Melani Dizon, Director of Education and Content, Davis Phinney Foundation: Dr. Savica, how are you doing?
Rodolfo Savica, M.D., Ph.D., Consultant and Professor of Neurology, Mayo Clinic, Rochester, MN.: Doing fine, good to see you.
Melani Dizon: Great, it's really good to see you too. I'm excited to talk about living well with young-onset Parkinson's disease. So, let's just jump right into it. First of all, can you just tell everybody a little bit about who you are and how you got involved in this work?
Dr. Savica: Sure. My name is Rodolfo Savica. I'm one of the consultants, and a Mayo Clinic Professor of Neurology, and I dedicated the last twenty years, it's been over twenty years now, of my life to working with Parkinson's disease. Especially, in the last decade or so, I devoted myself specifically to people that have Parkinson's disease, but they're younger.
I am spending time running a full clinic of people with, people that have early-onset Parkinson's disease. It's one of the few clinics that we have in North America devoted to Parkinson's disease affecting a younger population. As well as I am in my research lab and we are working on a number of initiatives and projects to try to understand, to try to advance the knowledge on Parkinson's disease, especially affecting a younger population. And ultimately to cure, or at least to delay as much as possible the disease, and to ultimately help our patient population, making sure that everybody's having a full life.
To be honest, I hope that one day I can, will, be able to retire and my help wouldn't be needed. This means that we accomplish at least the goal of helping people with this condition.
Melani Dizon: Right. That is a great goal. Let's keep that one going. So, there's been a lot of talk. There was a paper that came out called "Age Cutoff for Early-onset Parkinson's Disease Recommendations from the International Parkinson's and Movement Disorder Site Task Force on Early-onset Parkinson's Disease".
It came out and it is talking about people diagnosed before the age of fifty. And there was a blurb in the paper that I just want to read in case, people haven't seen it yet. And, I'll share it in the notes, but it said, "Authors who have first developed an interest in, and published on this subgroup of PD, have preferred the use of YOPD. However, there has been a shift toward the use of EOPD in the past two decades."
There are no clear publications detailing the rationale behind this shift but it seems motivated by an attempt to avoid age-related stigmatization. Thus, the recommendation of the early-onset Parkinson's disease task force of the MDS is to use the term EOPD to designate PD with an onset of motor symptoms before the specific age that was agreed on.
Now, the biggest concern I hear about the conclusion that this paper came to is that nobody living with Parkinson's was part of the task force. So, first of all, is that true? And then second of all, if it is true, how did the decision not to involve that community get made? And how was it determined that using the term young was actually a negative age-related term?
Dr. Savica: So, first of all, I'm guilty of the paper. I am the chair of the task force. Okay. And I want to clarify one point for people. So, this task force is part of the Movement Disorder Society. This particular task force in this society is a scientific society. So, it's based upon a group of people, researchers, and people from all over the world, the globe.
It's a global organization that has only scientific purpose, doesn't have any purpose of legislation, doesn't have a purpose in the, goal of the society, to have patient-centered care. This is scientifically based upon the idea of advancing science, not necessarily changing any legislation all over the world. It's true the experts in the field that participate in the task force are all physicians and Ph.D.s of the entire globe. They were a representation of people from Africa, from Iran, from China, from Asia in general, not just China, from Australia, from Europe, from North and South America.
And this task force has been working heavily in the last two and a half years, ever since the inception to try to harmonize. So, the goal of this space, this manuscript, is to harmonize and try to help. Having, number one, a clear cutoff for the age because at least we know what we are talking about. And current cutoff is about fifty and below. When [inaudible] have some kind of grace time, we can think about it.
Why we say that? Because according to different countries, in some countries, early-onset Parkinson's, young Parkinson's is considered below the age of sixty-five because of the need of the national system. In some other countries, it's forty and below. But why is this important? Because when we are pulling together data, we're not pulling, we're pulling data when we are trying to understand what we are talking about. If there are five different age cutoffs, it's impossible to know what we are talking and what are the actual numbers.
Because it's true, early-onset Parkinson's disease, young onset Parkinson's disease, is on the rise. But if, as you can imagine, if we change cutoff for the age of onset, we can have different chunks of result. So, the goal of this manuscript was to address the age, not to match the name to start with.
The second thing I want to write about, the name. The idea of using early-onset is because it's working very well. Also, against the opposite. So, early versus late onset works very well. Young, what's the opposite of young? Old. You know what I mean? And this is English. This is a global organization. So, in some languages, and I tell you for example, I speak a few of them, but I'm Italian. Even in Spanish, it doesn't work. Young wouldn't work. If you translate young in Italian it's not going to work. It simply doesn't sound right and can increase the confusion.
The way I see it is that we can use scientifically the word early-onset. So, at least we know what we're talking about, we know we are talking about this particular beast. But I think we can keep both. I have no problems in keeping young versus early. I don't have any emotional attachment toward one or the other. I think they're both equally relevant and they both have good reason why one versus the other.
