realization about 7 years ago, I spend the 10 to 15 minutes with new patients trying to figure out why they got the disease. And I, like, do they get exposed to pesticides as a young child because they live near a golf course or a farm? Do they drink well water? What were their jobs as teenagers? Did they work with industrial chemicals? Did they like to degrease engines? Did they work on cars?And then, because once I find it, I can make sure that they’re no longer still getting exposed. Some people are still living near a farm where Paraquat is sprayed. Some people are still drinking contaminated well water. Some are still living near a superfund site where this trichloroethylene can come into people’s homes and breathe it in. That could still be going on, and that has happened.And then there are also tons of comorbidities associated with it. I mentioned trichloroethylene, you know, I care about Parkinson’s disease, but trichloroethylene causes cancer. It’s been causing cancer for 100 years.Ray Dorsey: It causes, as likely causes, non-Hodgkin’s lymphoma, renal cell carcinoma, prostate cancer, multiple myeloma, liver cancer. So many male Marines developed breast cancer at Camp Lejeune that they create a swimsuit calendar of men, male Marines, showing off their mastectomy scars. I mean, the list of diseases associated with trichloroethylene is enormous, and you know, you and I were probably told nothing about trichloroethylene during our decade of medical training. So I think it’s really important to figure out what the cause is. In our book, we give the Parkinson’s 25, 25 ways to reduce your risk of ever getting the disease.Buying organic produce, washing that produce, because even organic produce can have residues of pesticides on it. Using a water filter and air purifier to reduce your exposure to outdoor air pollution, which was likely, when Dr.Parkinson described the condition in 1817, he did so amidst the London fog. Air quality in 1800 London is akin to what’s in Delhi, India today. So we give you 25 actions to reduce your risk of getting the disease, and 25 actions that might slow your progression of the disease. We know, again, from lung cancer that people who continue to smoke are more likely to have progressive lung cancer than people who stop smoking.It turns out that the same is likely true for Parkinson’s. People who already have Parkinson’s disease, who have, exposure to pesticides after they’ve been diagnosed are more likely to have a faster rate of progression than people who don’t, research done by Jeff Bronstein at UCLA. And we know that people with Parkinson’s disease who are exposed to high levels of air pollution after they’ve been diagnosed are more likely to be hospitalized for their condition. And, you know, asthma, you know, pulmonary, you know, if a child has asthma. Really, really important to stop getting exposure to air pollution so you can prevent asthma attacks. I think it’s the same thing for Parkinson’s disease. I think, quite frankly, it might be the same thing for most chronic diseases, whether it’s high blood pressure, or type 2 diabetes, or asthma, or pulmonary fibrosis, or lung cancer, or Parkinson’s disease, or Alzheimer’s disease. Halting exposure to the contaminants that are fueling the rise of disease might be the first, in some cases, one of the most important steps you can take to changing the course of those diseases.Robert Rogers: I like that. That’s really actionable. You could really imagine integrating that sort of conversation into the doctor-patient relationship, either in primary care or in specialty care when they have the disease. To take a quick backtrack for just a second, we have emphasized, I think with good reason and supported by evidence that you have created and expounded upon, the leading role of the environment in Parkinson’s disease. But it is a complex disease, and in individual patients, we do think of complex diseases as resulting from the interaction of environments and genes, and so the genetic contribution to Parkinson’s risk, while maybe not as large as the environmental risk, is not zero. And just quickly, you mentioned earlier in our conversation, perhaps a number around 15%. I know we can’t be overly precise in our quantitative estimates of these things, but is that the breakdown you would give, that roughly 85% of risk in the population comes from environmental exposures and 15% from genetics? Or, I would just love to clarify that.Ray Dorsey: Yeah, so we have the evidence, it’s not what I think, it’s what we know, and so if you rank order diseases from heritability at the top are type 1 diabetes, schizophrenia, you know, bipolar disease. At the bottom of the list are, Parkinson’s disease and breast cancer and mortality.So we know that the genetic