Evolution of Our Understanding of Parkinson Disease

Podcast Transcript

Dr. Alex Rae-Grant: Neuro Pathways a Cleveland Clinic podcast from medical professionals exploring the latest research discoveries and clinical advances in the fields of neurology and neurosurgery. Welcome to another episode of Neuro Pathways. I'm your host, Alex Rae-Grant, neurologist in Cleveland Clinic's Neurological Institute. In an effort to explore the latest advances in neurological practice, today we're talking about evolution of our understanding of Parkinson's disease. I'm very pleased to have Dr. Hubert Fernandez join us for today's conversation. Dr. Fernandez is director of the Center for Neurological Restoration in Cleveland Clinic's Neurological Institute. Hubert, welcome to Neuro Pathways.

Dr. Hubert Fernandez: Thanks for having me.

Dr. Alex Rae-Grant: I'd love for our listeners to get to know you a little better. Tell us a bit about yourself, where you're from, where did you train, and when did you begin your career at the Cleveland Clinic?

Dr. Hubert Fernandez: I was born in the Philippines, so I was born and raised in the Philippines, in Manila, and I did all my postgraduate training here in the United States. I started my internship at the University of Pennsylvania, Pennsylvania Hospital, my neurology residency at Boston University, and that's where I got hooked into movement disorders. I did my fellowship at Brown in moving disorders. I stayed there for a few years. My assistant professorship years were there. My associate to full professorship years were at the University of Florida until about 10 years ago. We got a call, my wife and I got a call, to move to Cleveland and so we've been here about 10 years now and it's been great.

Dr. Alex Rae-Grant: So you're here for the weather, right?

Dr. Hubert Fernandez: I’m definitely here for the snow     

Dr. Alex Rae-Grant: That's definitely for the snow. All right, so tell us a bit about where we are with Parkinson's disease today. What's the impact on society of Parkinson's disease?

Dr. Hubert Fernandez: Yeah, I may, I think this is an exciting time in some ways for a clinical researcher and a clinician in Parkinson's disease such as myself. We are also, a bit worried, the impact of Parkinson's disease cannot be ignored. It is the second most common neurodegenerative disorder, second only to Alzheimer's disease. About 1.5 million of our countrymen, North Americans have Parkinson's disease and we get about 60 to 70,000 newly diagnosed Parkinson patients each year. You may not realize that the most rapidly growing neurodegenerative disorder is not Alzheimer's disease, it is Parkinson's disease. So, the impact of that is unmistakable.

Now with Parkinson's disease, like any neurodegenerative disorder, it is a progressive illness, and as patients transition from an early stage Parkinson's to a more advanced stage Parkinson's when they develop motor fluctuations and also a lot of other non-motor features such as cognitive decline and other things, the caregiver burden is three times more. The expenditure, not only on drugs, but on a lot of other things. Hospitalization, loss of employment, is exponential as they progress through their illness.

Dr. Alex Rae-Grant: So really it isn't just an impact on the person with the condition, it's on a lot of people around them.

Dr. Hubert Fernandez: It is the patient, it is the caregiver, and from an economical standpoint, the society in general.

Dr. Alex Rae-Grant: Has the definition of Parkinson disease changed, and if so, how is that?

Dr. Hubert Fernandez: It is changing. I would say the way we diagnose Parkinson's disease remains largely the same, which means that you have to experience the motor symptoms of Parkinson's disease, at least two of the three symptoms of resting tremor, stiffness or we call rigidity, and bradykinesia, or we call them for what we call slowness.
So you need two out of the three features to have the general condition of Parkinsonism. There are other causes of Parkinsonism but, taking everything into consideration, it is a clinical diagnosis. Now what we are learning, what we have learned in the last decade or so, is that there is really more to it than just the motor symptoms of Parkinson's. And what's moving the needle earlier and earlier in the diagnosis of Parkinson's disease is a recognition of these would-be called premotor symptoms of Parkinson's disease. They can occur decades before the onset of the first pinky shaking, or the voice getting softer. So, these non-motor symptoms, we call them premotor symptoms or prodromal stage of Parkinson's disease include constipation, REM behavior disorder when they act out their dreams involuntarily, depression, anxiety. So these can occur, as I mentioned, decades before the onset of the motor symptoms. And this is relevant to us because in our quest to find disease-modifying agents, we have to really try to attack the disease as early as possible to give us the best chance of slowing disease progression or even stopping it altogether.

