(lighthearted music) – Good morning and welcome My name is Leslie Chambers I’m the President and CEO of the American Parkinson Disease Association And on behalf of everybody at APDA, I want to thank you for joining us on day two of the Third Annual Midwest Parkinson’s Congress, which is hosted this year by the Greater St. Louis and Midwest Chapters of APDA We had an amazing day yesterday with over 1000 participants, as we learned about the latest in treatments and research from our experts, scientists and clinicians, Dr. Perlmutter Shake, and Gilbert We are so grateful for their contributions to the field of Parkinson’s Disease and for everything that they do for APDA So thank you so much Today, we have another outstanding line of Parkinson’s experts, including leading industry professionals, who will be discussing the latest in cognition, deep brain stimulation, and the use of medical marijuana in the treatment of Parkinson’s Disease I like to once again thank our over 20 sponsors who helped make the Midwest Parkinson’s Congress possible And although I can’t mention them all now, I do wanna give a special thank you to our champion sponsors, the James and Allison Bates Foundation, and the JCA Charitable Foundation I would also like to thank our collaborating sponsors, ACADIA Pharmaceuticals, Ammeal, Emerson Hermetic Motors and Kyowa Kirin Please take time again today to visit our sponsors resource booths, so you can learn more about how our sponsors support the Parkinson’s community And you don’t have to worry when you visit the booth about missing any of our experts as all of the sponsors booths will have the conference broadcast live So once again, thank you for your participation, and enjoy today’s Congress (lighthearted music) – Hello, and welcome to the APDA Midwest Congress My name is Dr. Jennifer Goldman, and I’m delighted to be here today I’ll be speaking about cognitive and other non-motor behaviors and how to cope with their manifestations These are my disclosures as you can see here in the slides, and I will talk a little bit about off label medication uses So these are some of the objectives for today’s talk I’ll describe clinical features and concepts, as well as management related to cognitive and non-motor behavioral changes in Parkinson’s And I’ll also talk about what we can consider our top 10 life hacks or coping strategies as a way to illustrate things that people living with Parkinson’s and their care partners can do about these cognitive and non-motor behavior symptoms So the first one, the first of the top 10, is to know the symptoms And with that, I’ll start by talking a little bit about some of the common cognitive and behavioral symptoms that we can see in Parkinson’s, because we know that Parkinson’s while it has tremor, stiffness, slowness or walking changes is much more

than a movement disorder We know it can affect all these different areas and even more that are not shown on the slide that relate to cognition, mood, autonomic function, so blood pressure, bladder and bowels, behavior, sensory symptoms having to do with smell and vision and pain and musculoskeletal system and sleep And I know you’ll hear from some other talks in this series about sleep and fatigue So we will really concentrate our efforts on these three areas for today’s talk So I will speak to you a bit about cognitive changes, and I’ll talk about what it means to experience and our definitions for mild cognitive impairment and dementia We’ll talk about mood changes, represented by depression and anxiety And then we’ll talk about some of the features behavioral symptoms that are a varied bunch of behavioral manifestations such as apathy, psychosis, and impulse control disorders And through this talk, I’ll illustrate what these symptoms are and how we think about them as clinicians and researchers and how we define them to better understand them So first and foremost, I think my first immediate takeaway message is that not everyone with Parkinson’s will have cognitive or behavioral symptoms So that is first and foremost We know these topics can be difficult to talk about or hear about, they can be scary Mental health topics can often be loaded with a lot of stigma or fear or concern But it’s really important that we have accurate definitions and information And we do know that management strategies, team care and research can make all the difference So here, you’ll see the phrase, knowledge is power So I hope there’s some of these educational activities in this Congress and other educational sessions that you might attend, we can empower you and give you some of the tools and resources to understand the symptoms and address them if they are present So first to talk about what is cognition So cognition actually comes from the Latin root, cognoacere, to know And cognition is a very broad area So it represents our mental actions and processes of acquiring knowledge and understanding this through our thoughts, our experiences and our senses So it’s how we take in the world around us and process it and understand it, as well as interact with it One thing that I’m often asked about it or told is when people say they may have cognitive changes, they may say, oh, my memory is bad or my memory is not what it used to be But cognition includes much, much more than memory So it is not a direct equivalent, it does not equal memory, but rather it includes many different cognitive processes that you can see here in the circles below These include things like attention, learning and memory, working memory, a very specific type of memory, which is holding information in your head while you’re doing something else So like remembering a phone number, while you’re writing the list of groceries or talking to your spouse or so forth Comprehension, language, judgment and evaluation, problem solving and decision making, and reasoning are all aspects of cognition So here’s a slide that describes some of the cognitive symptoms Some of what we call as clinicians and researchers domains are kind of buckets that we put these cognitive symptoms into, and a number of the areas of the brain that are involved So here you can see, we might divide them into five different areas or cognitive domains The first one being attention and working memory, where some of those symptoms might include trouble concentrating, or difficulty keeping track of information in one’s mind, as I just mentioned with an example And this is often involved in an area as our frontal lobe, the very front part of our brain, including a very specific area called the dorsal lateral prefrontal cortex, and how it connects and relates to another area, kind of in the, you know, towards the back part of the brain called the parietal lobe, and an area called the basal ganglia, which we know is highly involved in Parkinson’s disease and dopamine regulation So that’s one area of cognitive symptoms Another area that can be commonly affected in Parkinson’s is called executive function And so you can think of this as Perhaps the CEO,