contributions are modest. Now, there are some important things that we should discuss. One, in the United States, 13%, probably smaller, carry a genetic cause or genetic risk factors, so it’s important. There are certain populations, for example, North African Berbers, Basque populations, Ashkenazi Jewish populations where these genetic mutations are more common, so it’s really important.And there are gene-directed therapies, aimed at some of these genetic underpinnings. Second, there are, genetic differences in the way we break down medication. So you might break down, you know, a blood thinner a certain way, and I might break it down more slowly, and therefore, the dose for you might need to be lower than for me. Similarly, there are genetic differences in the way we metabolize pesticides, for example, and we know people who are really slow at metabolizing these pesticides, too, changes in their gene might be at greater risk for developing the disease. But I think sometimes scientists like to say there’s complexity. I think there’s actually some clarity.Robert Rogers: very well said. I want to get out of genetic territory, but I want to ask you one more sort of practical question as it might relate to patients, because in this podcast series, we talk a lot about genetics and genomics as a general-purpose technology that might inform prevention and early intervention efforts for many diseases. Perhaps it might have less applicability in Parkinson’s than others, but if someone decides to get whole exome or whole genome sequencing, and we had a previous discussion about that, they can find out whether they carry variants in about 6 or 7 genes that are known to substantially increase their risk of Parkinson’s disease. And currently, none of these genes are considered what we would call Tier 1 genes in genomic testing, in the sense that they don’t necessarily have a defined clinical action path that one can undertake if you have that genetic risk. So, in contrast, a cancer predisposition syndrome, if you find out about that, you know that you and your family members are at increased risk of certain cancers, and there’s an associated screening and monitoring program for that. For some cardiovascular and some cancer predisposition syndromes, we have such pathways. We don’t for these Parkinson’s genes, and so how do you… how would you counsel a patient? How would you discuss with a patient who’s gonna get… who’s a healthy person, who’s gonna get genome screening, whether they want to find out about their Parkinson’s risk.Ray Dorsey: Yeah, so let’s do a deep dive on genetics. So, the most common genetic risk factor for Parkinson’s disease are mutations in a gene called GBA. If you have two copies of… mutations in both copies of the gene, you get a rare disease called Gaucher’s disease. If you have, mutations in one, depending on the mutation, your lifetime risk of developing Parkinson’s disease is about 10%. Said another way, for the most common genetic risk factor, about 8% of people with Parkinson’s disease, at least in the U.S, you have a 90% chance of never developing the disease, but 10% is still something to be addressed.Research, again, by Dr. Caroline Tanner and her colleague Dr. Ethan Brown at UC San Francisco, showed that people who carry a GBA mutation who are exposed to pesticides might have a heightened risk of a disease. So if I knew someone had a GBA mutation, I would be, like, doubling down organic produce, organic dairy products, because when you eat a cow, you’re not just eating the cow, but you’re eating what the cow ate, and the cow ate fat-loving pesticides, they get magnified, they get concentrated as they make their way up the food chain. I’d be especially careful about well water. About 40 million Americans get their water from well. Many of these wells are contaminated by pesticides. People could be drinking in this pesticide-laden water for years and not know. So if you do carry it, I would be especially concerned about pesticide exposure, regardless of age.LRRK2 the most common genetic cause of Parkinson’s disease affects about 2-3% of people with the disease, and these studies have been done in large parts of the world. But those who carry a LRRK2 mutation, only about 40%, the lifetime risk of Parkinson’s is only about 40%. Said another way, most people with the most common genetic cause of Parkinson’s disease will not develop the disease. Now, the gene-environment interactions have not been worked out well, at least to my knowledge, on that. My colleague, Dr. Brian and Dean Miranda and others are looking at this.But it turns out that trichloroethylene, that dry cleaning chemical that I talked about earlier, it mimics the biological effects of LRRK2 mutations. A little bit of science for your listeners. Genes