Parkinson's Disease Research in Women

Podcast Transcript

Introduction: Neuro Pathways, a Cleveland Clinic podcast exploring the latest research discoveries and clinical advances in the fields of neurology, neurosurgery, neuro rehab, and psychiatry.

Glen Stevens, DO, PhD:

Although Parkinson's disease is almost two times more common in men than women, women face faster disease progression and a higher mortality rate. They also have different risk factors, symptoms, and responses to treatment. However, because women have been historically underrepresented in Parkinson's disease research, the underlying causes of these observed sex differences and how to address them clinically is not well understood.

In today's episode of Neural Pathways, we're discussing ongoing research that seeks to elucidate the role of women specific health factors in the severity and progression of Parkinson's disease. I'm your host, Glen Stevens, neurologist/neuro-oncologist in the Cleveland Clinic's Neurological Institute, and I'm excited to have Dr. Ignacio Mata join me for today's conversation. Dr. Mata is assistant staff in the Genomic Medicine Institute within Cleveland Clinic's Lerner Research Institute. Nacho, welcome back to Neuro Pathways.

Ignacio Mata, PhD:

Thank you, Glen.

Glen Stevens, DO, PhD:

Last time we spoke on the podcast, we talked about the Latin American Research Consortium on the genetics of Parkinson's disease or what's called the LARGE-PD, which is an effort you are leading to increase representation of Latino populations and research on the genetics of Parkinson's disease. Today, we're shifting our focus to another underserved population that is women with Parkinson's disease. To start off, why don't you just give us a brief recap on the LARGE-PD effort that you're doing?

Ignacio Mata, PhD:

Sure, yeah. Again, we realized that most of the genetic studies that are being done, probably more than 80% of them only include individuals of European ancestry. There's a big underrepresentation of other populations that are non-European, including Latinos, but also Blacks, people from Asia, especially South Asian, or Indians, for example. I think our initiative, what it's trying to do is trying to recruit individuals from those backgrounds to really try to understand what is in common and what is different between them in terms of their genetic risks. But also we study environmental, social, economical, cultural factors that are also important in Parkinson's disease as it's a multifactorial, very complex disease.

Glen Stevens, DO, PhD:

In general, the percentage of Parkinson's thought to be caused by specific genetic mutations would be what?

Ignacio Mata, PhD:

I would say maybe three or 4% will be familial, but then there's also a genetic predisposition that I think together with environmental or maybe comorbidities can trigger the disease as well. I think genetics play a role probably in about 30% of Parkinson's patients.

Glen Stevens, DO, PhD:

We'll switch gears and we'll move specifically to women at this point, but what do we know and what don't we know about Parkinson's disease in women?

Ignacio Mata, PhD:

I think mostly is what we don't know. As you mentioned, women are underrepresented. I don't particularly agree with saying that they don't participate in research, although it is true that the numbers are a little bit lower. But I think one of the things that we identify is that women's health factors are the ones that are not really included when we collect data from individuals for any type of studies in Parkinson's disease. What I mean by this is that most of the questionnaires that we use ask for things that affect both genders.

You ask about smoking, alcohol consumption, where do you live, all these different questionnaires, but none of them really ask questions about, for example, pregnancies or birth controllers, things that really affect mostly women or hysterectomies, surgeries that are only sex specific. I think it's a missed opportunity to really understand how those factors might actually play a role, not only in Parkinson's, but in any other disease in terms of risk, but also progression of the disease.

In terms of Parkinson's disease, we know that women have a low risk. For a very long time we thought that estrogen was perhaps protective and that's the reason why women have a lower risk. But it's interesting because this is not true on all populations, and there's studies coming from especially China where the ratio is one to one. What it's telling us is that perhaps biology is not all and maybe there's other factors that play a role. I think that's how this project came along to try to really understand.

We realized that there was no questionnaires that were asked these questions. I had a PhD student of mine, who just graduated in December, Ship Parel, who decide to take that upon herself to design a questionnaire that people could use. Just put it freely online that people could use to collect that data. Again, it's mostly based on Parkinson's disease, but really could be adapted to any disease just to see how these factors might play a role.

Glen Stevens, DO, PhD:

Going to ping pong just a little bit, let me go back to your Latino study. Do you have data on males versus females in the Latino study and what did it show?

