Teasing Apart The Causes And Early Signs Of Parkinson’s

FLORA LICHTMAN: Hey there. This is Flora Lichtman. And you’re listening to Science Friday.

Each year, around 90,000 people in the US are diagnosed with Parkinson’s disease. It’s a neurodegenerative disease that can cause tremors and affect cognition. Scientists think that Parkinson’s happens when some neurons, cells in the brain, get clogged up with clumps of protein and stop working right.

Now, normally, proteins aren’t a problem. They’re good. We need them. But when certain proteins misbehave and fold into weird shapes, trouble can start. Misfolding proteins are found in lots of neurodegenerative diseases, like ALS and Huntington’s disease and Alzheimer’s. You’ve probably heard about plaques and tangles. Those are the protein clumps found in Alzheimer’s. In Parkinson’s, a protein called alpha-synuclein is thought to be the culprit, misfolding, clumping, and spreading through the brain. So what gets this protein ball rolling? And can it be stopped? That is what we’re talking about today.

Let me introduce my guests. Dr. Emily Tamadonfar is a neurologist specializing in movement disorders. She’s a clinical assistant professor of neurology at the Keck School of Medicine of USC. And Dr. Michael Okun is a professor and executive director of the Norman Fixel Institute for Neurological Diseases at University of Florida Health. He’s also the medical advisor for the Parkinson’s Foundation. And he’s written many books about Parkinson’s. His latest is called The Parkinson’s Plan– A New Path to Prevention and Treatment. Emily and Michael, welcome to Science Friday.

MICHAEL OKUN: Pleasure to be here.

EMILY TAMADONFAR: Thank you for having me.

FLORA LICHTMAN: Michael, did I get that description right about the misfolded proteins causing problems?

MICHAEL OKUN: Yeah. So these proteins exist normally. And so when we have something called alpha-synuclein, you need these things. And they’re important for regulation and for what we call homeostasis. And so when we think about Parkinson and Alzheimer’s disease and ALS and these diseases that are degenerative, when we think about them showing up in protein folding, it’s a clue. It’s a breadcrumb that’s telling us something is going on in this brain, in this body, that is evoking– it’s causing the body to have a response, to say, hey, you’re out of homeostasis.

But what we have to be careful of is we have to be careful of the enticing idea that it’s all that these protein clumps– that they’re the cause of everything. We have to be very careful of going down that road too far because it might be that this is just a signal, and a very important signal. But I think we have to be really careful to ask ourselves why does it start, Why does it spread, why does it progress, and to be humble and say, we really don’t have the answers to those questions yet.

FLORA LICHTMAN: Emily, I think people are familiar with some of the later stage symptoms– tremors, impaired movement, in some cases cognitive impairment. But you are studying some very early signs of Parkinson’s. And I know smell is one of them. What do we know about this?

EMILY TAMADONFAR: So there’s a very large observational study going on, and it’s been going on since 2010, called the Parkinson’s Progression Marker Initiative. And this study is including participants who have Parkinson’s disease and those who are at risk of Parkinson’s disease, what we call a– prodromal participants. And these are people who have diminished sense of smell, what we call hyposmia, which we think often predates motor symptoms, like stiffness, slowness, and tremor, as you mentioned. And as well, we have seen that patients who have something called REM sleep behavior disorder, which is a dream reenactment behavior– this can also precede some of the motor symptoms.

FLORA LICHTMAN: Dream reenactment behavior like acting out your dreams while you’re asleep?

EMILY TAMADONFAR: Yes, yes. This is something that is diagnosed based on a sleep study. But patients with Parkinson’s– many will describe yelling out in their sleep, thrashing around. It’s often noticed by their bed partners.

FLORA LICHTMAN: How early are these signs showing up?

EMILY TAMADONFAR: So this can happen many years, even decades, before motor symptoms can occur. And we know a large portion of people who have REM sleep behavior disorder– not everyone, but a large portion of them– do go on to develop Parkinson’s disease.

FLORA LICHTMAN: And smell, too– the smell loss, too– that early?

EMILY TAMADONFAR: Yes, smell loss as well. And so not everybody who has smell loss will have Parkinson’s disease. We see there may be many other reasons to have smell loss. But we do see in patients who have Parkinson’s disease– a large portion of them, before they develop motor symptoms, will have had a diminished sense of smell.

FLORA LICHTMAN: Michael, does the fact that it starts in the nose suggest that it is triggered by something we are breathing in?

MICHAEL OKUN: So there are a number of theories on this. And it’s not just the nose. So the nose would be one path to the potential start of Parkinson’s. The other is the gut. And people talk about this as brain-first– so coming through the nose– or gut-first, actually coming through the stomach and through your gut. And we find these abnormal protein clumps that you talked about in both places.