Dr. Alex Rae-Grant: So let's switch to talking about some new developments in Parkinson disease. Can you tell us about changes that have occurred and how these apply to Parkinson's disease and therapeutics?

Dr. Hubert Fernandez: Yes, for sure. I just gave an update on Parkinson's disease and I could only tell you that it was a challenge fitting everything in 50 minutes of a presentation. But perhaps the most relevant update we have in Parkinson's disease would be the emergence of targeted therapies. So prior to this, most if not all of our clinical trials for disease modification really had a shotgun approach so to speak. We took all comers of patients with newly diagnosed Parkinson's disease as best we could determine. And we studied one therapeutic agent after another for different reasons because we noticed that the general population exposed to a certain agent is less likely to develop Parkinson's disease. So maybe there's some protective effect of it.

So for whatever reason, we've tested drugs, A, B, C, D and E, and in earlier newly diagnosed Parkinson's patients and we've followed them for over three years, four years, or sometimes five years because progression is slow. And so it takes a little bit long to see the separation of those who got the real drug versus the placebo or a sugar pill. And after three decades of doing this over and over and over again, we almost have nothing to show for. None of our clinical trials have successfully shown to slow disease progression in Parkinson's. On the good note is the emergence of more targeted therapies in Parkinson's. For example, we are currently now testing human monoclonal antibodies that cling to and attack the pathological aggregated alpha-synuclein proteins. Alpha-synuclein are clumps of abnormal protein that are seen in brains of Parkinson's patients. They're seen early on and then they spread throughout the brain. And so the theory here or the hypothesis is that if we somehow are able to corral these abnormal clumps of proteins and prevent them from spreading, then perhaps we could slow disease progression in Parkinson's. So that's good.

The other focus of attention in clinical trials are gene targeted therapies in Parkinson's disease. We have now recently discovered certain genes, certain genetic mutations that actually cause Parkinson's disease. The first one is described as the alpha-synuclein gene mutation, but the most common genetic mutation is the LRRK2 gene mutation, L-R-R-K-2 gene mutation. It is present in about 5% of all genetic causes of Parkinson's disease. And we now have what we call LRRK2 inhibitors. So if we somehow can modify this genetic mutation and alter its expression, then we may really make a dent in disease modifying therapies at least for the subset of patients with the LRRK2 mutation.

Another example of genetically targeted therapies would be the GBA mutation therapies. So GBA is not a gene mutation that causes Parkinson's disease, but it increases the risk of developing Parkinson's about fivefold. GBA mutations are really seen in a rare lysosomal storage disorder called Gaucher's disease. It was kind of our observation that patients with Gaucher's disease have frequent relatives with Parkinson's disease. This was how it was discovered that maybe there is some connection. And so a meta-analysis of these GBA mutations show a fivefold increase in Parkinson's disease. And so, things that increase the glucocerebrosidase enzyme activity might improve Parkinson's disease. And there are now at least three companies investing in altering and improving GBA activity in the cell.

So hopefully when we have a bit more pathologically targeted agents and genetically targeted agents, our hope is that we would be more successful in coming up with meaningful disease modifying therapies as opposed to kind of our shotgun approach of giving all Parkinson patients with an agent that we think would slow it. So all these antioxidants have really been tested in Parkinson's disease and not much has shown. So hopefully this paradigm shift in our approach will give us a higher yield. So I'm excited about that.

Dr. Alex Rae-Grant: So I did want to change gears just slightly. I know there's some been some research in terms of physical measures that may affect Parkinson's patients. Some kinds of exercise approaches that have been studied at the clinic. Do you want to talk briefly about that?

Dr. Hubert Fernandez: Yeah, sure. So I think that's a two-part question. One is our quest for markers that assess progression in Parkinson's disease, and that has been an elusive target for us. To this day, not only do we still diagnose Parkinson's disease clinically, both the same way that we'd diagnose someone with migraines for example, there is no test for it. They just sound and look like someone with migraines, they must have migraines. So the same thing with Parkinson's disease. Some of the tests that we might be ordering for patients, they're really there to rule out other mimickers of Parkinson's, but not to rule in Parkinson's disease itself.

