Alice Chen-Plotkin, MD, from Perelman School of Medicine at the University of Pennsylvania, discusses how a recently discovered biomarker may aid in the understanding of cognitive degeneration brought on by Parkinson’s disease.
Can you discuss Parkinson’s disease?
Dr. Alice Chen-Plotkin: Parkinson’s disease is generally considered a movement disorder. It’s a problem with the parts of the brain that help you move smoothly as well as quickly. What happens is that in Parkinson’s disease, there is a particular population of neurons; they live at where my two fingers may cross – kind of at the base of the brain. Their job is to basically create a substance called dopamine. That dopamine projects all over the brain, and kind of bathes the brain in a way that makes movements more fluid and less stiff. It’s not that you don’t have strength, it’s that you can’t activate it appropriately. So, Parkinson’s patients, when they see a doctor, it’s often times because they have some of the cardinal symptoms. The cardinal symptoms are tremors, which some people have experienced firsthand with a relative or friend; rigidity, which is the stiffness in the limbs or stiffness in the neck muscles; akinesia or bradykinesia, which is just a slowness of movements. It’s almost like you’re a little bit in slow motion. The last cardinal symptom is postural instability or problems with balance. There are a lot of other features, but those are kind of the cardinal symptoms that we look out for.
Is Parkinson’s disease fatal?
Dr. Alice Chen-Plotkin: What will happen is that the neurons will continue to die overtime – more and more will continue to dysfunction and ultimately die. You can’t stop that, and in some cases people die due to complications as a result of that. In that kind of regard it is fatal. In due course, age is a risk factor thus is often occurs in older people. Sometimes it’s not always fatal because something else will get to you first. The problem right now is that we don’t have anything that slows down the death and degeneration of neurons.
Is there a cure for Parkinson’s disease?
Dr. Alice Chen-Plotkin: No. When you think about cure, you think about what it means. In Parkinson’s disease, by the time you get your first symptoms, actually thirty to fifty percent of the neurons that I was talking about are already dead. So, that means that you can have thirty to fifty percent less neurons than you are born with and still fully function normally. I think that the key thing that researchers are looking for now is a way to slow down that process by which neurons can function and die. What you could ultimately do then is slow down the progression, or even prevent the clinical onset in which case, from the patient’s perspective, they never get their symptoms or detrimental ones for that matter.
So if there are no symptoms, is the goal to be able to detect this?
Dr. Alice Chen-Plotkin: Yes. One thing, I say that thirty to fifty percent of neurons are dead . . . well, how do I know that? This information is actually obtained through an autopsy series where someone happen to die from a something completely unrelated the Parkinson’s disease. With that, you could see that these people who looked relatively normal had this much cell death. So, part of the hope is that you could find surrogate markers. You can’t look in someone’s brain and sort of find out why the cell markers are developing inclusions, which are basically just pathological accumulations of protein. You can’t do that but perhaps you may be able to find a surrogate marker. That is part of the reason that we commenced our research with biomarkers. A biomarker is just what it sounds like. It’s a biological marker of something that is going on. It is something that tells you what is happening in a disease process, or in any process for that matter without you having to look firsthand. In Parkinson’s disease, the two imperative biomarkers that we are looking for are things that have to do with pre-symptomatic diagnosis—finding out that the neurons are suffering in your brain before you ever have your first symptoms. The other ones are biomarkers that tell you something about phenotype – a class of symptoms in Parkinson’s disease that you otherwise would have no idea as to how it goes. Ultimately, that is what led us to look for biomarkers for cognitive impairment.
What exactly have you found?