the executive of the brain, or the conductor of the brains orchestra, putting it all together so processing information, organizing it, planning it, initiating activities, people may experience difficulty when multitasking They may also have trouble stopping and starting activities And this is all part of executive function And it involves a very front part of our brain called the prefrontal cortex and basal ganglia Language is another cognitive domain And this sometimes we can see in Parkinson’s in a number of different ways, probably the most common people may say they have difficulty finding the words they wanna say, it might be kind of on the tip of their tongue, but it’s hard to get it out or it’s slower to process it They may have reduced fluency of speech, so shorter sentences might be hard to find the word they wanna say And this involves a number of regions in the brain, but particularly between temporal lobe Memory, and I mentioned before memory has a number of different types One involves learning And so, how we learn get information encoded into our brain, remember it and are able to retrieve it So how do we recall facts or events And that’s one type of memory called declarative memory There’s also a memory of how we do things So how one rides a bicycle, or remembers a certain activity, and that’s called procedural memory And that type of memory often involves the basal ganglia Lastly, there’s visual spatial function And people may experience difficulty navigating the world around them such as sense of direction or getting turned around, and perhaps even lost in a new environment or we talked about how this might affect daily activities or driving We may test this in the clinic by having people draw objects as well This involves some of the back regions of the brain called the parietal and occipital lobes So as you can see, cognition can be a very complex area Cognitive changes can occur in Parkinson’s, but as I said, first and foremost, I will talk about some things that some people in their Parkinson’s journey may never ever experience So it’s important always to keep that in mind The frequency estimates of cognitive changes in the literature really vary quite a bit We think of mild changes, which could be slowing in thinking or slower processing, kind of like slower movements In more recent years, we’ve defined this as an entity called mild cognitive impairment, such as people may have mild changes, but they don’t necessarily affect their day to day, they might not affect their work or their hobbies, or their independence and activities of daily living And in some studies, this could occur in about 20 to 50% of patients These mild deficits might even be present at the time of diagnosis or an early stages And they may relate to some of the underpinnings of Parkinson’s, as well as the low dopaminergic state So having a loss of dopamine When people have more severe cognitive changes, and they affect more than one of those domains that I mentioned, to the point that they impact everyday function, such as difficulty with work or finances or cooking or driving or other activities, we call that a dementia About 40% of people with Parkinson’s depending on the studies may experience a dementia syndrome This is more common when people have Parkinson’s for more and more years, so we have more advanced disease But again, and I really mentioned this drive this point home that it’s very important to talk about these symptoms and have education and awareness and know what therapies are available But really that not every person with Parkinson’s will develop cognitive impairment or dementia or really any of the behavioral symptoms I might mention today So I just wanna turn, we’re going to switch gears and go through some of these symptoms as a broad overview, but let’s talk about depression So depression is a mood symptom, and it can be quite common Its frequency on average in Parkinson’s is about 40% But the estimates vary quite a bit in the literature We’ve now recognized that depression and anxiety which I’ll talk about in a moment, can even be a manifestation of Parkinson’s long before someone has a tremor or slowness or stiffness those motor symptoms that we used to define Parkinson’s, and so we think it can be part of this pre-motor or prodromal phase of Parkinson’s related to changes

already going on in the brain particular area called the brainstem, and changes in neuro chemicals such as serotonin, or norepinephrine, and even dopamine We know that depression can have this intrinsic relationship to the neurobiology of Parkinson’s But it also can occur as a reaction to many elements such as getting the new diagnosis, or changes in function or changes over time So it’s important for us to understand all those elements The common symptoms that we’ve seen people experiencing depression include sadness, sometimes decreased interest, or we call that anhedonia and anxiety Depression and Parkinson’s can often be what we call subsyndromal, meaning we know it’s present, but it might not meet the threshold of some of the criteria that are used in psychiatry literature to define depression Now depression can also have what we call motor, somatic or body and cognitive components And it’s important to recognize those because some of those can go hand in hand with Parkinson’s symptoms themselves, such that someone might have reduced facial expressions ’cause they’re not smiling as much Or we can also see that in Parkinson’s itself People can have changes in sleep, such as too much sleep, too little sleep, changes in their appetite in both directions, as well as slower responses And sometimes that can overlap with symptoms related to Parkinson’s itself Now, anxiety is another mood symptom associated with Parkinson’s And it too can be common, but it also can be very under recognized And I think one of the take homes from us talking about these cognitive and non-motor behavior symptoms is people don’t necessary Certainly always ask So it’s important to also give people with Parkinson’s and their care partners tools to bring them up, bring them up, so the clinician to your health care provider that these symptoms might be occurring So anxieties frequency is about five to 40% in the literature, and it kind of depends on how that studies are conducted and who they assessed and how they assess them But it’s been thought that about a third of people with Parkinson’s might have two or more anxiety disorders that we define in these contexts as listed below So anxiety can occur as part of depression It can also be part of something called generalized anxiety disorder, where people may have excessive worry or nervousness or tension It can be part of panic disorder It can be part of phobias, such as fear of going outside or being in social environments, and anxiety can also be part of the obsessive compulsive disorder spectrum (indistinct) is listed here, the two that are most commonly found in Parkinson’s include generalized anxiety disorders, and phobias And we know that anxiety sometimes can have this vicious cycle approach with tremor or Parkinson’s symptoms such that any sort of excitement, good excitement, cheering or anxiety can increase tremor But we also know that when people are anxious, they might have more tremor, or they might, you know, have concerns about situational anxiety such as crossing the street, or worrying about freezing or having their medicines on time So we recognize all of those too Anxiety also has a special place in the Parkinson’s symptoms and management because it can occur in a situation called non-motor fluctuations, particularly in an off state So it’s we’re much more likely, perhaps to ask about wearing off in the motor context, if someone’s medicines are not lasting from dose to dose, they might notice more slowness or more trouble walking, or more tremor But similarly, people can actually have non-motor fluctuations, such as before their next dose, they might be more anxious, they might even feel like they’re gonna have a panic attack and have shortness of breath or sweating, or palpitations, they might even feel a little bit more depressed And that has to do with a cycle of dopamine and the levels in the blood and getting up to the brain that vary with this fluctuations So very important to recognize those So as we go through some of these symptoms, I’m gonna move into the behavioral symptoms now And this is, gonna start with apathy So apathy is defined technically as a primary loss of motivation Sometimes people will say, you know, it’s their get up and go, got up and left