The same way for assessing the progression of Parkinson's disease. We do a physical examination, we make them walk, we assess the volume of their voice, we make them tap their fingers repeatedly and see how fast they are. At the end of the day, it's really how the patients feel and how the doctors assess their patients, whether they're faster and quicker, that tells both parties that their Parkinson's has progressed or stayed the same. And this is a crude way, to say the least, in assessing progression. So we are currently underway in testing actually pretty much everybody fluid that may come out, saliva, urine, blood, even cerebral spinal fluid for proteins and other compounds and markers that increase with Parkinson progression, but not necessarily with age. So that's kind of our quest.

The other big update we have, not only on the understanding of Parkinson's disease and our hope that we will finally have some disease modifying agents for Parkinson's and also our quest for a marker or a diagnostic test for Parkinson's and disease progression itself, are the treatments that we have.

And finally I suppose, the exercise as a treatment is no longer a soft kind of recommendation. It has finally gained traction, not only in the general community but actually the scientific community. This is something that we're really proud of here at the Cleveland Clinic because we think that we are one of the few people who started it all. Our preeminent biomedical engineer, Jay Alberts, started the science of our brand, our Cleveland Clinic brand, of physical therapy or exercise therapy, which is really forced exercise, as opposed to a voluntarily paced exercise. And so this started with an observation from Jay Alberts as volunteerism for the Iowa bike ride for Parkinson awareness, to a clinical trial that we conducted as an institution, and now it is part of our clinical practice. It is a prescription for our patients to exercise every day if they can, at least 30 minutes at a vigorous pace, as fast as they can possibly do. Resistance doesn't really matter to us. We focus on speed and the emphasized resistance, which is not necessarily the brand of exercise for other research groups. The good news is that any form of exercise is better than no exercise at all. But we do think that our brand of exercise, there's something special about it.

Dr. Alex Rae-Grant: So Hubert, before we finish, any other takeaway points? Anything else you wanna bring up in our conversation?

Dr. Hubert Fernandez: The good news about the state we're in, I know we haven't found a cure for Parkinson's disease. We don't have a diagnostic test for it. We can't even slow disease progression as of yet but, our patients do live longer as a whole now we have increased awareness of the illness. We are moving to the era of targeted therapies in Parkinson's disease, which excites us quite a bit. But perhaps the one take home message that I would give everyone is that, you need to be as active as much as possible with or without Parkinson's disease, but especially with Parkinson's. And trying not to compare notes. At our center alone, we have, we follow about 5,000 Parkinson patients, and I can tell you that not one of our patients would have exactly the same regimen as another Parkinson patient.

So it's a highly individualized illness. The jury is still out whether these really are all one in the same illness, or they are actually several different illnesses with different manifestations that look the same. This is one of the reasons why we're embarking on a huge database-capturing mechanism. We call it PD optimize, where every patient of ours that are seen in-clinic would fill out patient-reported outcomes to look at every organ system or assess every organ system in their body with very precise biomeasures of their motor and cognitive performance, along with the full clinical evaluation. This is our way of trying to contribute to the scientific community and determine whether we face different kinds of Parkinson's, different variants of Parkinson's disease versus just really one giant illness with different manifestations. This is one way of trying to tease that out. So yeah, my take-home message, exercise but don't compare notes. Parkinson's disease is such an individual illness. There will always be someone better than you and there will always be someone worse than you are, so always have the right perspective for it.

Dr. Alex Rae-Grant: Well, thank you Hubert. It's been a pleasure having you joining us today. We really appreciate your time and expertise and insights, so thank you for all your work.

Dr. Hubert Fernandez: Well, thanks for having me.

Dr. Alex Rae-Grant: This concludes this episode of our Neuro Pathways podcast. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast. Subscribe to the Neuro Pathways podcast on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. Don't forget, you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website, consultqd.clevelandclinic.org/neuro, or follow us on Twitter at CleClinicMD. All one word. That's at C-L-E Clinic M-D on Twitter. Thank you for listening. Please join us again soon.