Ignacio Mata, PhD:

Yeah. It looks like the risk in Latinos is very similar between women and men. In fact, we have more women participate in our studies. That doesn't mean, again, you have to do epidemiological studies to really look at those numbers, but it looks like it might be close to one-one, similarly to what we see in Asia.

Glen Stevens, DO, PhD:

Gene differences between males and females in your Latino study?

Ignacio Mata, PhD:

Yeah. We had a look and we didn't see any differences. Our numbers are probably not large enough because once you start breaking things up by ancestry and then by gender or sex, your groups get small, and that means that sometimes you might not be able to detect some of these things. Studies that have been done in Europeans doesn't seem to show that there is any differences in terms of genetic architecture between the two of them, although there are certain mutations that we see more often in females than males, for example.

Glen Stevens, DO, PhD:

The questionnaire that you mentioned that you're doing, how many questions, how long does it take people to fill them?

Ignacio Mata, PhD:

It takes about 20 minutes to fill out, and it's self-given. People can just take it. In fact, here at the Cleveland Clinic, we send it through MyChart and people can just fill it up in their houses.

Glen Stevens, DO, PhD:

You're sending it just to those with Parkinson's disease or?

Ignacio Mata, PhD:

Yeah. Originally we only did this through a couple of different avenues, but we are trying to collect also data on healthy individuals. I think this is very important if we want to look at risk. Our study, the one that actually has got accepted last week for publication, looked at a progression and differences in progression between women in particular, looking at these women specific health factors. But I think if we want to look at risk, I think we need to have healthy control data as well.

Glen Stevens, DO, PhD:

In the questionnaire, you mentioned some of the questions that you will ask that are different in women than men. Any other specifics within the questionnaire that are worth sharing with us?

Ignacio Mata, PhD:

The way we did it, and obviously one of the things that we wanted to be careful was with recall bias. It's very hard to ask somebody in their 60s or 70s how good their menstrual cycle was or what kind of birth control they had and how some of the pregnancies might be. What we did is that we put everything in REDCap through a three decision mechanism. If the person is premenopausal, for example, or menopausal, the set of questions that they get is different.

It's more relevant to the stage that they are. We don't bias our data again by recall bias. Some of the questions might be different, and I think some of the concerns might be different as well in women, for example, that are childbearing or they're thinking about having kids, but they've been diagnosed with the disease. The questions are adjusted to those stages.

Glen Stevens, DO, PhD:

Any specific different genes in women versus men?

Ignacio Mata, PhD:

None that we have identified. However, one of the genes, actually the LRRK2 genes, we don't really understand why, but it looks like having a mutation in this gene plays a role in the progression in women more than in men. It doesn't mean that it causes the disease less or more, but it looks like it affects the progression and we don't really understand why. Perhaps there's an interaction between some of these women health factors and this gene in particular that makes the progression be faster and worse in women with this gene.

Glen Stevens, DO, PhD:

To go back, other thoughts as to why severity could be worse in females than males?

Ignacio Mata, PhD:

Severity, actually I think women present the disease in a milder way, at least in the motor sense of the disease. Parkinson's disease is known mostly for their tremor, most of the motor symptoms. It's in fact called a movement disorder. However, in the last probably 10 years or so, we have identified that there's a lot of non-motor symptoms that also affect the disease. That's what the difference is. If we look at the motor symptoms, it looks like that women have a more benign form of the disease.

However, they present a lot more non-motor symptoms. I'm talking about depression. I'm talking about anxiety. They also have less hallucinations, for example, or they have less dyskinesia. I wouldn't say that the women have a worse disease, but it's definitely different, which I think it really affects the rate at which women get diagnosed with Parkinson's disease. To me, this is one of the biggest things that we're realizing is that there are definitely differences on the rate of diagnosis.

I don't know if this is the cause of why we think women have less Parkinson's or not. One of the reasons is because it really starts with non-motor symptoms for a long time. A lot of clinicians might not think that that's disease and that causes a delay in diagnosis in women. But again, it's more complicated than just that because I think there's other factors, mostly cultural and socioeconomical factors, that makes women perhaps have a delayed diagnosis.

Glen Stevens, DO, PhD:

Well, it's interesting you say that because as a neurologist, I'm an observer. I think my children would say that when we're out traveling or we're somewhere, I'm always observing people behavior, always looking at people. I'll say to my kids. I'll tap one of them. I mean, they're growing now, of course, but I would say to them when they're younger, I would look at somebody, I'd say, "What's the disorder?"