But apathy has an intersection with both behavior, cognitive and mood And actually, it can be quite common with estimates of its frequency from about 15 to 70% Interestingly, apathy can overlap with depression, so loss of interest, loss of motivation, but it can often be distinct So it’s helpful to try to tease them out as as best that we can to differentiate depression from apathy Apathy can be associated with decreased functional independence, so not doing activities, reduced initiation or participation in activities And this is something often as a clinician, we hear more from the care partner, sometimes more from the spouse of the person living with Parkinson’s, ’cause it might be more troublesome And this is where it’s so important to include both parties and the whole team to address some of the psychosocial issues aspects or resultant factors such as from apathy or other behavioral symptoms, as we know this can affect the quality of life and relationships of people The next behavioral symptom that I would talk about is psychosis And psychosis really represents a broad spectrum So it includes several different symptoms that fall under this umbrella called psychosis They include illusions, which are misperceptions, so looking at something, but something’s really there, but it looks like something else So looking at perhaps a tree, and it looks like a lamppost or four legs of a chair, and it looks like a dog or different patterns This is distinct from hallucinations, where someone might see something but there’s not really anything there Hallucinations tend to be visual but they can occur in other sensory modalities that I’ll talk about in a moment But often they’re described as seeing something out of the corner of one’s eye, it’s very quick, lasting only seconds might have movement, animals, small children And sometimes people can keep insight so they’ll know it’s not real, or they can turn their attention to something else, and recognize that what they were seeing wasn’t really there The third part of psychosis is something called delusions, which are far less common, maybe more common, when there’s also cognitive impairment or dementia, and these are false beliefs So thinking something’s really happening when it’s really not, they tend to include thoughts of paranoia, or suspiciousness or infidelity as well Now we know that psychosis can occur in Parkinson’s there are a number of contributors, some of which could be medications, older age, longer Parkinson’s duration and the presence of difficulties with cognition and sleep So it may have a multifactorial etiology As I said before, visual hallucinations tend to be the most common that we see or hear about But sometimes people may experience these in the auditory system like hearing music, or hearing voices, smelling things that aren’t necessarily there So it’s important for clinicians to ask about all these different circumstances Again, not everyone will experience the situations or behaviors And I do wanna mention that psychosis in Parkinson’s is quite different from psychosis in case you hear about it in psychiatric conditions, such as schizophrenia, or even in depression, with psychotic features So they have very different symptoms and very different contexts The last behavioral symptom that I wanna touch upon is something called impulse control disorders, and this also represents a range of behaviors that include the four most common ones that we see But there may be others And these are pathological gambling, compulsive shopping, hypersexuality, or increase libido in sex drive and binge eating They’re less common, but frequencies have ranged to up to about 10% What they share is that they’re repetitive and reward seeking behaviors What they link to Parkinson’s about is ’cause they’re linked to dopamine So in a sense, when we treat people with Parkinson’s with dopaminergic medicines, sometimes that dopamine increases the drive to the reward system too much and it produces impulse control behaviors that really are often driven by the medications that we use to treat the motor and other symptoms

This can be common in medicines called dopamine agonists, but also other Parkinson’s, dopamine medicines However, there may be some risk factors, such that people may have a prior history of psychiatric disorders or addiction, they may have some cognitive changes and have impaired decision making that helped, you know, contribute to the presence of these impulse control disorders Much of the time when someone stops the drug or lowers the dose, these types of behaviors can go away or remit So now that we covered the basics on some of the cognitive and non-motor behavior symptoms, I wanna move on and talk a little bit about some other strategies and pointers here So number two, I think it’s important to know that the field of Parkinson’s is continually evolving And I just wanna share a couple examples with you on that So I mentioned before this pre-motor or prodromal period when we’re talking about depression and anxiety, and really we too get smarter and smarter as we learn about the science and neuroscience of Parkinson’s and our treatment So what we’ve now recognized is these non-motor symptoms may occur years or decades before the motor symptoms And this has redefined how we think about Parkinson’s and how we can think about disease modifying strategies and times to intervene, such that we can aim to have drugs that address very early symptoms, or perhaps alter the course of Parkinson’s This has led to new definitions just to highlight this here with research criteria for prodromal Parkinson’s, and rethinking how we define Parkinson’s, which opens up our windows of opportunity for thinking about disease modifying strategies We’ve also come to realize that many of these neuropsychiatric symptoms that I’m talking about are part of Parkinson’s or can be part of Parkinson’s And I like this slide from a number of years ago it focuses on publications, but it just shows you how the tremendous increase over the decades of research has focused on these cognitive and behavioral symptoms here And that really, these are part of Parkinson’s, which goes well beyond motor disorder And then lastly, just to keep up with the times, this is hot off the presses, as we think about redefining Parkinson’s, a publication that just came out a week or two ago redefining the faces and images of Parkinson’s to broaden it across a greater diversity of the population Okay, so my point number three is to recognize your individuality often represented by how snowflakes, one is not like another And we know that in Parkinson’s, each person is unique in his or her journey Not everyone will experience the same symptoms We know that people have differences in their progression And this may be resulting from a whole variety of factors, their genetics, their environment, their personality, their medical history, and many other facets And this goes for the cognitive and behavioral symptoms that I’ve been speaking about as well So there’s this thing, which I do think remains true is that if you’ve met one person with Parkinson’s, you’ve met one person with Parkinson’s So your individuality may play a role in the symptoms that you may experience as well as perhaps the treatments that are best for you We know in a couple of examples here, that cognitive and behavioral symptoms can be associated with different clinical motor symptoms So there’s some literature suggesting, although not exclusively, that people who have more difficulty with their postural stability or their balance and more gait rather than tremor may experience more cognitive or behavioral symptoms We’ve also learned that there might even be gender differences such that female people, female patients or women living with Parkinson’s may exhibit greater mood and apathy symptoms Genetics too may play a role and there are several genetic mutations listed below and alpha-synuclein, glucocerebroside or GBA that may be linked to greater cognitive or neuro psychiatric symptoms And then APOEe4 has been a little bit conflicting in the literature, but represents a susceptibility factor with the e4s in Alzheimer’s and it may also play

