In this presentation, Natalie Diaz, MD, discusses the current spectrum of motor and non motor clinical features of Parkinson's disease, the clinical criteria to diagnose it, and current medical and surgical treatments, and the pipeline for symptomatic and disease modifying therapies in Parkinson's disease.
Okay, welcome back from the break everybody. Hopefully you are rested and restored and uh ready to keep going here we have four more excellent talks coming up again. A little housekeeping. You can ask questions during the presentation. Either by clicking on the ask a question button below the video or by writing in a question to the right of the video. Please do ask questions during the presentation. Um Don't worry if you feel like you're waiting to ask your question because you think oh maybe they'll get to it later, just ask the question because sometimes there's a little bit of a delay. So better we have the question and if it ends up getting addressed in the presentation, great, but would love to know what you're wondering out there. So please ask your questions. And again. Finally, uh to get your CMI credits, you'll click on the get credit for physicians or get credit for non physicians and you'll be directed to complete an evaluation. You have to complete that evaluation to get your CMi continuing education credits. Uh So with that we will keep on moving here and I have the great pleasure of introducing dr Natalie Dias. Dr Dias is a board certified neurologist and fellowship trained specialists and movement disorders. She um as a specialist in movement. As a movement disorder neurologist. Her clinical practice focuses on the evaluation and management of patients with Parkinson's disease, a typical Parkinson Ian disorders. Huntington's disease, dystonia and Ataxia and she is here to provide an update in Parkinson's disease diagnosis and treatment. And with that, thank you so much for spending some of your saturday with us. Dr Diaz take it away. Thank you very much. Um So I'm a clinician and I've been a researcher for many years. Um Currently I have no disclosures here for this um cmi presentation today. So I'm going to quickly go over this clinical spectrum of Parkinson's disease. Looking at both motor and non motor symptoms, I'm going to review a little bit about where we are in our ability to diagnose Parkinson's disease and how to filter out some of the conditions that may look like Parkinson's um review some of the medical surgical and other lifestyle strategies we use for treatment and then take a little look at where we're going in sort of our treatment of Parkinson's. So you Parkinson's is considered a chronic neurodegenerative condition. And this is a long haul condition very slowly progressive spans, decades. And that's one of the things that helps us filter out things that may not be. Parkinson's the fact that it's slow growing and can last for for many years. It is a more and more common condition currently affects more than a million americans With 60,000 new cases diagnosed every year, more than seven million worldwide. And we expect this number to grow and maybe double in the next couple of decades as the population over 65 is growing by far. Most cases are sporadic, Only a small number are directly related to mutations that cause the disease, but most are considered a genetic interplay of um some variation in the genes that make people susceptible to these conditions, coupled with some environmental exposure that they come across in their lifetime that you know, and somebody who's genetically susceptible triggers the onset of this pathological cascade. And then once started propagates on its own. We believe with very distinctive pathology of hyper phosphor relation of proteins, abnormal folding of proteins into these structures that we called Lewy bodies. And we think of this as a multi system disease with degeneration and Lewy body formation um in the central and peripheral nervous system, bringing about some of the symptoms. I'll discuss diagnosis is still clinical. We use the UK brain bank criteria mainly clinically and in research to help us diagnose this condition. So we use the cardinal features to help us diagnose parkinsonism mainly brady, can asia where there is not only a a slowing of movement but a decrease in amplitude of movements coupled with evidence of tremor in the limbs or the jaw at rest, an increase in tone and rigidity with passive movement. And once we've decided that somebody has parkinsonism, we have certain supportive features that guide us towards Parkinson's the fact that this condition tends to start on one side of the body tends to after a couple years affect the other side but remains a symmetrical for the most part is a slowly progressive condition over many years. Um Generally people tend to have a pretty good response to dopamine based medications with the response that tends to last at least five years. Um And the induction of what we call dyskinesia is five or 10 years after they start dopamine based medications. These are the unwanted involuntary movements that people can get are generally supportive of Parkinson's disease because they signify to us, especially in the first decade, the degeneration in the brain and those dopamine producing parts