Because if you could really just look at one characteristic or one exam finding in a patient, probably watching them walk is the single best thing to do because you can define so many disorders that way. Of course, we don't know for sure what the right answer is, but in my mind, my kids got very good at diagnosing various disorders. But I think it's really true now, and I hadn't really thought about it before, now that you mention it, but I think in my life I've seen so many more or acknowledged an understanding of many, many more men than women.

I'm trying to think of it's uncommon that I actually see women that I look at that I think they have a classic gate that I'd say is Parkinsonian. But with men, much so. It really makes sense. I'd never really thought about it before. Because if the incidence is very similar, then you should be seeing just as many of each, but I'm just not recognizing the subtly that their phenotype and genotype variants.

Ignacio Mata, PhD:

I think that's one of the biggest things. Again, that speaks to the heterogeneity of the disease and how we need to deal with these differences and really pay attention to some of the perhaps more specific women's health factors and really understand what the disease might be in them which might be different to males.

Glen Stevens, DO, PhD:

Well, I'll have to bring my kids back for a refresher course or my grandkids. I'll be able to impart this new knowledge to my grandkids as they go through so they'll be much better diagnosticians, although it's a little harder to tell mood from a distance.

Ignacio Mata, PhD:

Yes, that is very true.

Glen Stevens, DO, PhD:

A little harder. Any specific results from what you've looked at so far in your studies that you can share with us?

Ignacio Mata, PhD:

Yeah. We've done both. Yes, looking at every single factor individually and also modeling how some of these factors might interact. Again, we only look at progression because we didn't have data for healthy individuals yet. But it looks like women specific factors like postnatal depression play a role. Also, something that we were very intrigued about, it looks like vaginal birth had a difference between C-section. I'm not entirely sure if it's because of the hormone changes that happen through vaginal that doesn't happen through C-section.

Glen Stevens, DO, PhD:

In which way, higher or lower?

Ignacio Mata, PhD:

Worse progression. Same thing with diabetes, pregnancy, there were some factors, vitamin B12, although that's not really gender-specific, but we saw a difference. All these classify somebody to have a worse prognosis than individuals that do not go through this. There are some interesting results. Unfortunately, we only had about 300 women that responded to this questionnaire. We run it through PD GENEration, which is a Parkinson's foundation initiative, where these individuals not only have clinical data, but they were also genetic tested for seven genes.

We had all that information available, and then they mail the questionnaire to all the participants. Out of I think 900 women that had participated at the time, we got a response for about 400 of them. Our cohort is still a little bit small. I think there has to be more done. I think now that the questionnaire is out in the wild, I'm hoping that a lot more people are using it. In fact, I know that folks inside, which is a Michael J. Fox initiative, also through online questionnaires is going to release or I think already released a similar questionnaire, so we're going to have more data.

And then people in the Spain that I collaborate with have also translated our questionnaire and they're running it over there as well. We'll have also different populations. Because at the end of the day, there are differences in culture and birth control and some of the things that might be important for this. I think studying very diverse cohorts might be really good. We are also running this in LARGE-PD, so we'll have also information for Latinos or Latinas.

Glen Stevens, DO, PhD:

Are you changing your questionnaire as the results come through? Is it a constant evolution?

Ignacio Mata, PhD:

That's a very good question. We haven't changed any questions, just for language purposes. I think that's the only changes that we've done. In LARGE-PD, for example, we deal with a cohort that has a much lower year of education. A lot of the questions seem very complex and very hard to understand for somebody that maybe has only four or five years of education. We had to change some of the language. But in terms of questions, because our results are still preliminary, we didn't want to change anything based on that.

I think once we have better data, hopefully we'll have a more finalized version of the questionnaire that will include some of the most important factors. One of the things that we want to do here at the clinic is actually incorporate this into the Brain Study. The Brain Study is a great study that is happening here where they're going to recruit around 200,000 individuals that are going to be followed up, because that's the other thing that you also want to do. If you want to look at progression, you want to follow people up even before they have any symptoms.

It will be great if this questionnaire gets incorporated in there. We get that data. In 10 years from now, we can see all those women develop Parkinson's and see what they have in common versus those that didn't develop Parkinson's.

Glen Stevens, DO, PhD:

Yes. We had Dr. Najma and Dr. Machado in speaking about the Brain Studies.

Ignacio Mata, PhD:

Excellent.

Glen Stevens, DO, PhD:

Very exciting information will come out of that down the line. How do you see data from the questionnaire being applied to future research?