a role in cognitive symptoms in Parkinson’s all that may still be controversial or conflicting Here you can see in the diagram, which is taken from literature not related to Parkinson’s, but related to cognitive changes in the general population When we think about what we individually bring to the table, there may be individual risk factors and individual protective factors And some of these are modifiable, some of these we may have some control over like our diet, whether or not we drink alcohol or smoke or have diabetes, how much physical and cognitive activity we do So there may be modified risk factors that we individually can work on to help alleviate or ideally prevent some of these cognitive and behavioral symptoms So my next point is to focus on building your care team And this is something that I think I could probably talk a ton about but it’s really important in Parkinson’s because there it can affect many dimensions, not only physically, but with the cognitive and behavioral symptoms we’re talking about And the other ones I’m not going to include in my lecture, like constipation or bladder dysfunction, vision changes, that it really takes an integrated approach with a team of providers So not one person can address all of this alone, and it really speaks to having a team approach This team approach gives a deeper dive, a deeper investigation into the motor and non-motor symptoms, and helps people living with Parkinson’s explore the treatment options from many different perspectives, both medication, surgical, non-pharmacological and even others It helps provide objective and data driven information that we can use to inform our clinical decision making And helps people manage and assess their symptoms over time So there are a number of studies that show that there’s great benefits for teamwork for patients and their care partners too, in order to address all these different elements, as well as even the psychosocial elements of how this affects people living with Parkinson’s, their relationships, work, hobbies, and others And I will say as someone who practices in an interdisciplinary care team setting there are great benefits for us as healthcare providers, to learn from our colleagues and be able to tackle issues from multiple different perspectives So my next point is to take a multifaceted approach to management And going through all the treatment regimens and ideas would take a whole nother talk into itself So I just wanna provide some considerations and pointers for cognitive behavioral issues in particular So it’s very helpful and important to have objective assessments at baseline And to follow these over time We do a lot of this on the motor front So we’ll do finger tapping and other walking tasks And we often do those on every visit It’s helpful to have a check in even once a year, or perhaps more frequently on how someone’s objective cognitive and mood symptoms are doing And there are a number of ways that we can do this either in the clinic or working with neuro psychology, working with our speech language pathologists, to assess cognition If people are having problems in these areas, it’s also important to exclude other causes So are there medical syndromes or complications that are contributing to a decline in thinking or just psychosis, someone having an infection urinary tract infection that might have triggered the acute onset of hallucinations We need to review medications for both Parkinson’s and non Parkinson’s reasons because sometimes these can lend themselves to confusion or hallucinations or psychosis Those might be pain medicines, or bladder dysfunction medicines It’s important to think about management strategies, and I’ll talk a little bit about medications and non pharmacologic strategies And again to have this multifascinating approach Whenever we talk about cognition and behavior, in Parkinson’s, we should also address day to day activities, whether that’s work, driving, safety in the home environment, and in that interdisciplinary or multidisciplinary care team to address adjustments in the psychosocial impact of these changes So we wanna broaden the care team for the person with Parkinson’s in their care partner

across the management of these cognitive and behavioral symptoms Just go back Okay, I just wanted to go back to this slide to talk a little bit about medication management And this could be a whole course unto itself So I listed all the symptoms that we talked about before, and a few of the treatments that we have that are FDA approved, and others that we might consider So for dimension Parkinson’s, there’s one medicine that’s FDA approved, and that’s called Rivastigmine or Exelon, and it’s a colon esterase inhibitor as a type of medicine And that has been studied in trials to help with cognition and thinking For mild cognitive impairment, they have been a number of studies but to date, there hasn’t been a medicine that has come through with meeting the clinical trial outcomes that were planned But we think about medications and we think about strategies to enhance cognition, including working with cognitive activities, occupational therapy, speech therapy, brain games, and exercise, which we’ll talk about For depression, they’ve been a number of randomized controlled trials looking at antidepressants in Parkinson’s Most of these medicines are really drawn from the general population So there’s not a specific antidepressant that is linked to Parkinson’s treatment per se But we do know these medicines which are often selective serotonin reuptake inhibitors, or serotonin norepinephrine reuptake inhibitors that SSRIs and SNRIs can be highly effective in treating depression Depression is a very treatable symptom We often work with our psychiatry team and geriatric psychiatrists, primary care doctors to manage these depression symptoms Similarly, these SSRI and SNRI medications often work well in anxiety So we know that we can help manage anxiety with medications We may also think of specific medicines for that are called anxioltics Sometimes they can have side effects that can affect balance or thinking So we wanna use some of these very cautiously And again, working on situational anxieties to help alleviate or work around specific situations that might be triggering anxiety For psychosis, we very often start by looking at the Parkinson’s medication regimen and its adjustments So we might need to lower doses of dopaminergic medication reduce them or perhaps stop certain medicines that we are using to treat the motor symptoms And this is taking approach that balances the motor and the mental function In the U.S. Pimavanserin or Nuplazid is FDA approved for the treatment of Parkinson’s related psychosis There are other medications that have been used off label and studied to help treat psychosis as well, including Quetiapine and Clozapine As I mentioned before, for impulse control disorders, one of the first things that we would do would be to counsel a patient about these medications and potential side effects, but really to reduce or withdraw that particular medicine, such as a dopamine agonist, such as pramipexole, or (indistinct), for example And often by reducing and potentially discontinuing that medicine, we can stop those impulse control behaviors But this can take a team approach and working with a psychiatrist for other strategies as well Apathy is one of our trickier behavioral symptoms to treat And it often takes a combination of thinking about how it can be helped by different dopaminergic medicines, the antidepressants, and even the cognitive enhancing medicines like Rivastigmine that I mentioned for cognitive changes Specifically, in depression, there has been a lot of work done looking at a specific technique called cognitive behavioral therapy Here you can see two studies that illustrate the benefit of cognitive behavioral therapy which is geared towards reframing our thoughts and our behaviors and actions So working on kind of deconstructing why we might have these negative thoughts and reframing them into something that’s more than that constructive

This has now been looked at using a telephone based approach And in this in both of these studies, the cognitive behavioral therapy improved scores on depression rating scales And in the telephone group, it outperformed what is abbreviated as TAU treatment as usual on all depression, anxiety and quality of life measures This is often done by a psychologist, a specific counselor with training as well, but can be very effective in combination or solo to medications for depression So turning to exercise Exercise is one of those areas that we know helps with so much in Parkinson’s, so it certainly helps with motor function And as you’ll see many of these non-motor symptoms So I just put up here some of the guidelines from the CDC regarding what people should be doing for regular exercise So that’s 150 minutes per week of moderate intensity exercise, done as listed below So a minimum of moderate intensity aerobic plus two or more days of strengthening, or perhaps a high intensity workout and two or more days of strengthening, or an equivalent mix of moderate and high in two or more days of strengthening And again, talk with your doctor if anyone has any medical issues Talk with your doctor about getting started on your exercise regimen But what we also know is that exercise can help motor function but it can help cognition as well This is one example of a study that I was involved in looking at 51 people with Parkinson’s who didn’t have any significant cognitive issues at the time of the study, and they tried two different types of physical exercise So they had a progressive resistance exercise training protocol, or a more general, kind of what’s called modified fitness count exercise protocol And what they found is both groups in exercise had improved cognitive performance in some of those domains that I mentioned earlier in the talk So exercise is good for the brain Exercise is also good for people’s mood And this is a compilation of a number of different studies of different sizes So as you can see here, some of them had very small numbers of participants all the way up to 231 Looking at depression, finding in most of these studies that exercise physical exercise had an impact on reducing depression More recently, there have been some studies looking at yoga, versus in this case, stretching and resistance training exercises on anxiety and depression in a clinical trial And so in this Randomized Clinical Trial or RCT, for eight weeks, the group looked at mindfulness yoga versus stretching and resistance training in 138 people with mild to moderate Parkinson’s, and they administered clinical rating scale, looking at anxiety and depression, what they found was, the therapies were both effective and safe But interestingly, yoga performed better than the stretching and resistance training on its effects on anxiety and depression, perceived hardship and health related quality of life The next point I wanted to make is geared to maximize function and quality of life And so it’s helpful and important to take a look at your everyday activities Whether that involves self care, leisure, things in the house or work and think about how cognitive and mood symptoms might play a role We can strategize so we can work with people to help plan their day, help them expend energy so they can do the things that they wanna do and balance out some of the symptoms, whether they’re cognitive or apathy or fatigue Often this is where the role of an occupational therapist might come in And interestingly, not as many people in the world as you can see by the United Kingdom survey, the Dutch survey and United States data are often referred to as occupational therapists So somewhere between 10 to 25% of people, but occupational therapists, number studies support this can help support better functioning of people with Parkinson’s in their day to day activities, planning them coming up with strategies, I keeping track of them and looking at fatigue and energy conservatives strategies