One thing that we are taking advantage now after this manuscript is that we would like to make sure that the patients now are involved in a conversation. The task force is of the MDS, is moving into a study group, which is a different kind of nature that can be more inclusive. It can allow people to participate. We have an organization that reached out to me from the UK that is working in trying to give a response, a scientific response of why young is more important. And I think many patients can do the same. I think we have to keep both terms, but we should all agree that we know what we're talking about.
Whether it's early or whether it's young, as long as we talk about it. That's, to me, very important. And again, I have no emotional comfort. I, as you can see, I go back and forth between early, young.
Melani Dizon: Yeah.
Dr. Savica: It doesn't change too much for me as long as we know what we are talking about here.
Melani Dizon: So, it sounds, what I'm hearing is, it sounds like for sort of research and clinical reasons, having the term that is global. People do research from multiple countries together, right? And so, if you're talking about it, saying it one way and someone else is saying it another way, right? It's like that's a challenge. And so, clinically, research using early-onset, having that nomenclature that's common, is important and great.
Dr. Savica: Very important. Also, because I want to tell you up to now, 2021, 2022, there were no such initiatives everywhere in the world. So, the move, as our society took the problem, faced the problem, say, okay, we have an issue, we had to fix it. In the past we had this, even this conversation. And as you can know, in the literature, people were talking about young, juvenile for a while, or early, and it was a lot of confusion.
And it was this condition, Parkinson's disease affecting the young, which was considered a rare disease affecting a small amount of the population that has some familiar genetic problem. And it's not true. So, we have to do a lot of steps. And to be honest, we, and I, and that's why I'm here. But you know that, you know myself, you know, the way we, I think, but everybody knows the way I think. We need to partner up together. In the right steps at the right time to lobby about the problem, to think about the problems, and to raise awareness. But first of all, we have to understand what we are talking about globally.
Melani Dizon: Yeah, yeah.
Dr. Savica: Globally, because we are using English, clearly, as the main language. And, we should because it's the scientific language, but it's not working, again, seem to be silly, but it's not working everywhere the same.
Melani Dizon: Yeah, yeah.
Dr. Savica: And that's a problem. It's a problem because we had to raise awareness in entire continents where there's not too much access to information. North America, UK, all the, even Australia. So, all the English-speaking countries and continents are taking the lead in this initiative. And these debates are fantastic about young, early or whatever. But we had to think about beyond that.
Melani Dizon: Yeah.
Dr. Savica: Because if you think globally is more meaningful to me, understanding, giving an idea and not a fixed strict cutoff, but of age. But an idea about what we are talking about knowing that we're doing something different than Parkinson's disease affecting later ages. That will be already the biggest message. Then we can call it young, early, whatever and it doesn't matter to me, again because I don't have an emotional component attached to that.
And based, we based this decision, on calling it early just because of the available literature. What was there was not based upon a decision made, I don't know where, by some bigwigs in their, in their offices? No. No, it was about what was already published in the literature.
Melani Dizon: Right, right. Well, I mean, that makes sense. And I'm really appreciative of, talking through that because I know, a lot of people in our community feel very strongly about keeping that term. And I think part of it is, from my experience in the US and the UK, that is, and a little bit in Australia, but it's just like sort of a cultural, they feel like they can belong to a YOPD community versus an early-onset community. So, I think that's, that's part of it. Right? And, it's-
Dr. Savica: Absolutely.
Melani Dizon: -it's different for people who are, I think that there might be a case, right, for keeping both the terms in play, one for clinicians, researchers, and one for those living with it, if they so choose to use that? If, that,-
Dr. Savica: As long as we know what we're talking about.
Melani Dizon: -Right, right. So, part of that is, we're going to define that. So, in some ways like you said, you've said before that YOPD and late-onset or early-onset and late onset, are two really different diseases. And based on, where you landed with the age, how were you able to get everyone to agree? And what were some of the different things that people are bringing to the table? When somebody said well, we call it sixty-five years old because that's the retirement age, well, we brought them down to fifty. How did those conversations go and where, how do they make sense? Right, because I think in my head I'm like, hmm so, if it's truly a different disease, is it truly a different disease if I'm fifty-four and I'm fifty, how does this work?
Dr. Savica: So, let me tell you. Number one, that was not an easy process. I am talking about years, years seriously, or multiple meetings where I remember the first meeting, I said "oh, oh my God, what I, what I've been through now?" I don't know what to do because my role is to mediate the different, being the chair of the task force is to mediate different solves of the problem and try to come with an organic plan. And it was tough.
It was tough because, you know, people are coming from different backgrounds, different countries, a different way of calling, coding, identifying and reimbursing the diseases according to a different system. But I would say all my colleagues were quite reasonable about it. We tried to identify, and that's what we did, the biological underlying reason why fifty would make sense.