encode proteins, which are the workers of cells. Not surprisingly, the LRRK2 gene encodes a protein called LRRK2 kinase, and it increases the activity, that mutation increases the activity of LRRK2 kinase. Turns out that trichloroethylene actually does the same thing, it increases the activity of LRK2 kinase.So we know from the genetic research, which is important to have been done, and it’s very helpful for us understanding the pathophysiology, and it’s perhaps easier to study, that the environmental risk factors are often mimicking the pathophysiological changes that we see in the genetic forms of disease, and, you know, as you mentioned at the outset before we got on the air, you know, you study mitochondrial function, and almost all the environmental causes of Parkinson’s disease, almost all the genetic and environmental causes of Parkinson’s disease lead to dysfunction of the energy-producing parts of cells called the mitochondria.Robert Rogers: So, that’s a really great overview, and it sounds like what you’re saying is, perhaps it, like on all questions around diagnostic testing and genomic testing, it is an individualized decision. There are benefits to perhaps knowing that you carry this increased genetic risk in terms of your ability to modify your exposure, be extra diligent about modifying your exposure to certain environmental variables. But on the other hand, that has to be weighed against any increased anxiety that it might cause in a person when, ultimately, even the most penetrant of these genetic mutations, actually, you still have a less than 50% chance of developing disease.Ray Dorsey: There’s a great study called PD Generation, led by the Parkinson’s Foundation. Huge call out to Roy Alcalay, Dr. James Beck and others. Offers free genetic counseling and genetic testing for people with Parkinson’s disease, and they… they looked at the results of the first 8,000 people that they did genetic testing, and only 13% of them carried a genetic cause or genetic risk factor for the disease. And so we can answer these questions definitively because we’ve done research.And because organizations like the Parkinson’s Foundation has invested money and time and energy into addressing these important questions, we now need to just turn the page and invest even more money, time, and energy toward investigating the more important environmental causes of Parkinson’s disease and many other brain diseases.Robert Rogers: Great. Let’s switch gears for a second and talk about this exciting new era we’re in of new tools and procedures to detect very, very early, perhaps even totally preclinical Parkinson’s disease, because these technologies, I think, are going to allow us to have a more precise approach to early intervention. You mentioned this very interesting statistic that you said, on average, when somebody presents clinically with Parkinson’s disease, by that point, about 60% of the relevant neurons are already gone or significantly damaged, and so it seems very intuitively appealing that if you could pick off the process before it gets to that point, you could really make a difference. So, could you give us a little bit of an overview of, kind of, the current state of that exciting field, the current techniques that have been developed and are being developed to detect very early or preclinical Parkinson’s?Ray Dorsey: Yeah, so there’s been a lot of headway in this. There’s some great research done by my colleague, Dr. Andrew Siderowf, and his colleagues working on the Michael J. Fox Foundation’s PPMI study. Parkinson’s Progression Markers Initiative, and they found that there’s a marker in the spinal fluid of this misfolded protein called alpha-synuclein that can help identify people with Parkinson’s disease and give you an objective finding to help differentiate those who have Parkinson’s disease from those who don’t.There’s, increasingly available skin testing, so we know that Parkinson’s disease doesn’t actually begin in the brain, it actually begins outside the brain, at least for the vast majority of individuals, either in the gut or in the nose, and some of the pathology can spread to the skin.And there is a company that’s developed a skin test that finds misfolded proteins of people with misfolded protein of alpha-synuclein in individuals with Parkinson’s disease and some other Parkinsonian disorders. Now, how soon they can find that hasn’t been well established, but that’s out there.Are there imaging tests that can identify loss of dopamine-producing nerve cells in the brain? There currently are, to help differentiate whether people have Parkinson’s disease or a different other tremor disorder. Those tests might be helpful for identifying people before they have the diagnosis.There might be blood-based