There are also a number of tips and tricks There’s a great role and a growing role for technology in utilizing ways to remember medicines or, you know, pay your bills or plan your day But don’t forget the simple so often just keeping a list or a Post It Note can be just as good as a fancy Gizmo or gadget But there’s no shortage of gadgets and apps to help with medication reminders, adaptive equipment, augmentive technology and communication to even help with speech volume or speech recordings And now we’re moving into the world of wearable sensors, where we can actually have real time monitoring such as for falls and alert symptoms, systems and perhaps also for these cognitive and behavioral symptoms So again, just a reminder to be creative and there Many solutions that can can play a role All right, we’re coming towards the end here The eighth point is that it takes two or more people to tango And this is a plug for looking at relationships and more, particularly when we’re talking about cognitive and behavioral issues So it’s essential to recognize the potential for caregiver stress, worry about these symptoms or living with someone who is experiencing these symptoms This is more common with advanced Parkinson’s with greater motor symptoms and with greater presence of neuro psychiatric symptoms, such as dementia, or psychosis or many of the other ones that I mentioned We need to address these caregiver challenges and stress across all stages of Parkinson’s We need to consider how having these symptoms and having Parkinson’s might affect Changes in roles what people were doing in a relationship and adjusting to a new normal Parkinson’s can affect the whole family, not only the spouse and the significant other, but other people, friends and family And so with someone experiencing cognitive changes or apathy, we wanna work to help maximize, you know, getting out and being engaged or being social It’s helpful to plan ahead and to maintain healthy coping skills, and again, not being afraid to ask for help There are many resources and ways to connect particularly with people who are the care partners joining us today They include the Parkinson’s team Again, this may also include a social worker, psychologist, Counselor, spiritual personnel as well Their numerous support groups, community networks in Parkinson’s foundations who can help with these cognitive and behavioral symptoms A few particular strategies for coping to help take control Again, these can be high tech or low tech, but making checklists for specific tasks So remembering medications or meals or exercise, when to do it and put it on the calendar Using Post It Notes as reminders around your house, keeping assistive devices like a (indistinct) or Walker within your line of vision, so remember to use it when you go to walk Often people if they have cognitive changes can have trouble with accessing or retrieving information, but it might be there it might take longer So often, giving cues can be helpful or given choices rather than open ended questions There are many different memory strategies that can be employed Again, asking for help we call those human reminders Having a routine is very important, particularly if there can be cognitive changes, apathy, sleep disturbances, getting enough sleep can often help too with many of these mood symptoms And again, being kind to yourself and practicing gratitude can help with some of the mood symptoms as well And empowering people to address and tackle these situations So a few thought for the caregivers in the audience, particularly in light of cognitive and behavioral symptoms, is to take time for yourself and to be kind to yourself too To build in breaks, building breaks in your day, and to create your own support system too Find ways to express your feelings, whether that’s at a support group or friends therapist in a journal, that can be often helpful, particularly if someone’s experiencing these cognitive and behavioral changes Sometimes, such as in psychosis or in other behavioral symptoms, it’s important to recognize that it’s sometimes the disease talking not your loved one

Again, education and support and cherishing those moments and practicing gratitude Just a plug to participate in research because this helps us advance our field and have more drugs and therapeutics to help treat the symptoms and give more options to people Many current research studies could be found on ClinicalTrials.gov And in terms of research, there can be an important role for people with Parkinson’s to participate This is a growing area of engagement And we really need to you know, work on this together, whether it’s for motor symptoms or cognitive and behavioral symptoms And this slide just illustrates a couple ways that people with Parkinson’s and their caregivers have been involved in research from setting the agenda to help developing research questions, working on study design and more And this really is a way of medicine that is changing and becoming more of a participatory medicine, where people are involved in the actual process and are partners with clinicians and researchers There are many benefits to this and including promoting growth and well being that have been looked at in a variety of different literature, fashions but really having patients engaged in research is critical to our pipeline Lastly, to keep up hope, so we know that in just a pull one area here, this is from a very recent paper that looked at drugs under study in So active Parkinson’s drug trials this year from January to close to current These are many different drugs that are in the pipeline of study, whether they’re disease modifying therapies or symptomatic therapies, and on this talk on cognition and behavior, which often are non dopaminergic So they’re related to different brain chemicals, acetylcholine, serotonin, norepinephrine, rather than the dopaminergic motor symptoms Here you can see in green, here in the bottom part, all the different compounds that are being studied for these types of symptoms And, you know, about 30 to 40% are in phase two and phase three trials And lastly, no matter where someone is in their journey with Parkinson’s, whether it’s early stages or middle or more later stages, there is something that I think we can always offer, whether it’s medications or therapies, counseling, palliative care for all these non-motor symptoms and cognitive and behavioral symptoms, we have that education and awareness dialogue with their care team There’s something that we can offer And so with that we put together a slide that illustrates many of these cognitive and behavioral symptoms And I will thank you for your attention Appreciate your attending this talk And this is just a glimpse of where I work here at Shirley Ryan AbilityLab and Northwestern in Chicago Thank you so much (lighthearted music) Thank you all for attending the APDA Midwest Congress, both yesterday and today, and hope this has been very educational for you It’s been my pleasure to be part of this So we have a number of questions that were submitted And thank you all for is really terrific questions So I’ll read them and answer them And one of the first questions regarding the non-motor fluctuations that I mentioned for which anxiety and sometimes also depression can be part of, and so this person asked if I am experiencing anxiety, when my medications are wearing off, what might I need to do? And I think there are a couple thoughts on this And these could be brought to this person’s medical care team for further discussion, but sometimes it’s helpful to keep a diary, to understand when symptoms are occurring