of the brain are more localized there and there's less degeneration in what we call the post synaptic receptors. So these last three are very important because some of the mimics of Parkinson's disease that are more widespread disorders um tend to have sometimes in early response to these medicines that wanes after a couple of years and don't tend to mostly get these dyskinesia. So we use these supportive factors to help us filter out some conditions now. Um we use a lot of those motor features that I just described um to help us diagnose. And these can be manifested in many different ways. Loss of facial expression, a lowering of the voice slowness and movements such as getting up from a chair walking real slow with small steps losing a balance tremor, but there are a lot of other symptoms of Parkinson's disease that hide under the service that people can experience. Um and yet can really affect their quality of life. Things like constipation, urinary function, sexual dysfunction. Ortho static hypotension show a tendency to get dizzy if they stand up too quickly feeling tired and fatigued and sleepy during the day. As well as a variety of what we call neuropsychiatric symptoms, anxiety, depression, a tendency towards compulsive itty problems with sleep, memory loss and executive function in planning and multitasking. Um and hallucinations and some of these can be present even from very early stages of of of the conditions. Some even predate some of the physical symptoms. So people can have constipation, loss of smell, mood issues, problems with acting out vivid dreams when they sleep. Some studies show decades before they start their physical symptoms. So we use that as part of our diagnostic tool. But when these symptoms sometimes become so prominent in the early years of the, of the parkinsonism, we start to think that maybe we're dealing with one of our Parkinson's plus conditions where more widespread degenerative processes going on, causing some of these non motor features. Sometimes the diagnosis of Parkinson's is very simple and sometimes it's difficult to sort of separate out other conditions that might look like Parkinson's. These can include things like essential tremor, especially when people have tremor that occurs both at rest and when they're doing activities if people are older and are certain medications that block dopamine in the brain that they've had strokes or a build up of what we call micro vascular disease in the brain, they've had trauma or sometimes when we're not sure if the symptoms that a person is portraying a real or not. We have a couple of tools that we use. One such tool is something that's called a dat scan. This is a nuclear medicine scan and a radio isotope that's given intravenously helps us tag those cells deep in the brain that produce dopamine. This is where degeneration in the brain can happen and lead to some of those physical symptoms. Normally we should see this nice lima bean or comma shaped structure. But when somebody has Parkinson's disease, they start to lose the tail of that comma and it starts to become more of a period. So this scan can many times help us distinguish patients that may not have what we call a dopamine urgent deficit or have loss of cells and degeneration in those areas of the brain so separate out these conditions that don't have dopamine degeneration. Now, there are some conditions that are Parkinson's like that are also degenerative that sometimes can very much look like Parkinson's in the beginning. These are what we call our Parkinson's plus syndromes or a typical Parkinson ian disorders and these are the ones that have not only Parkinson's that, but some of those non motor features that I discussed can sometimes be very prominent in the first couple of years of of their of their condition, Things like cognitive dysfunction and dementia, hallucinations. Um they can have a lot of blood pressure, lowering bradycardia, severe urinary retention early falls. Tremors that are really out of proportion and very asymmetric. While all these things can happen in Parkinson's they tend to happen much more later in the course when they happen early. We think of these conditions and we generally break them on pathologically into what we call cynically aapa these and tell oppa these cynically apathy is being um those structures that I mentioned that have alpha C. Nuclear and proteins that accumulate in those areas and tau apa. These being conditions where we get an accumulation of tau in certain parts of the nervous system that degenerate. We used to just follow these clinically but now we are starting to develop tools where we can look at biological tissues such as saliva and skin and sweat glands where we can maybe find some of these abnormal proteins. There is one such test that is commercially available. This is called the Sin one test. This is a skin biopsy where we can find the hyper foster related um alpha Sanou Cleon in the skin and the small nerve endings of the spin skin. That might push us into thinking somebody who's got tremor or somebody who's having dementia or somebody who's having a lot of issues that look like Parkinson's but we don't think is really Parkinson's could have a c nuclear apathy versus one of these other protein