Dr. Alice Chen-Plotkin: Most people who have Parkinson’s disease will develop cognitive impairment as well as dementia. There have been myriad long-term studies that show if you have had Parkinson’s disease for more than twenty years, eighty percent of those people develop dementia. That means that twenty percent of those people probably never do. It’s not completely straightforward either. In one year you are a little bit impaired and in two you become a little more impaired. Some people become demented right away while others never become demented. When people come into my clinic, they ask, “Do I have Parkinson’s disease?” I have no idea. “Am I going to develop dementia?” I can tell them with some degree of certainty, “Well, with people that are older there is a higher risk of getting dementia,” however, that is not very useful to patients. I think that if we are ever going to intervene in this process of stopping cognitive impairment in diseases, we first must understand what is happening and moreover understand who is most at risk. What we went looking for is something that is easily measured from the blood, because it is biofluid that you can get to most easily. That would tell us whether a person is more likely or less likely apt to becoming cognitively impaired or demented. Basically, we took blood, measured 150 proteins at the same time from the blood samples from these patients, and we looked for blood markers that tracked how people performed on cognitive tests. We found that 11 markers seemed to track with the cognitive performance, and in fact one marker epidermal growth factor (EGF) correlated with cognitive performance. The thing that was really exciting was that we looked at the data and discovered people with low EGF levels did not do well on the cognitive tests. Furthermore, there was a group with low levels of EGF that performed well on the cognitive tests. We then thought what is going on with this group. Luckily, it takes a while to gather all of the samples.
By the time we ran the study, we realized that some of the samples had already been collected almost two years before. What we looked at was the people that had those low EGF levels and ultimately obtained high cognitive performance, how did their cognitive performance change within the next month to two years. What we found was that the people who had low EGF levels were much more likely to develop dementia within the next two years – eight times more likely than those in the other groups. That then sort of paves the way for using this as a potential predictive biomarker. The study that I am referring to involved approximately 180 patients, which isn’t that many, but what we had to do was count on the people that already had this follow-up time for – this data regarding the predictive value we only had for about 55 patients. What we really need to know within the next couple of years is basically if other sites are seeing the same result that we do, and if we can kind of see this predictive trend in many, many more patients.
Does this mean that down the road there may possibly be a blood test that predicts the onset of Parkinson’s disease?
Dr. Alice Chen-Plotkin: This marker is not actually for Parkinson’s itself. It’s for the cognitive impairment in Parkinson’s disease. What I am hoping for is that within the next couple of years is that we are going to marry with many Parkinson’s disease clinics, and a lot of them will test for this EGF. Some of them are doing it with us while others are performing this task on their own. I am happy for anyone that is doing it on their own because in some ways it is better verification if they do it without our aid. What we did was that as soon as we had this potential blood marker, we moved it onto testing platforms that are commercially available to any lab. We published that study so that these clinics would go ahead and do the test on their own. We are hoping that within the next couple of years, we will see similar results at some of the other sites. Moreover, there are some rather big national efforts to coordinate biomarker trials. I think that if this EGF result seems to be replicating at a few sites, the next step would be to see if it holds true in a large national cohort. Then, if there is a large national cohort that shows this, we start to develop it into a large clinical test. My guess is that it will be helpful in the planning of clinical trials. For example, when I was saying that the problem with trying to interrupt the cognitive impairment of Parkinson’s disease is that we do not have any therapies for that. If you are a company that wants to develop a drug to change the course of cognitive impairment for Parkinson’s disease, you can’t have a twenty-year trial. It would be extremely unlikely. I have never seen anything like that before. You’ve got to identify a pretty at risk group to test that medication in. That might be the first clinical diagnostic use to basically enrich for a population of people who are at risk for clinical testing and things like that.
So you are in need of further evidence?
Dr. Alice Chen-Plotkin: Exactly. It could be noise. There is always the possibility with these early, early studies is that what you are following is just an epiphenomenon, or basically something that is noisy or some weird cohort that is part of your patients. You need to know that it is true again and again and again with other patients. This is the first step right now. The next step is everybody tests it exclusively with his or her patients.
So next, you would need the company to develop the drug that allows a larger population to use the drug?
Dr. Alice Chen-Plotkin: Yes. That would be my hope. That is kind of what motivated me to start this kind of research.
Do you think that you will see this happen within your time?