in relationship to their timing with the Parkinson’s medicines, we often think about doing this for motor features or motor complications like dyskinesia and wearing off But it can also be helpful for anxiety or mood symptoms with that cycle And for some, that means if people are experiencing wearing off mood changes, like anxiety or depression, we might want to adjust the frequency of the Parkinson’s medicine or the dose of medicine or have something that perhaps is more smoother acting that gives a longer duration So those are a couple different strategies, often that might need to be combined with medications to to treat the anxiety or depression, as well and some of the non pharmacologic strategies I mentioned in my talk So thank you for that great question Another question had to do with the medications that can be associated with some of these non-motor behaviors, like hallucinations, or impulse control behaviors Now, we know that to some degree medications that increase dopamine or enhance dopaminergic transmission in the brain also act on some of that reward and pleasure circuitry that I mentioned So on one hand, any medicine that has anything to do with increasing dopamine could have this as a potential side effect However, what we also know is that certain dopamine receptors in the brain have different characteristics And some of these receptors are found in areas of the brain that are very involved in cognition, thinking, emotional response, and they’re part of our cortical limbic circuitry and in some cases, the dopamine agonists may favorably interact with these types of receptors often called the D2 and D3 dopamine receptors So there may be a higher, potential higher likelihood with some of those medicines But again, it’s a much more complex questions So it’s not as simple as just one medicine versus another But it’s really putting the whole picture together with someone’s level of cognition, their abilities, their medical history, psychiatric history, addiction history, and so on and so forth So thank you for that important question Another question came up to talk about different strategies for mild cognitive impairment And this is certainly something I could talk about for a long time near and dear to my work in my career And there’s a growing emerging studies in terms of cognitive therapy, so there’s not a uniform or standard or evidence based program for cognitive therapy But this is a growing area And I think some of these trials that we see engage in cognitive rehabilitation therapies, learning different strategies, perhaps for tasks that involve attention, or recall or memory They may include cognitive exercises, or brain games, many of these you may see on various computer programs or apps on one’s phone or iPad And I think what we’re trying to learn is how useful they are, and is their carryover So if we train our brains to be much better at one task, does it make a difference on all those other tasks and how does it play out in the real world? This is an area often that speech language pathologists and occupational therapists can be helpful in helping someone with these therapies Another question had to do with support and resources for spouses who may be living with someone who has compulsive behaviors And now, there may be a great role for support groups and other resources geared towards Parkinson’s symptoms So Parkinson’s support groups certainly could play a role in this area Often will work with psychiatrists or psychologists who may play a role And then other behavioral groups So even drawing from people’s experience in addiction or other conditions that are not Parkinson’s, but may be helpful for these sorts of impulsive and impulse control behaviors Okay, so another question that came up

And thank you all for sending these questions are terrific Has to do with cognitive problems and couldn’t even mimic other conditions such as attention deficit disorder And because some of the areas we see that can be affected in cognition and Parkinson’s may relate to attention So paying attention concentrating on a task, keeping multiple items in one’s head, as we’re trying to do other things like working memory, or executive function that I spoke about with planning and organizing and multitasking, there can be quite an overlap in terms of these types of symptoms What they share in common, in part has to do with the different regions of the brain that are affected, that are highly involved in allowing us to pay attention and concentrate or having trouble with that, and that’s part of the frontal area of the brain, particularly the prefrontal area So often cognitive symptoms can mimic some of these other attentional disorders, which can occur in a variety of neurologic condition So we might need to tease that out And sometimes objective testing might be helpful, working with neuro psychologists might be helpful and so forth, great Again, talking about some of the cognitive problems and this question has to do with if someone has cognitive problems, can they last for days or weeks and then that person might snap back into a better state, if you will? And there is something called fluctuations So we often think about this in terms of motor function, but there are also fluctuations in cognition that can occur and these may be periods of fluctuations and levels of attention or arousal or alertness And for some, when people might be experiencing more significant cognitive impairment, they may be coupled with these fluctuations These fluctuations are also found in conditions that fall under the umbrella of Lewy body dementia That includes Parkinson’s disease dementia, and also a related condition called dementia with Lewy bodies where fluctuations can be prominent and this may present as someone you know, being very clear at times, and then perhaps their thinking is not as sharp or maybe a little bit more muddled, you know, a day here are a couple days or weeks and then people may go back to their more lucid state I will say that if someone is experiencing acute changes in their cognition or acute changes, such as psychosis or hallucinations If it’s often important to investigate if there’s something else going on And that’s we’re looking at infections like urinary tract infections, new medications, adjustments, even in the Parkinson’s medicine doses, could they have been changed and is that a contributor to this acute onset or this fluctuation? Okay, so some of the, great So one question has to do with non medication interventions, which often play an essential role in the therapeutic management for cognitive and non-motor behavioral symptoms, either alone or in conjunction with medications And so this question has to do with psychosis, wondering if there are any non medication interventions, and there are some So there are some things that have been helpful for people experiencing psychosis We know that for many hallucinations occur in the visual system or visual hallucinations, and they might be more present when it’s darker out or in the evening hours, or when there’s not as great contrast between light and dark So for some having a nightlight in the hallway or at night, light that turns on automatically in the hallway could be helpful and could help illuminate the path or reduce shadows or changes in perception So that’s one particular strategy There have been other coping strategies that have been studied and published, including people who have taken to art to actually depict their hallucinations, whether it’s watercolor or drawing or painting, and for some that can be variable therapeutic