based um degenerative conditions and the sensitivity on this one is very good. So the dad scan has been shown that in some studies over 90%. But there's been mixed results with the dads get. Whereas the skin biopsy, the sensitivity and the specificity of separating out conditions that are so new. Cleon based From those that are not, is actually pretty good over 95%. So once we make the diagnosis of Parkinson's, how do we begin the discussion with patients about how to treat? Well, there's always, as a treating physician, there's a couple of things that we always keep in mind and that is that all the therapies that we currently have available or not curative, they don't slow the progression, but they are very good. They're symptomatic therapies to help people alleviate the symptoms. We also know that these medications and therapies can have their toxicities, can have their long term complications. So it's very important to think about what we're going to do in the beginning and this is a very individual conditions. So it's important to know that there is no specific algorithm. We take each person and we look at their age, their physiologic profile. What are their comorbidities. What are their ability to tolerate some of these medications? What are the symptoms were going to treat and kind of tailor our treatment to all those factors. Once we start therapy we have an arsenal of therapies that we can consider. So there are the standard therapies that we start with. There are the levodopa preparations. This are medications that help the remaining machinery in the brain create more dopamine. We have medications that are dopamine agonists. These are medications that act like dopamine in the brain. We have what are called an E coli energy mix and amantadine. These are good for patients that have a lot of tremor or they have Estonia as part of their condition and then we have what are called Ameobi inhibitors. These try to boost dopamine in the brain. What happens is after a couple of years, these medications start wearing off between the doses or patients may develop what are called dyskinesia, involuntary movements of five or 10 years into the condition and we know this this is part of the condition, but we also have a mainstay of adjunctive therapies that help boost the levodopa that we're giving. They also have longer onset of action extended release formulations to help smooth out the effect. We have one that is not dopamine based at all that also helps smooth out the effect of medications and we have rescue therapies that people can use as needed. And we've had an explosion of these over the last three years. So the all the ones that are in red here are the new medications that have come out in the last three years that are all a junked of therapies when people start developing problems after about five or 10 years now, Deep brain stimulation is our mainstay therapy. This can be a great therapy for a lot of people, but not for everybody. We think of who is a good candidate for this are people that have had Parkinson's for at least four or five years. Kind of flesh out the things that are not Parkinson's disease have a good response to these medications, but they just don't last long enough for the kids. They don't tolerate them or they have a lot of tremor, which many times is not as responsive to oral therapies. We've had an explosion of advances over the last couple of years. We now have three companies um that supply deep deep brain stimulation platforms. Most of these companies now have platforms that have rechargeable batteries where people can get mris they have what are called directional needs that kind of abled us to mold the programming so we can steer it to where we want to go and diminish the risk of side effects. And Abbott has actually come out with one where we can actually do a virtual visit and program remotely for those patients that can't come into clinic or live in areas where they can't come see the doctor easily. Probably the one of the most amazing advancements has been medtronic. They came out with what's called the perceptive platform with brain sense technology. Um This is where the implanted electrodes can pick up abnormal activity. Um where we can see it, patients can also log in their symptoms as they feel them. And we can sort of better adjust the programming depending on where we're seeing most of the abnormal signals. The future of DBS is going to be what we call adapted or closed loop DBS. This is where um the uh the DBS adjusts picks up this stimulation and can adjust itself so that eventually it will take out the programmer by picking up these abnormal signals and learning how to correlate it with the patient's symptoms and give stimulation as needed after it learns about the patient. So, you know, after we have this discussion about medical and surgical therapy, many patients always ask me, well, what can I do? Is there anything that I can do adjust my lifestyle um to help in this treatment? And the answer is yes. There are many things that patients can do that involved diet exercise and sleep, that not only can it help them feel better, can help their symptoms, but whether it's accumulating evidence that this can actually help in sort of the neurodegenerative process. I'm