biomarkers that in the future could do so. You can imagine AI being really good at helping identify some of these early subtle features of the disease.But more fundamentally, this is fundamentally a preventable disease, and the way to address lung cancer, the way to address Parkinson’s disease, is to stop smoking and to stop getting exposed to these environmental toxicants.We can just create worlds without these diseases. Parkinson’s disease was extraordinarily rare for 99.9% of human history. Two centuries of Parkinson’s disease is enough. It’s time to say goodbye to Parkinson’s disease.Robert Rogers: Very, very compelling rallying cry, and I really like in your books and in your writing, you know, really identify Parkinson’s as this terrible enemy, and really that we have to have multiple, multiple layers of defense, and by far the most important is changing and modifying our environment and our risk of exposure to the things in the environment so that we prevent the initiation of the Parkinson’s pathology in the first place. But then, for the unlucky percentage of people in whom the beginnings of this pathology starts to take hold, there have to be interventions to identify that at an early enough stage, and then add interventions to retard the progression or one day halt it. And I just want to ask kind of one more question about, compare, really, how we can make more progress along this early intervention and early detection front. And maybe a helpful point of departure is a little bit of a comparison to where we are in that prevention and early detection and intervention landscape with Alzheimer’s disease, right?So Alzheimer’s is, I believe, epidemiologically the number one most common neurodegenerative disease, Parkinson’s number two. They share these similarities in that, you know, they’re both named after a very astute doctor who lived somewhere between 100 and 200 years ago, and noticed very distinct things in the first patients who they wrote about. And both, even before we’re in this current modern era of molecular biology and genetics had these pathological hallmarks that skilled people could see under the microscope. And you mentioned the Lewy bodies, these alpha-synuclein inclusions in Parkinson’s disease, and perhaps the equivalent, so to speak, it’s an imperfect analogy, in Alzheimer’s disease are these plaques composed of beta amyloid. And in the case of Alzheimer’s disease, and I don’t want to get too detailed in that discussion, because in short order, we’ll have a dedicated episode to Alzheimer’s, but basically, there were many false starts in developing therapies that sort of blocked or reduced the burden of these beta amyloid plaques, but then after many years of trying, there are now approved therapies that help to clear out some of those plaques, and they were first shown to have some clinical benefit in people with early stages of Alzheimer’s disease, so people that had symptoms but were not fully, fully gone. And then, as that was shown, you’re able to kick off clinical trials that pull those therapies earlier and earlier into the disease course. So now, people with the very earliest stages of mild cognitive impairment, and in fact, there’s even studies that are ongoing of people that are completely asymptomatic, but you can detect radiographically a burden of these amyloid plaques in their brains. They’re people who are at high risk.And I don’t think we’re at quite the same point in Parkinson’s, in that we don’t yet have an approved disease-modifying therapy that acts on that pathologic hallmark of disease that we can then bring forward into early intervention. So I would just love to hear, sort of, your own roadmap or overview of what’s going to have to happen and how we get to that similar place.Ray Dorsey: So… a lot to unfold, So, Parkinson’s described in 1817, Dr. James Parkinson, Dr. Aloise Alzheimer, a psychiatrist with a penchant for the microscope, describes Alzheimer’s disease in 1906. It’s kind of odd that the disease that affects 7 million Americans wasn’t described until just over 100 years ago. Did we miss a lot of Alzheimer’s disease, or is Alzheimer’s disease a new disease, and I… we probably missed some, but I think that it certainly wasn’t as common 200 years ago. George Washington, John Adams, Thomas Jefferson, Ben Franklin, none of these individuals, as far as we know, had Alzheimer’s disease, and even though almost all of them lived to over their 60s and some into their 90s.In 2003, a really smart German pathologist named Heiko Brock, who’s studied the pathology of both Alzheimer’s and Parkinson’s disease, put forth a new hypothesis for Parkinson’s disease. He says that the pathology… that Parkinson’s disease is not primarily a brain disease. Parkinson’s disease has its roots not