Dr. Alice Chen-Plotkin: Absolutely. If it is going to go; if it is going to die – if it is not going to replicate – than no. It’s a lot to think that all of these things are going to happen. I am a physician scientist. I actually run a research lab four days out of the week and for a long time my research was far more basic. It involved the mechanisms of disease. I see patients one day a week, and a lot of my patients (who are very open to that) know that I run a research lab and ask, “When are you going to do something that is related to me?” I thought to myself, “Maybe it’s time that I do something that is related to what some of these patients are undergoing, and actually translate into real-time (in my lifetime / in their lifetime) for something that could help them in some way.” That was why I started looking for biomarkers in the first place. The other thing is that the first screen that happened at the University of Pennsylvania, it first of all was a huge collaborative effort with the entire neurology clinic involved, as was the Center for Neurodegenerative Diseases Research where I had done training before. The other piece of it was that it was a partnership between the University of Pennsylvania and Pfizer. Basically, the way that they did it was Pfizer gave a grant to the University of Pennsylvania – we then wanted a little bit of separation. Once they gave the grant to the University of Pennsylvania, they had no control over how we did our science. The reason that they did it was that they were interested in this area as an area of development. What’s nice about the partnership being made in the beginning was that if we were ever going to try and translate it back, we already have a partner. We aren’t incessantly searching for one.
Can you talk for a bit about your patient Michael?
Dr. Alice Chen-Plotkin: Sure.
When did he start having symptoms?
Dr. Alice Chen-Plotkin: I think that I have basically been taking care of him for about two years now, and I think that prior to my meeting him, he had already seen a neurologist so maybe he would have had symptoms for six months to a year. He came to our clinic because we are a subspecialty clinic – as many patients do for a second opinion because it’s a little bit of shellshock. “I’m fifty-something and someone is telling me that I have Parkinson’s disease. I just want to be sure.” He came to our clinic for a second opinion, and what I did was basically confirm that he had Parkinson’s disease. Subsequently, he continued to come to our clinic for treatment, so I have been taking good care of him since. He is exactly the kind of patient that I think this sort of thing would be useful for. He’s young. He’s in fifties right now. Chances are, he is going to live with Parkinson’s disease for twenty years or so. If you sort of play out the statistics, he will have an eighty percent chance of developing dementia at some time in his life. That’s huge. He has no idea when. He has a family. He is a blogger, and does many things that require his brain and personality to stay intact. I think that this is the type of thing that can give him hope (not right now but within the next few years) and give him a sense of what is to come, and also give you a sense of what risks to take. Whenever you enter a clinical trial, say someone is trying a novel medication to try and delay the cognitive degeneration brought on by Parkinson’s disease, the reason it is a trial is because you don’t know whether it is going to work or not. If you don’t know whether it is going to work or not . . . you might be sort of taking a risk for what ends up to be no benefit. It’s rather difficult to determine whether or not to take that risk. You know that it is more likely that you are going to develop cognitive impairment, and you might be more willing to take that sort of risk. That is kind of the thing that I would want to know if it were me.
Is there anything else regarding the current study that you would like people to know about?
Dr. Alice Chen-Plotkin: It is important to know that so many people did this. I started the work when I was doing my last stage of training. The clinic that I work in, we have basically collected a good 400 samples just since the end of this study and that’s huge. We published the study just months ago, and that is how quickly people have rallied to the cause to basically enroll their own patients. That is the kind of thing that it takes to move results quickly. It means that everyone wants to see this happen. The other aspect to this is seeing a result quickly doesn’t mean that it will work. A result quickly just means that you get your answer quickly. It’s possible, but what I want is the results quickly. It could happen that in two years we discover that this particular angle didn’t pan out as well as we had planned, however, I want to know quickly so that I can work towards getting results that help these patients.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Kim Menard
Penn Medicine Department of Communications
Philadelphia, PA(215) 662-6183
Kim.Menard@uphs.upenn.edu
To read the full report, New Parkinson's Test: Predcting Dementia, click here.
New Parkinson's Test: Predicting Dementia -- In Depth Doctor's Interview Medical News and Health Information
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