not going to talk about exercise. Our next speaker is going to talk about this, but we find that diet is something that I stress a lot with my patients. There is an accumulating evidence that diet not only is good for general health and cardiovascular health, but it's important in brain aging as well as maybe helping in this neurodegenerative process. And studies are showing that our Western diet may not be the best diet, high fat, low refined sugars, low fiber, all these things may change our gut microbiome a uh produce inflammation and more whole food plant based diets like the mediterranean diet and what we call the mind diet, which is a combination of mediterranean and what we call the dash diet for hypertension, may play a role in sort of adjusting the neurodegenerative process. So there is accumulating evidence associating these types of diets with the risk of developing Parkinson's disease in large cohorts of prospective health studies in those that are genetically programmed to develop Parkinson's may delay the onset um in those people that have Parkinson's disease, it may slow down the progression of both their motor symptoms as well as maybe help a little bit in preventing some of the cognitive symptoms that people can have as time goes on. So this is definitely a discussion that we help with patients when we are talking about treatment are these types of diets. Sleep is also something that is very prominent in people with Parkinson's disease. Is anybody that treats Parkinson's, we know that almost everybody has problem with sleep for a number of different reasons. People have problems with starting sleep and maintaining sleep. Um We do discussions about sleep not only to improve quality of life, improve energy um and improve their symptoms during the day. We used to think that, you know, sleep with just a passive process, but we've learned over the last decade that a lot is happening in sort of regenerating the body, especially during steep slow wave, non rem sleep. And the brain is no exception. We know that the brain actually during those stages of slow wave sleep, it seems that we regenerate proteins that we lost. We regenerate neurochemicals that we lost and the brain may actually filter out and release through the lymphatic system, toxic proteins and other chemicals that accumulate. So there are studies using sleep studies that have shown that when Parkinson's patients have less time in what we call that non rem deep slow wave stream, these patients tend to have a faster progression in motor symptoms and may have a earlier onset in some of the cognitive and mood issues that happened in Parkinson's. So another reason why we tell people and counsel them about getting good sleep. Try maybe therapies to help them to get good sleep, prescription medications and over the counter medications. But I do a lot of counseling with patients about healthy lifestyle about, you know, trying to maintain good um um sleep habits. Um and um and how important sleep can be. So that's where we are kind of in our knowledge of Parkinson's currently, where are we headed in our treatments. Well, there's an amazingly, even during the pandemic there has been a lot of, a lot of movement in the research into new therapies and Parkinson's. And actually in 2020 there are over 100 different compounds being studied for the treatment of Parkinson's disease, roughly about six or 60% of those being in more advanced Phase two and phase three. Uh studies we tend to generally break them up into what we call symptomatic therapies, just geared towards treating the symptoms that people have and more what we call disease modifying therapies, Trying to alter the risk in the course of the condition. Um and generally in the last couple of years we've seen about 60% of the research looking at different therapies has been more in symptomatic therapies in about 40% disease modifying therapies. When we're looking at symptomatic therapies, we're looking usually more at currently. Um newer formulations of therapies that are already out there. A mainstay in therapies like Leva dopa and dopamine agonists. So there's interesting studies looking at patches of levodopa, which is one of our standard therapies, what we call patch pump, where they have a little micro battery trying to push the medicine into the skin um and increase absorption. There are under the skin um needles for subcutaneous infusions of leva dopa and dopamine agonists. Um There are newer types of dopamine agonists um affecting more the D. One as opposed to the D. Two dopamine receptors that are thought to maybe have a better symptomatic benefit and less cognitive and psychiatric side effects. And there's even um gene therapy uh studies that are very interesting looking for ways to kind of boost the medications that we're giving by working on some of the enzymes that turn leva dopa and the medicines that we give into more dopamine. So helping the body produce more dopamine. There are also studies looking at what we call non dopamine based targets. So these are targets where we're using things like they're looking at chemicals like glutamate, which is one of our excitatory chemicals in the brain and is thought to maybe be involved in some of the long term complications of