There's [inaudible] reason, there's a number of papers/pubs previously published on this particular different cutoff of age noticing on how things switch around fifty to fifty-five. And I agree with you, this is an artifact, but using fifty, this is an artifact because if I am having Parkinson's disease and I have been diagnosed and my symptoms started at fifty-one, would I be not considered early-onset? No. I think biologically people need to be still considered early-onset despite they're one year above this cutoff.
We had to try not to be dogmatic, especially in this particular cutoff and saying before or after, because it's not working this way, this is not what medicine, modern medicine is about. For sure we know that somebody's young, and to me, somebody's young as long as, even the concept of young, we talked this in the task force, is really different according to different culture.
I remember this was raised by a colleague from Japan, he said, a young in my country is something different than yours. And I say, you are right. That's why early would be working scientifically a bit more better in your case, but it doesn't really matter. To me, and to us, what is early-onset Parkinson's? Why is it different? What are the differences of early-onset Parkinson's compare, compared to people that are older in age? Whether it's fifty, whether it's fifty-five, whether it's forty-seven. Are there differences? Yes.
And this goes to the concept that is currently developed by a number of colleagues, that there are no two Parkinson's disease that lookalike. Clearly, we can try to lump together things, especially as we get a little bit older. Assuming that the disease is caused by an accumulation of a number of problems; the famous Lewy bodies, the famous alpha-synuclein. And it's true as we get older, this is more likely the cause of the problem. The common outcome is that accumulation of alpha-synuclein, and the reason why it's accumulating comes from different sources.
But when we are younger, this is not necessarily a common outcome. The common outcome is a damage, a dysfunction. Whether it's temporary, whether it's permanent, of the dopamine activity in the brain. The vast majority is contained in the basal ganglia. But there are other areas of the brain that contain dopamine, so it's not necessarily just in basal ganglia.
So, the common theme of Parkinson's disease is that dopamine activity doesn't work very much. In earlier, not even early, earlier-onset Parkinson's disease. The more we get close to our teenager years, it's likely that we are dealing with a different disease that is not due to the accumulation of alpha-synuclein, it's not due to accumulation of aging proteins that are present as we get older. Because, clearly, my brain when I'm in my thirties is not the same brain when I'm in my sixties or seventies or eighties.
Aging is taken and removed out of the equation, which is a major driving force for degeneration. So, in earlier-onset Parkinson's disease: fifty, fifty-one, fifty-two, fifty-five, even fifty-seven, depends on what we see. What we need to be looking at is what are the, what is, or what are the underlying reasons? What process of dopamine energy dysfunction is happening? And, it can be metabolic, can be autoimmune, can be after infection, can be inflammatory. We know what happened afterwards. But the tension is to understand what happened at the very beginning. Because if I know what happened at the very beginning, I not only increase my knowledge, but I may be able to impact the process.
And with the current technology, we start to understand a little bit more about the situation. That's why I keep saying earlier-onset Parkinson's disease, young-onset Parkinson's disease, it is way different than later-onset Parkinson's disease.
Melani Dizon: Okay. So, if you, we, do look at much earlier onset. And, you said there can be a few different things at play; it could be an infection, it could be environmental, it could be all of these different things. How does that impact treatment?
Dr. Savica: Absolutely. Excellent. So, it impacts for a reason. The main, the gold standard treatment of Parkinson's disease, as we all know, is to supplement carbidopa (dopamine) with levodopa, or with agonist. We know that. Unfortunately, we don't have new treatment for that. Something that can help restore the cells, something that can help the dopamine to be reproduced. We don't have that, yet, at least. But the treatment can be highly impacted because our knowledge on dopamine is a knowledge based on older individuals, not on younger individuals. It means that we know the time to dyskinesia, the time to fluctuations and response to the medication. Even the response to the medication, even the absorption of the medication, is based upon what we have been knowing for decades on later-onset patients.
Early-onset patients are totally different. I have patients that do not respond well to the oral agents. I had to use different kind of agents. I have patients that do not respond well to the regular Sinemet carbidopa-levodopa, I had to use different formulations. I have patient where I'm not able, despite, I know there's a problem to easily replenish their [inaudible]. Why? Because the disease is systemic. So, it's affecting the absorption, it's affecting the way they respond to the drug. And if they have coexistent problems, such as, for example, metabolic problems affecting some enzymes that are responsible for motility or for movements of the bowels or for whatever, we are not going to have the same kind of response.
So, knowing these underlying causes, these concomitant causes, can guide me, counseling what to do, preventing problems. And if I do, for example, a genetic test. And I see that people have specific genetic mutations, I know how they will respond to the medication. So, knowing that there's a difference between earlier and late, and within early-onset, having a number of subtypes that we are still struggling to identify, but we all know there's a subtype.
People that are in this field know, people that are listening to us, for sure they don't look alike. They have different backgrounds, they have different symptoms. They have different ways that the disease is affecting them. We still have the same disease just because this is the name we call it, but ultimately, it's just, "just", the common theme is a reduction of dopamine in the brain. That's what it is.