And then of course, you know, even anecdotally, I’ve had people make up a story about them, and have a name to go with the person who might be visiting who’s not really there And so there are all sorts of creative coping strategies that can help people can navigate this There are other situations So this is a question about agitation And for this question, this person asks about episodes of extreme agitation and what to do about that And so for some people, I particularly in more advanced disease or with greater dementia symptoms, people might also experience agitation And this is one of those areas where trying to figure out what might be the cause might be helpful So sometimes if it’s hard for people to express themselves, verbally, they may have other behavior manifestations that come out to try to convey what’s going on So is someone in pain? Do they need to go to the bathroom? Is there something that’s bothering them? So I’m trying to get a sense of that as best as possible to understand if the agitation might be linked to certain times of the day There’s a phenomenon called sundowning, such as when the sun goes down People may have some behavioral changes or confusion And there are other medications might be used to reduce agitation Again, working with someone’s physician, neurologist, psychiatrist can be helpful in that regard One question someone asked about the use of electroconvulsive therapy or ECT to treat extreme depression and Parkinson’s and thank you for that question I did not talk about other modalities outside of medication and psychotherapy or cognitive behavioral therapy for depression But there is been, there may be a role for what we call neuromodulation or ECT for depression that’s refractory to medications, such as with transcranial magnetic stimulation or TMS and then for refractory cases ECT And then again would be a conversation with a psychiatrist and the psychiatric team ECT has been shown in some older studies on in its treatment of depression, but there are some side effects and cautions to be wary of that might affect temporary confusion and behavior So again, under medical guidance Another question that came up, that seemed to be a popular question here had to do with recommendations for off periods And I think thinking about off periods, we wanna think about are they the motor symptoms, or the non-motor symptoms that are part of the off period And some of those strategies globally are trying to smooth out the day So smooth out the Parkinson’s regimen, whether that’s with different doses or shorter intervals, reduced frequency, longer acting agents that cover the day, or even surgical interventions So I think there are a number of strategies that can be helpful for off periods So with that, I’d like to close and thank you so much for your attention and joining us here today (lighthearted music) – Hi everyone, we are going to do some breathing exercises

and singing exercises and then sing a song to help us practice using our lungs and our voice So first we’re gonna start off with some breathing exercises, what we will do is I’ll start a metronome and then we are going to say Z, should quickly Two Zs for every click that you hear So let me get my metronome out (beeps) That everyone can hear And so, will breathe out for four, breathe in for four, and then two Zs for every click that you hear so ready, breathe out and (blows) Breathe in Okay We’ll do that again And I let the timer go on for about a minute just so when you run out of air, it’s not gonna be the same time as when I run out of air So, just to give you that extra time getting nor towards, all right, so we’ll do that again Just go until you run out of breath Don’t pass out or anything, but do try to challenge yourself So breathe out and I’ll count to four, ready and (beeps) (blows) Breathe in All right, very nice work, everyone Okay, our next exercise we’re gonna do is a familiar one for most of you that are singing with us in the choir It’s ♪ I know, I know, I know, I know ♪ This helps with breath control This helps with the muscles in your throat, especially that epiglottis that we’ve talked about before in these videos that is so important for swallowing It also helps with pitch range, which helps in just everyday’s speech You don’t wanna have a voice where you just say you speak everything at one pitch level, or one note, I should say All right, so we’re gonna sing ♪ I know, I know, I know, I know ♪ When you’ll release your arms, you’ll sing ♪ I know, I know, I know, I know ♪ So we’ll do that one more time starting in, starting a scale or pitch, so ♪ I know, I know, I know, I know ♪ ♪ I know, I know, I know, I know ♪ ♪ I know, I know, I know, I know ♪ ♪ I know, I know, I know, I know ♪

(lighthearted music) – Hello, everyone, thank you so much for joining us My name is Tao Xie I’m an associate professor in urology I’m the Director of Movement Disorder Clinic and it’s DBS Program and also the director of I/R Center of APDA at the University of Chicago Medicine Today, I’m gonna share with you my talk on deep brain stimulation in Parkinson disease, optimal patient selection limitations and the new developments This is my disclosure There’s no conflict of interest to the contact I’m gonna talk today The education objectives today will cover indication with DBS, which is about what DBS can help and then what target should we choose, if so? And also what’s the limitation of DBS? What DBS cannot help and other potential issues? And what’s the new developments we have had so far to make the DBS better in terms of better symptomatic control less side effects or less complications, et cetera So what’s the DBS? DBS, deep brain stimulation Stimulating a specific area in the deep brain Those area we also called the nucleus are very important to coordinate and control movement Specifically, there are three targets approved by FDA First one was VIM, ventral intermediate nucleus for treating medication refractory tremor, the trauma can be from essential tremor, or Parkinsonian tremor since 1997 The second one is STN, subthalamic nucleus, and otherwise the GPi, Globus pallidus internal for treating Parkinson’s disease since 2002 And the GPi is also approved for treating dystonia in 2003 And we also know that STN can also be used to treat a certain dystonia and Parkinson’s disease This is a location as you can see on the right side of the slide, this is VIM, this is STN, and this is a GPi Today we’re gonna focus STN and GPi for Parkinson disease So, this is the sagittal view As you can see, this is the VRM in the thelamus, this is the STN below the thelamus and this is the GPi So when we talk about stimulating the nucleus in fact, we not only just a nucleus we also stimulated the fibers connected in nucleus connected to the widespread area of the brain, including important sensory motor cortex and other structures in this way, only in this way it sounds like possible when you’re still in such a small area, you can have a huge clinical benefit Then the question is, how do we put the DBS electrode First of all, we have to identify the target by an atomic target, electrophysiological target and then eventually we have to verify that the stimulation into the types of works Works meaning that it can control the symptom Parkinson disease Parkinsonian syndrome or Parkinsonism And also without any side effects or complications So specifically, we have to get a brain MRI first and also had a CT with step through tactic frame and then we merge them together and then overlapped by an atomic address, which will help us to identify the anatomic target and then we send a needle size or smaller probe down towards that target In the meantime, we’ll also record the signature