And one of the real amazing and mysterious things about Parkinson’s is when we look at the genetics of Parkinson’s, about 13 to 15 people out of every 100 have a single piece of DNA that is abnormal or mutated. And that causes their Parkinson’s. But the vast majority of people don’t have that single mutation.

And so we are now shifting a lot of our science, a lot of our effort, a lot of our research toward trying to understand what environmental factors and environmental influences might be impacting Parkinson’s– why it starts, why it spreads, why it progresses. And there are two areas that have really raised up and are in our radar of what could be going on. One is air pollution, and the other is pesticides and water. And so things that we take in from the environment seem to be related and have a high association for more cases of Parkinson’s and other degenerative disorders that you mentioned as well.

FLORA LICHTMAN: What specifically?

MICHAEL OKUN: We worry about pesticides– so things like paraquat as one example of a pesticide that is highly associated with Parkinson’s disease. When we think about water, we think about trichloroethylene. And also, we think about dry cleaners as being one of the big offenders. And this is also a chemical that’s used to degrease. It’s a chemical that’s used in the airline industry. It’s a chemical used by factories. But when folks throw it away, it actually gets into the water supply and can actually vaporize and get up into the brains of folks with Parkinson’s disease. And so trichloroethylene is a chemical.

And then in Alzheimer’s disease and in some cases of Parkinson’s– and it has a higher association with Alzheimer’s as air pollution. And so we are beginning to shift our thinking to being more preventative as we see study after study showing us these associations.

FLORA LICHTMAN: Does this suggest that we could be preventing Parkinson’s if we had different regulation around certain chemicals?

MICHAEL OKUN: So I believe this is true. As we begin to uncover these associations, we have to be careful because Parkinson’s probably isn’t one disease. Parkinson’s is a whole-body disease. There are probably a lot of different causes. And so the question comes up– is, do we have needless cases? And can we spare this generation and the next? And I think the answer comes with the courage to follow the science and to do the experiment and to remove these things, especially when there are alternatives or ways that we can live better.

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FLORA LICHTMAN: We have to take a quick break. But when we come back, we’re going to talk lots more about this, including about early warning signs. Don’t go away.

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OK, we’re back. I’m talking with Dr. Emily Tamadonfar and Dr. Michael Okun about Parkinson’s disease. Emily, tell me about this longitudinal study you mentioned, PPMI. What are you trying to learn?

EMILY TAMADONFAR: So the goal of PPMI– it’s really about early detection. Can we more accurately and more early detect Parkinson’s disease, and also to speed the development of new treatments? So it’s really twofold in that goal. As we think about developing treatments to slow disease progression, with that, we need to also think about, how do we diagnose earlier and more accurately?

FLORA LICHTMAN: Is there a blood test for Parkinson’s? Are there biomarkers you can measure?

EMILY TAMADONFAR: We don’t have a blood test for Parkinson’s. But we do have other biomarkers. And so that’s been one of the challenges– is can we identify and validate biomarkers? Through this Parkinson’s Progression Markers Initiative, we’ve been able to validate alpha-synuclein seeding amplification assay, which is a spinal fluid biomarker. But it’s hard to obtain spinal fluid. It’s not the most comfortable process for people. So we are still looking to identify other biomarkers that are more easily accessible, like in tear fluid, blood samples.

FLORA LICHTMAN: And how does the test work for participants?

EMILY TAMADONFAR: The participants in PPMI– they get a series of tests. So they actually have a lot of tests when they come into the office. They not only have clinical assessments done, they also undergo imaging studies, including dopamine transport imaging studies. And our goal is also, I think, ultimately to identify biomarkers and have some quantitative data with that so we can better track disease progression and response to treatment.

FLORA LICHTMAN: How do you test smell loss?

EMILY TAMADONFAR: So there’s actually a validated smell test where you can– participants can receive that in the mail.

FLORA LICHTMAN: Like a card that– like markers with a smell? What should I be envisioning?

EMILY TAMADONFAR: Exactly, exactly. So it’s sort of like– if you can envision those scratch-and-sniffs. So with those smell tests, they’ll have different smells. And they’ll receive a score based on how well they did with each of the smells.

FLORA LICHTMAN: Emily, if I find that I do have smell loss, does that mean I’m at higher risk, that I have Parkinson’s?

EMILY TAMADONFAR: It doesn’t mean you already have it. But you may have a feature. And this is part of what we’re trying to understand. So not everybody with smell loss will go on to develop Parkinson’s. But you may qualify to participate in the study in some form. But I wouldn’t say, if you have diminished sense of smell, that you should necessarily be very concerned, you go on to have Parkinson’s disease. It’s something we’re trying to understand better.