Personally, I think we should, we're talking about young versus early, I think we should call the disease a different name completely, if we could. Completely.
Melani Dizon: Yeah, that's interesting. Well,
Dr. Savica: Drop Parkinson's disease and talk about something else.
Melani Dizon: Something else. Because that brings up this idea that later-onset: you get a clinical diagnosis, you have two out of the three of the cardinal symptoms, often those symptoms are not showing up for younger-onset. And so, how do you diagnose somebody who really doesn't present like what we think of as somebody with Parkinson's? And what is the sort of clinical, bright-light that says you have Parkinson's, or you have young-onset/early-onset Parkinson's?
Dr. Savica: So, unfortunately, I have to repeat myself in a sense. That the clinical criteria that we use, are the ones used as you say, later in life. And as you say, very well, they don't necessarily present the same way they are in early-onset Parkinson's. On a young-onset Parkinson, they're not. And people present in a very different way to the point that sometimes, and there's some studies that are showing up, we don't have yet this data. I cannot say very much about it because we have not yet published this data. But there is a huge, massive, delay from onset to diagnosis.
Melani Dizon: A lot of people will get diagnosed with like an orthopedic issue, right?
Dr. Savica: Truly. One of most common presentations is the presence of dystonia, for example. [Inaudible] dystonia after a marathon, people are thinking they have a muscle sprain, and they go to the orthopedic surgeon. But it's very difficult to make this diagnosis, very difficult. We, unfortunately, need to yet use the famous cardinal signs. But together with the cardinal signs, I think it's imperative for experts on the field to look beyond and start to use: DAT scan, PET scan, MRI, other diagnostic tests, lab works, genetic tests that can confirm what we're dealing with. And, especially in early-onset Parkinson's, in young-onset Parkinson's, we need to make this extra effort to confirm what's going on.
Melani Dizon: So, does a DAT scan always, in somebody young, and so for the people who don't know, what is a DAT scan checking? And then, what if the DAT scan doesn't say anything? Where do you go, what do you do?
Dr. Savica: A DAT scan is a particular test that is ordered by your physician that is talking and showing the activity or some specific nuclei of the brain called basal ganglia. And, this particular test, should give you two set of answers: yes, no. So, either you're positive, or you're not positive. Unfortunately, still, based on visual representation. So, it's the radiologist who reviews and says you are positive, or you're not. Many times, I see negative results that actually are indeed positive, or vice versa.
Melani Dizon: And that's because of training on the-
Dr. Savica: I think so-
Melani Dizon: -on the part of the reader. Okay.
Dr. Savica: Because of training. And, also, we have now some abilities, for example, at Mayo and in many other centers, where we can quantify the actual loss. So, getting a more objective measure of the loss of the activity. The test is quite specific and sensitive but it's not telling the full story. Because if it's positive, it's telling us one thing, what I told you before, the domineer energy activity is at lower. But, if it's negative, it's not telling you that you don't have Parkinson's. Yeah, it's more likely that you don't, but it shows only one piece of the equation, not the full piece. So, it cannot be the only test that people are coming to do. Say, I have a suspicion of Parkinson's, let me do the DAT scan. It's negative, you don't have Parkinson's. It's more likely, but I cannot yet exclude it.
In Italy where I'm from, we use this technique ever since the late '90s. It's been around for a long time. And I remember when I was a young doctor, people were coming to me with a piece of paper without saying a word. With a DAT scan result and say, doctor, what do I have? Do I have Parkinson's or not? That's not the way you have to make a diagnosis. You cannot base upon one test only. What this test should be part of, is a bigger effort involving multiple aspects, to try to understand what's going on.
Melani Dizon: Okay, okay. So, one of the things you talked about was response to medication. And sometimes, young-onset they don't respond to normal levodopa interventions. And this is interesting, because for a long time, I want to get into deep brain stimulation and why it can be beneficial for young people. But, at the same time, you know the argument was always. Well, if you respond to levodopa, you're going to respond to DBS and that's not necessarily the case. So, this is confusing.
Dr. Savica: Oh, 100 percent confusing. It's a dynamic and constant changing world. But, it's true. In the past, when I started to train, they were saying, oh, if you are looking to do deep brain stimulation you can get the same response, the carbidopa-levodopa [inaudible]. So, it's crucial that you have a good response and it's still valid if you have a good response, even if it's fluctuating response to carbidopa-levodopa. The likelihood that a deep brain stimulation works, is done properly, is higher. But it's also true that some people cannot tolerate carbidopa-levodopa, and not necessarily that they don't respond, they simply cannot tolerate it. Or they don't respond, or whatever, they cannot use the drug.
In these circumstances, deep brain stimulation can be a very good alternative. As well as a Duopa pump, let's not forget about the pump. The pump is saving some problems with absorption in the small intestine getting a faster constant absorption. So, those are two things that we should consider, not only brain stimulation. But, I'm saying deep brain stimulation can be a good alternative even in absence of a levodopa response. But telling the patients, hey, we are not sure. I have patients that despite my best attempts, they didn't respond to anything. My next step is that, okay, you're getting worse, I need to be doing something, we need to be doing deep brain stimulation. Knowing that maybe the response is not optimal, but is one of the last, one of the few things I have in that circumstance.