Parkinson's and trying to block some of those excitatory or um maybe toxic uh neurotransmitters. And there's also looking at different types of chemicals that are neurochemicals in the brain that are thought that our module a torrey to maybe play a role in some of our long term complications in terms of disease modifying therapies were all over the map as we're trying to learn more about Parkinson's, there are therapies that are targeted towards alphas to nuclear and the formation of Lewy bodies. So they're therapies that are looking at trying to decrease the amount of alphas nuclear and that's being made, trying to prevent the phosphor relation as well as the aggregation of alphas nuclear in these toxic proteins and then how to better improve clearance of these proteins out of the brain and out of the body. There are also therapies that are looking at trying to modify genetics and genetic risks. So um there are some genes that are not only involved in mutations that directly cause Parkinson's disease, but a lot of these same genetic mutations have risk profiles, meaning that there may be variations in the gene that could put people at risk. And so there are a lot of therapy is looking at, how can we modify that risk genetically to try to bring down the risk. And then there's other types of therapies, looking at trying to bring down the brain and central nervous system inflammation. How can we increase in, bring any oxidants better into the brain so that we can mop up some of the free radicals and toxic proteins that can accumulate with some of the processes. And can we attack the nervous system from other ways through either our gut or through our nasal mucosa. And try to prevent some of the processes that are going on there that we think may be areas where the degenerative process in the pathological process may actually gain entry into the nervous system. So the disease modifying therapies and the trials that are looking at some of these are are being approached from all these different ways to see if we can alter the course of this condition. So in summary, um, you know, this is a chronic long term condition that we really think of as a multi system condition can affect the gut, can affect the heart, can affect the brain. Um and it's due to the accumulation of these toxic proteins into Lewy bodies. What we call a a sin nuclear apathy. The diagnosis of Parkinson's disease is still considered a clinical diagnosis, but we have some newer tools that we use to help separate out some of the mimics that sometimes can, especially in the first few years look like Parkinson's disease. We now have an arsenal of medications, of symptomatic medications that we can use and just incredible advances in surgical therapies to help us better approach these patients as they move through their advanced stages. As I mentioned, lifestyle changes such as diet, sleep and exercise are very important in counseling these patients. And we have very exciting research looking at not only how to better treat this condition, but also how do we modify the trajectory of this condition? Thank you very much. Excellent. Thank you so much. Dr diaz some great questions coming in, please, if you have questions, get them in. Now there is a little bit of a delay. So if you get them in during the presentation even better, but if you can get them in. Now, that is fantastic. Uh first question here, what is known or what work is being done with lithium as a neuro protective agent to protect against conditions such as Parkinson's disease. So, before you answer that, I'm just curious about just neuro protective agents in general with regard to Parkinson's disease and would love to hear your take on that. Yeah, absolutely. So, you know, it's important to state that we have nothing that's neuro protective right now. Right. Nothing that we can say definitively that is neuro protective all the therapies that we have available that we prescribe or surgery is not protective at this point. Right? There all symptomatic, but there is a lot of research going into them. When we talk about protective, we talk about therapies where we can identify people very early on in the condition or even people that we think are at risk for the condition. Whether we can at that point either stop it or slow it down. Right? So we talk about therapies in halting the progression or the onset, Right? And we hope that we can keep refining our diagnostic tools so that we can diagnose people as early as possible and when we have those therapies available, that would be the time to sort of act on it. Right? So there there's been incredible amount of interest in this. And unfortunately, you know, what happens is the way that we've been able to study this is very complicated in Parkinson's disease, as we learn is a very complex condition, as you can see by the way that the trials are going looking at all the different ways that we could modify this condition and of course when we start looking at these we we look at them through first in vitro, but then we move on to a number of animal models that we know that are very good. The problem is that we're learning is you know, we're very different from the rat and the monkey and the animals that we study. So, you know, unfortunately a lot