FLORA LICHTMAN: Michael, do we understand how the protein misfolding spreads? If it’s starting in the nose or the gut, why does it keep going?

MICHAEL OKUN: So we actually don’t know the answer to that question. And one of the other very interesting, but also perplexing things for scientists is that everybody with Parkinson’s disease doesn’t have these abnormal synuclein-alpha misfolding within their brains. And we see differences in different types of genes, genetic forms of Parkinson’s. And not everybody– it’s not a one-size-fits-all.

And so we have begun to rethink this disease. And in fact, the idea that Parkinson’s is just a disease of dopamine– we have now rethought that. We don’t think Parkinson’s disease is a disease just of the brain. We see it in the nerves outside the brain. We see it in the gut. We see it in the salivary glands. We see it in the skin. And so it’s a whole-body disease.

FLORA LICHTMAN: Do we have any treatment that can slow the progression of the disease now, Emily?

EMILY TAMADONFAR: No. We don’t have any treatment, as it stands now, that we know will slow progression of the disease. There are other interventions that we emphasize, including things like regular physical activity, diet, these sorts of things that we know can have a really positive benefit overall. But as it stands now, we don’t have a treatment that we know slows disease progression.

FLORA LICHTMAN: This must be so frustrating for both of you who have devoted your lives to this. Of course, it’s devastating to patients. But it must also hit you hard.

EMILY TAMADONFAR: I’m very optimistic. I do think– we were just talking about PPMI and the importance of these biomarkers. And it’s really important, I think, in the context of building– staging one thing. Patients always come in and ask me, is– what stage am I in? And that paradigm is shifting to this biological staging.

And why that’s really important is, as Dr. Okun was saying, putting into context all these different biomarkers. And some people may have certain positivity in some of the biomarkers and not in others. And putting that together to design clinical trials to develop more precise treatment plans for patients– this is really critical now.

FLORA LICHTMAN: Michael, what about you? Are you optimistic?

MICHAEL OKUN: I am optimistic. So as Emily said, we don’t have the data yet as to what might slow disease progression. But we do know that certain things are really important. And study after study is showing that exercise, as Emily mentioned, is like a drug. It’s now in major guidelines, prescribed by every expert. So anybody who’s listening should know that having an exercise regime– whether or not you can stand up or not, there are ways to exercise. Exercise is a very powerful drug. And there’s data to suggest that it may have some effect in slowing the disease– although still debatable among scientists. Sleep is super important.

And so I think we’re entering an era of medicine where we can be more preventative. We can think about what we can do to prevent diseases, to try to stop them from developing. But even if you have a disease, the first thing you should do is remove some of these things from the environment and improve your situation.

So if you have Parkinson disease, get a carbon water filter. Make sure that your– you have air purifiers around, particularly if you’re in an urban area or an area without good air quality. And wash your fruit and get those pesticides off of them. There’s no reason we shouldn’t be doing those simple things.

FLORA LICHTMAN: Well, I would love to see society at large work on some of these problems because we are in a time where health optimization is the name of the game– that it’s now everyone’s individual responsibility to keep themselves healthy. And just to push back slightly on that, I would love to see this as– personally as a society-wide effort.

MICHAEL OKUN: 100%. And so we all want this to go faster. And I think the way to make it go faster is for each one of us– and every time that I go on the road for the Parkinson’s Foundation or talk about the book or talk about Parkinson, I always tell, the most important thing you can do is listen to people and ask people with Parkinson to tell their stories. The more we tell the stories of each other– we are a community, we are a village– the better chance we’re going to have to decrease the amount of time that we can get to prevention and we can get to reducing the numbers and the burden of this disease. So tell your story would be a key message.

FLORA LICHTMAN: Emily and Michael, thank you so much for joining me today.

MICHAEL OKUN: Honored to be here.

EMILY TAMADONFAR: Thank you so much. It was a pleasure.

FLORA LICHTMAN: Dr. Emily Tamadonfar is a neurologist specializing in movement disorders. She’s a clinical assistant professor of neurology at the Keck School of Medicine of USC. And Dr. Michael Okun is a professor and executive director of the Norman Fixel Institute for Neurological Diseases at University of Florida Health. He’s also the medical advisor for the Parkinson’s Foundation.

This episode was produced by Annette Heist. And if you like the podcast, please rate and review the show wherever you listen. I want to thank listener Reformed Luddite, who wrote, “This is the first thing I listen to each morning. I especially enjoy getting to hear from the scientists themselves.” Me, too. Thank you for listening. See you next time. I’m Flora Lichtman.

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