The question you had to ask, "Why you didn't respond?" Why? We don't know. There are some people that have some genetic makeup, some environmental problem, some disease that is different, still causing a damage in the basal ganglia, but is different. That does not have the same rate of response, or responding at all, to carbidopa-levodopa. And not because you have complications of, or immediate, immediate dystonia or dyskinesia, so abnormal movement. Simply, there's no response. And, it's a problem.
But let me say something about deep brain stimulation. We have to be very careful there. There's some data that are surfacing that do not necessarily warrant the use of deep brain stimulation early on. Even in early-onset Parkinson's, unless it's really needed. So, what I don't want, and I don't want to people think, okay, I am destined to do deep brain stimulation. It's not true. I'm doomed to do the stimulation. It's not true. And I will need deep brain stimulation for sure. It's not true. It's something that can be used as a tool in some selected cases. And, especially I would say in early-onset individual, young-onset people, we are to be extra careful, even extra careful.
Melani Dizon: Do you think it's gotten to the point where it's being used too much?
Dr. Savica: No, not necessarily. But I'm worried that we're going to go there and it's not going to be good. Because we have some data that support that is not always great to be doing that. This data had been presented to the [inaudible] Society by my group showing that surprisingly people that have, with early-onset Parkinson's disease, young-onset Parkinson's, defined fifty or below, that underwent the deep brain stimulation that had an increased slightly, a slight increased risk of cognitive decline. Which, I don't like the idea and I wasn't expecting that.
I'm not here to say, to hide the data. To me, the data needs to be out there because they, we, have to be saying, okay, we have to be careful. It means that we can do it, but, we have to be careful. It's not something that we can jump to conclusion very easy because it's still a procedure and there's a lot of moving pieces. And, again, we are using, adopting technology tested in older individuals, in younger individuals. Which is not exactly what we would like to do, but is the way it works.
Melani Dizon: Right. Okay. So, can we talk a little bit about how progression looks? For both different groups?
Dr. Savica: That's one of the most difficult questions because if the groups are different, I mean, if we do macro groups later-onset, early-onset, I can give you some solid data.
Melani Dizon: Yeah, yeah, yeah. That one. Let's do that one
Dr. Savica: Later-onset, the data that we have, survival. So, in other words, time to death after the diagnosis. In general, speaking about twelve to fourteen years after the diagnosis. So, if somebody is diagnosed with Parkinson's disease at seventy-five, he or she will looking at about ninety-ninety-two, which is not bad. You are getting old anyway. And the causes of that are the usual ones for the western world. So, cardiovascular diseases, cancer, pneumonia, so, [inaudible] stuff. In early-onset Parkinson's it's totally different. From diagnosis to death to last encounter, is forty-eight years.
Melani Dizon: That's amazing.
Dr. Savica: So, this is the, and I'm giving you generally speaking numbers that encompass a full array of different individuals, clearly. So, there are people that may be having a shorter duration, people that have a longer duration, but there are exceptions to the rules. We're talking about large numbers here. But, this is an attestation to show the major biological difference between the two conditions.
Melani Dizon: Yeah.
Dr. Savica: For forty-eight years. And, I tell you, I always tell my patients if they come to see me. They know that, if you're a woman and you have tremor, that's the best you can be, being a woman.
Melani Dizon: You know that you are later-onset because you have that mo- is that right? Because there-
Dr. Savica: Whether you're late or whether you're young, being a woman and having tremors is great. The prognosis is much better. And a woman makes sense, and not to do with estrogens, I wish it was with estrogen. Well, women currently speaking, they've been exposed to a higher level of estrogens throughout their life, clearly, you know. Man is on the opposite of it with testosterone. If you ask me, we have very little information about the role of testosterone in the degeneration of any sort of degenerative diseases. We are trying to fill this gap as well, but it's not going to be easy.
But what makes a difference? There is one little gene that is very important. Chromosome X. Chromosome X is crucial for our life. There's no life without at least one chromosome X. You have condition with X and zero, Turner Syndrome. But you don't have a condition with Y and zero, they're stillbirth. So, chromosome X is the most important, single most important chromosome that we have.
It's one that is not necessarily studied formally, even with the whole genome sequences, studying the full genome is not always studied. Because it's very difficult to study, there's other redundancy. It's a nightmare for our colleagues in genetics. They hate the chromosome X to be studied, super difficult to explore. But that is single-handedly the most important of good prognastic factors for Parkinson's disease, being a woman. And, again, I'm not talking about gender here, I'm talking about chromosomes. Yes. X, X and X and Y, that's what it is.
Melani Dizon: That's interesting. Okay. So, let's, let's talk about women for a minute.
Dr. Savica: Sure.