Ignacio Mata, PhD:

Well, the first thing, we are generating awareness about these topics. Really this whole idea came from conversations with women, patients with Parkinson's that told us, and this is why it's so important to listen to patients because they live with the disease. These were early onset. These are very active, young, early onset Parkinson's group that has a lot of women. They were saying that a lot of them actually developed a disease after the first or second pregnancy. They were also saying that through the month, through the menstrual cycle, both the symptoms but also the drugs didn't work as well.

Some of the symptoms changed, which made us realize that we need to pay attention to this. I think this is a conversation that needs to happen between the clinicians, the neurologists, and the patients. I think because a lot of the neurologists are actually male, I think some of these conversations might not occur naturally. One of the things that we are raising awareness is that patients need to bring this up to their patients. In a lot of cases, they were saying that they were changing their medication based on the menstrual cycle without any advice from their doctors.

Just based on their own experience saying, "Oh, well, the drugs don't work as well after my menstrual cycle, so I'm going to take a little bit more just so it makes the same effect." I think those are some of the biggest things that I think we can create with the results that we have right now. Once we identify some of these factors, I think this will help us with the models that we're trying to do to predict who is going to develop the disease. We mentioned about genetics, but genetics is not all. We're going to need environmental factors. I think in the case of women, we need to incorporate those women as specific health factors into our models to really be able to predict who might be at high risk to develop the disease.

Because one of the things that is very hard in Parkinson's disease is that once somebody starts developing the symptoms, 80% of the dopamine neurons that produce dopamine are dead. The disease, we think that has started maybe 10, 20 years before that. If we can identify individuals that are high risk, we could potentially do neuroprotective therapies. If we can get to that point, we could use these models to really identify the subgroup in the population that need to be treated with this neuroprotective. Since we don't know much about women, I think we're going to be in a much worse position to be able to predict in women who might develop the disease.

I think this could be huge to equal the balance and make sure that we can do a good enough job in both sexes. I think this also speaks to the efforts of the NIH to make sure that, for example, in animal models, both the females and the males are used. Because for many, many years, only the males were used because the females go through the cycle. It's a lot harder to understand because it's more heterogeneous. In this, I'll use this to link to my underrepresented. With Latinos, originally they were not included in the studies because they're so complex that people said, "Oh, well, it's better just to exclude them than trying to deal with this complexity."

I think in women it's the same thing. I think we need to deal with it. If we want to have equal opportunities and equal treatment for Parkinson's, we definitely need to include all these factors that are affecting only women.

Glen Stevens, DO, PhD:

Well, you really answered the last question that I was going to ask you and that I was going to ask, are there animal models that are different between male and female?

Ignacio Mata, PhD:

There are no good animal models for Parkinson's disease. A lot of them are acute. That means that you get the disease after an injection with MPTP, for example. We know, again, that disease takes years and years. To start with, we don't have good models for Parkinson's disease, but I don't think there have been that many studies comparing actually females to males.

I think this might be something that could be guided by some of the results from our studies to determine and maybe play around with some of those factors and see how they can affect both the risk, but also the progression of the disease in the different sexes.

Glen Stevens, DO, PhD:

Any final takeaways for our listeners?

Ignacio Mata, PhD:

I think just, again, to say how important it is to be inclusive in research in this case, not only including women in research, but really understanding and making an effort to understand the differences that might be. It is going to affect not only clinical care, but for example, participation in clinical trials. There's a very underrepresentation of women participating in clinical trials mostly because a lot of the times there are requirements, like they have to be in birth control or they have to be postmenopausal.

The changes in hormone levels and those kind of things do not affect the results. But I think instead of that, we just need to understand that, incorporate them, and then try to see how that responds.

Because at the end of the day, you cannot base the response of a drug based on white males for Black women, for example. We don't really know how that is going to interact, and I think we really need to put a lot of effort into try to understand these differences. I think that's the only way forward to be able to understand this for everybody.

Glen Stevens, DO, PhD:

Well, Nacho, it's been great having you back. We appreciate all the fine work that you're doing and look forward to chatting with you in the future again. Thank you very much.

Ignacio Mata, PhD:

Thank you, Glen.

Conclusion: This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcast on iTunes, Google Play, Spotify, or wherever you get your podcasts. And don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultqd.clevelandclinic.org/neuro, or follow us on Twitter @CleClinicMD, all one word. And thank you for listening.