of compounds that show a lot of promise initially kind of gets stuck there and we don't know if they truly could be helpful for for humans. Somebody mentioned lithium. So lithium is an interesting compound. Right? So if you look at some of the things that I talked about protein accumulation and Lewy body formation and these inclusions, lithium is one of those compounds that has been looked at in smaller studies. And there was brewing interest for a while looking at, not even only in Parkinson's disease, but in what we call protein, open these conditions where you get an accumulation of abnormal proteins that misfold and go into these clumps and there was this idea that lithium may prevent that aggregation. Unfortunately, it doesn't seem at this point that it's panned out or at least the early studies didn't. I think there are still continued interest in this. Um, lithium is not an easy medication and I don't recommend people take lithium just on that off chance because it can have its long term complications and needs to be very monitored. Right because there is a narrow therapeutic window and if if people overdo it or long term therapy sometimes can be associated with complications. Follow up question that's kind of related to that. Is are there antidepressants orang geopolitics that you tend to reach for for anxiety and depression in Parkinson's disease. Yeah, that's a really good question because everybody knows that anxiety and depression and mood disorders are very prevalent in Parkinson's disease right sometimes even years before. Um and for some people it's mild and for some people it can be very prominent. Unfortunately the antidepressants haven't been with its and it's amazing with the prevalence that the mood disorders have that it hasn't been better studied as to what is the ideal antidepressants that are anti Elizabeth politic to use in Parkinson's disease. And so we just take our guidance from the general literature in the psychiatric world and in sort of you know which ones to use the SSR is, we use a lot of them the SnR rise as well. So I usually go for those um and it depends on if I'm you know looking at other issues if it's dual depression, anxiety, if they're sleep issues, you know some of them tend to be a little bit more activating, some of them tend to have also a little bit more and a colon ergic activities. So I may want to avoid it in somebody who's older or somebody who maybe it's got some urinary retention issues. So there's no guidance from a Parkinson standpoint, which one is better, We kind of take it from our psychiatric partners as to how good the these compounds are in in treating anxiety, depression and then use the individual sort of characteristics of one depending on the comorbidities of the patient. Okay. One other quick one because we're over time. But these are good questions. So I'll make up the time somewhere we talked about. We've got a question about neuro protective stuff. What about somebody mentioned high incidence of Parkinson's disease in Nebraska and wondered about connections with pesticides, pesticides, herbicides. They also go and ask about cancelation antibodies. But let's skip that for now and just talk about toxins, neurotoxins. Parkinson's any thoughts on that? Absolutely. So beginning of my lecture I mentioned, we think that most cases of Parkinson's are due to this sort of combination. We think of something that puts a patient genetically sort of at risk, that's not enough. They probably will come across something in their lifetime that they're exposed to, that that individual cannot process as well. And that together is what sets off the process right now, there's been a lot of interest in a lot of environmental triggers from pesticides to, you know, living in places where there is a lot of manufacturing a lot of agriculture people that work in certain professions with heavy metals welders and different things like that, you know what we eat, what we drink. So there's been a lot of interest and studies and you know, in terms of pesticides again and these are all what we call association studies, right? We have not yet been able to identify causation, but we talk about associations. So when we look at areas of the country where we have maps of where pesticides, you know what pesticides are being used in quantity and and for how long central California tends to be one of those areas where we've been, you know, producing studies from there. Um, there seems to be a higher incidence of Parkinson's disease in certain areas where these chemicals are approved and it tends to be sort of an explosion or risk. So not just a one time I've lived there for a couple of years, but people that have been there for many years. Um, and there seems to be a higher incidence, but not everybody in those communities develops it, which is why I say it's probably an interplay of several innate factors. And then you give people, you know, sort of these exposures and it puts people at risk. Well, thank you so much. I'm hoping we have a sequel to this. I have more questions. I want to know what you should do if you're the child of somebody with Parkinson's to reduce your risk so many things. But I think that environmental toxins is actually a great segue into our next talk