Melani Dizon: It seems that so many of the biological processes that women experience; menstruation, pregnancy, breastfeeding, menopause, hormone fluctuation, all of those things. That the distinction between YOPD and later-onset and women is probably even more important, right? So, what are some of the biggest differences you see for your early-onset women versus later-onset women? And, are you seeing a big difference between post-menopausal, and regardless of age, right? Like later menopause, early menopause, that kind of thing?
Dr. Savica: Let me tell you first, one sore spot, is that women have been absolutely under-represented in scientific literature. Early-onset women as well, with Parkinson's, has been very much not represented, not necessarily studied. There's a number of studies that shows the women are living a delay, a [inaudible] delay in getting to a specialist, compared to men for Parkinson's disease in North America. So, we're not talking about any countries that aren't developed. I'm talking about North America. The most important country could, could for, in this moment, in the western world.
But, clearly, there's a lot of needs and a lot of things that needs to be done. Because I tell you something shocking, women and men are different. Okay? Women and men are very different. And the disease, and I'm not talking about social rights here. No, no, no, no. They're biologically different and even the diseases are looking different.
Because I give you a practical, very simple example. We're talking about estrogens, okay? Women need more levodopa compared to men to have the same effect. And this increases the risk of dyskinesia in women compared to men. Why? Because the circulating estrogens that women have more, are displacing the amount of levodopa in the blood. So, they need more. But, and this changes as we get older, that is why, and many, many women can tell you that, with early-onset Parkinson's during their menstruation, during the menstrual period, things can get definitely worse.
Melani Dizon: It's like their medications don't work at all.
Dr. Savica: Perfect. And then better, and then worse again. And then, maybe, after menopause. And menopause, is again, a moving target. We cannot tell you. Talk about when it's going to be early, or menopause, it's difficult to say. But, after, let's say after the age of forty-five, where many people start to enter at least in some biological changes, things level up a little. But, to the point, they're not.
Another thing I want to mention, women are different. Pregnancy and Parkinson, a complete, abandoned field that now we are trying to fill the gap with some colleagues in the Netherlands. Doing a PD registry for women that are in pregnancy. And, actually, I want to mention this name, Dr. Austerban. She's a gynecologist from the Netherlands, she had Parkinson's disease, she has Parkinson's disease. And she had two pregnancies without Parkinson's, and a third pregnancy with Parkinson's. So, not only she is a physician, she is a patient, she's firsthand experienced that. And, we always have been very careful, but this is another topic that has been abandoned, and has been neglected in the literature. And we need to do that, we need to study more.
And other things seem to be [inaudible]. Still about women. Veterans and women. Women that are in the army. There's, not very many data about early-onset Parkinson's in the army. And I'm pretty sure that's something that we need to be looking to that. But I'm pretty sure there are even less for women, and we need to fill these gaps. So, there's a number of gaps, but from a standpoint of seeing patients every day and doing research on the topic, there's massive difference between men and women in terms of responsive medication, because women require more.
In terms of role of estrogens, I always ask for menopause. I always make sure that people are not taking estrogen. Sometimes they're taking estrogen, I say, take progesterone instead. And I try to involve, whenever I can, and whenever there's something, let me pass a term, fishy. I'm always involving somebody in the womens health clinic because we need to be understanding that.
But another thing I say about women that is very important, autoimmune diseases, women are definitely more prone to [inaudible] immunity compared to men. And that is the fact that women are able biologically to grow a parasite in their, their, in their body, which is, you know, a pregnancy. So, women [inaudible] have the tendency to be more autoimmune disease compared to men. And this is an important role of new inflammation in development of early-onset Parkinson's or Parkinson's in general. And men do not have this issue.
Melani Dizon: So, are you saying there's a link between people who get autoimmune early and then develop Parkinson's? Or-
Dr. Savica: Not necessarily.
Melani Dizon: Or is it common for them to have-
Dr. Savica: I wanted to say they're linear, but clearly there are some types of Parkinson's disease that have been ignited by inflammation. It means started, or at least manifested, earlier because there is an immune response. And this means that, clearly, immune response has a role in the developmental disease. And there's a difference between men and women there, a hundred percent there's a difference.
Melani Dizon: Wow! Okay, let's chat a little bit about this-
Dr. Savica: One other thing about women and Parkinson's, another neglected topic. Sexuality, it's being completely neglected. Man is easy. Quote, quote, I'm a man, man is easy. You ask your patient, "Hey, do you have an erectile dysfunction?" That is easy. That is not a difficult question to ask. And sometimes you see Viagra or Cialis in the medication list, so, you already know the answer.
But how many physicians are asking the same to women? Are asking, and I'm not talking about erectile dysfunction, it wouldn't be working in women. But what is the correspondence of erectile dysfunction? Is dryness, vaginal dryness, pain during intercourse. How many people are asking that? Not very many. And that's an important thing to do. But this comes to a question, a topic I want to talk to, and that's about education. Educating the new generation of physicians, of colleagues, and so forth. That will be something we want to talk about, maybe later.