first in the brain, but outside the brain. He said, when I look at the brains of people with Parkinson’s, I first find the pathology in the smell center of the brain.And in nerves that go to the gut, called the vagus nerve. And he thought that the pathology of Parkinson’s disease might begin in the gut, much like polio, and that it could be due to neuroinvasion of some kind of infectious particle. He thought a virus, which likely is not the case, at least for the vast majority of individuals. But that this pathology could spread like a fall of a row of dominoes up the vagus nerve, the pathology spreads to the vagus nerve, then up to the parts of the brain that control sleep. Then up to the parts of the brain that control movement, and up to the parts of the brain that cause thinking. As the dominoes fell, new symptoms would develop. Constipation, sleep disturbances, acting out your dreams, REM sleep behavior disorder, Parkinson’s disease, dementia.Well, it turns out that the pathology of Parkinson’s disease is not the only one that begins in the nose. He made less out of the nose, but in 2019, a really smart Danish scientist, Per Borghammer, said there’s two forms of Parkinson’s disease, one that begins in the gut, he calls that a body-first form. And then a more common form that he says begins in the nose, the smell center, the olfactory bulb that he called a brain-first form of the disease. And we know that for both Parkinson’s and for Alzheimer’s disease, one of the earliest features of the disease is loss of smell, and that one of the earliest places you find the pathology of both diseases is in the smell center. And we know that, air pollution plays an enormous role in Alzheimer’s disease, and a more modest role, but important role in Parkinson’s disease. So I think both these diseases, in many cases, begin in the smell center.And they’re both exploiting the front door to our brain, which is our nose, which doesn’t have the normal protective blood-brain barrier. And allows chemicals and pollutants, some really small one-third of the width of the width of our hair, to penetrate the nerve responsible for smell, called the olfactory nerve, hanging up in our upper nasal passages. And with it, it brings in dangerous hitchhikers, like toxic metals, lead from gas, iron from brakes, platinum from catalytic converters, and setting up the disease.What separates these two diseases right now is that we have great markers of Alzheimer’s progression. My friend, my colleague, my classmate, Dr. Dan Skovronsky, and others developed imaging of amyloid plaques. He did so when we were still in training. He created one of the first imaging companies for amyloid called Avid Radios Pharmaceuticals that was later bought by Eli Lilly. And now he’s the Chief Medical and Scientific Officer for Eli Lilly. And because we have these great imaging markers for amyloid or beta amyloid in Alzheimer’s disease, we can more readily determine whether new medications, including medications that target that misfolded protein can reduce the amount of amyloid in the brain, and whether those reductions in amyloid in the brain can be associated with clinical improvements.And we have a whole new class of medications that can lower the levels of amyloid in the brain, and appear to have a clinical benefit, and have been approved by the FDA, and have benefit to people with Alzheimer’s disease.We don’t have such, great imaging markers for, Parkinson’s disease. My colleague, Dr. Ken Marek, has developed a little bit… has developed an imaging modality, but it’s a little bit less sensitive than the amyloid,compound amyloid imaging, in part because the concentrations of the misfolded protein in Parkinson’s disease are much lower than that in Alzheimer’s disease. So if we want to get highly effective treatments, I think we need an objective marker of the disease.Imaging could be one way to do it. Markers in the spinal fluid, the skin, the blood might be others, but that will be the way to get us better treatments. But I still say an ounce of prevention is worth more than a pound of cure, and we can just create a world without these diseases, just like we can create a world without lung cancer, a large portion of lung cancer. We can create a world without Parkinson’s disease, a large portion. We can prevent the vast majority of ALS, we can prevent a lot of intellectual disabilities, we can prevent a lot of Alzheimer’s disease.Robert Rogers: An ounce of prevention is worth a pound of the cure. Words of wisdom from an inspiring scholar and innovator in the field of Parkinson’s disease. Dr. Ray Dorsey, thank you so much for joining us. I really learned a lot from our conversation.Ray Dorsey: Thank you very much, Robert. 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