Melani Dizon: Yeah. Oh, there's so much to consider, right, yeah. Okay, let's talk a little bit about exercise.
Dr. Savica: Sure!
Melani Dizon: Because it's such an important topic and I want to get your sense on the value of it. Is it the same for people with young-onset as it is late-onset? What have you found?
Dr. Savica: I think it's even more important.
Melani Dizon: Do you give the people the same recommendation no matter what age they've been diagnosed?
Dr. Savica: So, yes. Everybody should move, okay. Because if you reduce the risk of having cardiovascular diseases, strokes, hypercholesterolemia, and everything else. Clearly, your brain would have a better well being and you will live longer. That's a fact, any age, but in early-onset it's even more important, more important. Why? Because it's possible that some of the major changes are indeed mitochondrial, are working on the mitochondria. And we need to activate these little organelles somehow and exercise is one of the ways that we activate the organelles.
I always say, especially in patients or to patients that are young and are on top of their life. I said, okay, "Do you like to do boxing? Do you like to do Rock Steady Boxing?" Which is great. "Just do regular boxing. Just do regular exercise." You have to compare yourself with people your age. Because, clearly, if you're forty-two, it's not fair for you to compare with somebody who's seventy-two. To start with, it's not fair, because there's aging there and you are not aged yet. You will, because we're all going to, we are going to be, but you're not aged yet.
So, it is good to make sure that you compare yourself with somebody your age rather than somebody with a disease affecting you later in life. But, all my patients, I say to engage in exercise, and sometimes to tailor the medication intake according to the requirement of their exercise.
Melani Dizon: Can you give me some examples?
Dr. Savica: Sure. If somebody is training for a marathon, the requirement of dopamine, it should be higher during the marathon. So, I always say to my patient, let's try to find a threshold that works for you daily. Imagine, like insulin, right? People are having, in their diabetes, they're taking insulin in a baseline level, that is, I don't know, 100 units, let's make it easy. But there are moments of the day, maybe because you're working out, maybe cause you're busy, that your requirements are higher. So, the sensors are telling to the diabetes patient, hey, you need to take more because your insulin is off, maybe you need to take extra fifty units, and so forth.
Same story with Parkinson's. Somebody's taking, let's say one tablet or part of dopamine, doesn't matter what, three times per day. Maybe, on the particular day that they're training for the marathon, they need one and a half, maybe four times per day. Maybe an extra dose in between the intervals. And, then on the weekend, when maybe they're not working out, or they're chilling out with their family, they need less than one. So, the amount of medication can change according to the needs and exercise. Sometimes it makes you require more, and people need to be taking more.
I don't want people to grind through that, because my biggest concern is falling. If somebody falls and breaks a bone, or bones, it's not good. And, so, the biggest concern is making sure people are not falling. Beecause, if they do, we have a problem and the trajectory is going to be different then.
Melani Dizon: So, somebody actually told me, they wrote in and said that a lot of people will tell them, "Hey, you have to have your medication same time every day, and you know, no matter what". And she says, "I don't listen to that. I just take it when I need to take it." And, she said, "I can see where for some people it needs to be more regimented because you know they're going to do it". But what is your opinion on people taking this into their own hands and saying, well, I'm just going to take it when I think I need it?
Dr. Savica: First of all, nobody knows their body better than yourself, right? Your own, what your body requires and what body needs. So, I'm not, I don't know, I don't feel what, neither you do, but nobody feels what a patient feels. So, they know better than anybody else. So, I tend to listen when they tell me, number one. Number two, that is an important thing. There's truth in both, clearly, that's why I told you before, a threshold is good to know. It's good to know if levodopa works for six hours and then you need it again. So, clearly, you need to be taking every six hours because otherwise there's a drop. That is two substantial attempts, or five hours, and so forth.
But it's also true that some people, again within young-onset Parkinson's, their different subtypes. Some people do not have these massive wearing-off, or not having wearing-off at all, but they still require the medication. So, this patient, I agree with this patient, I don't feel the need of taking the meds. I need it only when I know I feel that. I'm fine with that. But, if he or she start to wear, declines wearing-off, then you have to do both. A little bit of a regimented, stable, same time every day, more or less. Plus, some extra that people may need in some specific circumstances.
Melani Dizon: Okay, great. We are almost out of time, but I have to ask you this question. Hopefully we can cover it, just a general coverage of it. Dementia and cognitive decline, young-onset versus late-onset.
Dr. Savica: Sure. So, let's start with dementia. Dementia is a memory decline, clinically-defined as memory decline that people/patients may or may not realize they have but family members they do realize they have, that has a significant interference in the activity of daily living. So, in other words, when somebody has dementia, he or she is not able to function independently. That's the clinical definition.
As we get older, let's talk about late-onset Parkinson's. As we get older, after the age
of seventy-five years of age, 40% of all of us human beings are accumulating plaques and tangles in the brain that are the same plaques and tangles that you see in Alzheimer's disease, so, as a function of aging. And, it's true, that the data on Parkinson's disease, later age, a later phase, pointing at about 35%, 40% of patients, may have some sort of memory problem - from very mild to very severe.
But the memory problem that people with Parkinson's have, is not the same memory problem that people with dementia or Alzheimer's disease have. It has to do with do [inaudible] energy clause, is affecting other circuit on the brain. Usually, the executive function, the planning function, what we call the visual spatial abilities. So, the ability to know where your body is in the context of space. And the ability to, as I mentioned before, execute to a plan, a multitask plan, is going to be tough. Clearly, also, memory process and short-term memory can be affected.
Early-onset Parkinson's is totally different because there's no aging as far as we can tell. So, the plaques and tangles are not there. And, it's true, depending on what part of the circuit is involved, we may have a different form of memory disorder. And one thing I said in the past, I say it again, the first treatment is to optimize carbidopa-levodopa, dopamine. Because, sometimes, the memory decline is because the medication is dropping. So, increasing the medication to potentially provide some massive benefits. So, I do not treat memory disorder in late, or early, if I'm not at first optimizing the medication, number one, because that is a problem.
Number two, memory disorders in the young. The most common complaints I receive: I have brain fog, I have problems at times during the day, I struggle, I feel like I'm in a cloud. And this can be again a functional fluctuation of the medication, but, sometimes it's not. Sometimes, it has to do with the different circuits that are involved, the different frontal circuits are involving earlier-onset Parkinson's disease. Because if you ask me about the frequency of dementia, of clinically-defined dementia in early-onset Parkinson's disease, it's not very common. It's not very common. The clinical definition.
So, if I do a formal test, I look at the biomarkers and I have a diagnosis of dementia, it's not very common, but the complaints of brain fog, memory disorder are very high. And they can interfere substantially with employment, with work, with social life, because it's almost being fatigued all the time. I mean, this burden, this is at least what my patients told me and I tend to listen to them. So, that's what they told me, a burden on top of their head, that's the most difficult one. And, sometimes, it's not easy to treat. But I think it's worth doing it, it's worth treating it. Again, most of my, some colleagues don't, don't even know about that, and it is a problem because those are concerns that are raised by the patient.
Typically, the neurologist will do the maneuver, see their tremor, and say, "Oh, you're doing good", but that is a tip of the iceberg. There's so, many, more things that if they're not asked, or if they're not reported by the patients, are having a massive role. And, I don't know what you, what my patient in front of me, what is the main problem with my patient? They yet to let me know, but I have to ask. Because if I don't ask, for sure the tremor is under good control, fantastic, but that's not the problem, there's way more. Memory decline, brain fog memory issues, seem to be one of the big ones in spite of normality, "normal results for dementia".
Because, remember, we talk about it before the Lewy bodies are not necessarily there. And if they're there, they can be a common outcome coming from different sources. But it's not necessarily the main driver of the symptoms that we see in earlier, younger patients.
Melani Dizon: Okay, oh gosh, I have so, many more questions. Hopefully, we can do it again. We can do it again. Is there anything that you're really excited about in the research, or work that you're doing, that you want to tell us about before we say goodbye?
Dr. Savica: Yeah, yeah, sure. No, absolutely. So, initially there are very many, very, very many. What I'm excited about is that there's a couple of potential targets, medication targets to try to help a specific subtype of Parkinson's Disease. We're working with a number of, we are working with some blood biomarkers that can be also target for potential medications that are already available in the market. They should be reported to do something different, so that would be something quite interesting.
There's, maybe, a couple of trials coming out. But, my problem with the trials, is that there's not very many trials. And, I'm trying to be diplomatic here, there's not very many trials, only, on early-onset Parkinson's. There's not, and it's wrong, but it's also wrong to lump early-onset Parkinson's together, we have to divide, we have to differentiate. So, one of the things I'm excited about, that my team is trying to, really trying to understand the different, what we call phenotypes, different types of disease, to see how we can potentially customize the treatment for different people. That would be another thing.
What I'm excited, about I hope that there will be some grant call, some research grant calls from NIH, from Michael J. Fox, from maybe you guys, from anybody, doesn't matter who, that will be devoted. This is my wish, devoted only to early-onset Parkinson's. That is to me the biggest, biggest weak link that we have at this moment, because all the current research is not necessarily devoted to early-onset Parkinson's, but to Parkinson's in general.
Which is okay, don't get me wrong, I'm not saying it's not right. But we have spent an hour and everybody here in this call knows that what we talk about here is completely different. And this means that the approaches that have been used so far, and I'm not saying anything that we don't know, they have not necessarily led to advanced science. So, I hope that my wish will be, indeed, and this what excites me, if we will have one day at one point something specifically for early-onset Parkinson's.
Melani Dizon:That's great. Well, I hope it comes, I hope the day comes sooner, rather than later. Thank you so much for being here. I'm so grateful and I can't wait to share it with everybody.