neuro will discharge to make sure that the anatomic target also fits the physiological target And once we get there, then we place the probe with the stimulator device, the electrode and then we stimulated the patient Make sure that all the symptom we want control can be get control immediately, including trauma, it can immediacy, the trauma stop in the operating room, and other symptom like rigidity and the bradykinesia can also be see improved when you test it And that’s not enough We also have to make sure that there’s no side effects or complication when you stimulate just those target What if we encounter some issues for example, you feel the symptom controlled right in the meantime you also feel numbness, tingling or pouring sensation or vision problem or abnormal sweating et cetera Then based on this symptom, we know where we should adjust can move around the target about a one to two millimeter and to get rid of this complications, we will not find the right target until we get the maximum therapeutic benefit and sensor people window with no side effects with normal stimulating parameters Once we finalize the placement of the electrode, then we also need to put to the battery also called the impulse generate IPG on the scaling of the interior Chester below the collarbone area and then connect this battery to the electrode and then by programming this battery, we can send a signal to the brain and control the various movements or coordinated abnormal movements in Parkinson patients The parameter we send to control the including the pulse rate, the voltage and stimulating frequency So why do we need a DBS for patients with Parkinson disease? Parkinson disease patient symptom parkinsonism particularly the cardinal symptom of bradykinesia, resting trauma and the rigidity usually respond very well to dopaminergic medication particularly over the first five, seven years but as time goes on, the patient developed a motor complication with rapid wearing off the medication feels like last shorter in duration and then with quicker retelling of the parkinsonian symptom And also when the medication is on the patient develop dyskinesia, which is a an excessive involuntarily intensive like a movement If you watch TV and Michael J. Fox, you know what is like they can be on your neck, arm or leg or trunk or throughout the body, which initially can be managed by medication adjustment, but as time goes it become more and more difficult to be well controlled, then you need to consider deeper brain stimulation And also, trauma may not always respond well to medication to current available, terminological medication, even some anticholinergic medication, but some patients somehow never respond to any medication In those cases, you also need to consider DBS So then who is the candidate? What’s the DBS criteria? In general, they should have good response to levodopa because the rough rate of the amount of the extent of the response to the medication to turn the extent of response to the deeper brain stimulation Patient still has good respond to levodopa, particularly bradykinesia rigidity and trauma, you don’t have to respond to the different medication, you still can be a candidate for DBS And then if you are also developed a symptom like a motor complication like we call rapid wearing off as just mentioned or dyskinesia, which is excessive in (indistinct) dancing like a movement Then you can consider DBS Also we would like to the patient has pockets in duration for more than four years to increase the confidence level of diagnostic certainty because some patient can mimic Parkinson disease, but may not be Parkinson’s disease, they can present with parkinsonism by infection may not be Parkinson’s disease but on so far

only Parkinson’s disease responds well to DBS So the patient also should not have a significant cognitive impairment such as dementia or should not have uncontrolled a psychiatric symptoms such as uncontrolled depression and psychosis Also, they should not have significant focal lesions in the brain to prevent from implanting electrodes, they should also have reasonably good healthy conditioning in heart (mumbles) lung and the general systemic, healthy to tolerate the surgery And also the patient and the family should have reasonable expectation for DBS with good family support for follow up programming after surgery So then, what’s the evidence on the beneficial effects of DBS? This is a one of the early people published in 2001, New England Journal Medicine It shows you that if we target the STN after the DBS follow up in six months, as you can see that the on period without dyskinesia significant improved from 27 to 74, and the off period from baseline 49, reduced to 19% in six months Similar improvement can also be seen from GPi Suggesting that STN and GPi GBS, reduce the off period and improve the on period without to dyskinesia impacts and patient DBS is also better than best medical therapy for PD as you can see a bunch of study there across more than 10 years period And Dr. Andrew Williams in UK did a meta analysis And this the data shows here suggesting that in selected patients basically based on the criteria we just mentioned, the patient always favors surgical treatment compared to physical medical therapy And particularly, as I mentioned that the trauma patient, even the trauma has not responded to the medication, they still responded to DBS very well, and that that’s also the case as you can see here, and according to this study, there’s no significant difference between STN and GPi in terms of trauma control after DBS Then the question you might have is which target is better, STN or GPi? This is a study compare these two target due to the limited time I will not go to detail, but the conclusion is that there’s no difference in motor function or self report reported function between these two groups Patient undergoing STN stimulation required a lower dose of (indistinct) medication than those undergoing GPi stimulation roughly after STN DBS patient can have reduced the dopamine medication by 20, by 30 to 50% But GPi usually don’t see much change or you have less than 20% of the reduction if you put all the different study paper together And cognitive function can be slightly worse, impatient with STN DBS in terms of visual motor function of processing speed But depression also worsened after the STN but improved after DBS duration I think the motor symptoms are similar between these two targets but non-motor symptom instruments depression probably selected for the GPi based on the study about medication reduction As more see STN that’s very important in the when select your targeted for individual patients depends what their problem is and what you would expect to target to improve For example, if the patient present Parkinson disease with good respond to medication by medication doses too high with medication, side effects, hallucination, proper job, et cetera then, STN probably is a good target because after the DBS you can reduce the medication and reduce this medication induced side effect Just as an example So the question you might have now is,

how early should I start the DBS Usually in older days we become patient with motor fluctuation average is about like four to five years after the onset of motor fluctuation of dyskinesia rapidly wearing off At that time, it was also usually about 11 to 13 years after the onset of Parkinson’s disease I mean, this is a study we call the Early Students Study published in February 2013, in Europe It shows that if you pick up a patient within two years of (indistinct) motor fluctuation at that time is about seven to eight years after the onset of the disease DBS compared to medical therapy significant improve the quality of life So they conclude that earliest stimulation can be used in patient with PD and early motor complication because as you can see here, the quality of life is better Another question you might ask is, what if we put a DBS for this patient without motor frustration? We call the early-early stimulation A study by the (indistinct) group, published paper 2018 and 2020, this neurology shows that earliest early stimulation in their pilot trial without a motor fluctuation in the two year and five year follow up can slow rest tremor progression and reducing medication need as you can see here, this is a two year study results The red bar stands for the medication therapy group As time goes the the tremor gradually progressing, they’re getting worse And also they found that tremor not only just total score but also spread it to the other side initially, without tremor, a wider DBS group, you don’t see a significant change over the two year period suggesting that the probe a DBS could also be beneficial in very early stage even without motor complications You know, this is still pilot trial more multi site trial is ongoing now So they’re not DBS sounds great, very effective in control, cardinal symptom of Parkinson’s disease, bradykinesia, rigidity and tremor and the motor fracture and bradykinesia However, DBS also has its limitations The benefits are axial symptom, such as swallowing function, freezing gait and balance is not very effective, particularly in the long-term can even be worse based on some meta analysis data And also there’s no direct effect on non-motor symptoms such as cognitive functioning, autonomic function, et cetera So, this is a well cited meta regression study of long-term effect the DBS on balance and gait and the cardinal symptom on the left A and C is medication off state, as you can see that with a five year follow up period, most STN GBS patient is doing well having no symptoms, (indistinct) rigidity and the resting tremor They are axial symptom balance and gait, gradually, gradually getting less effective Okay, almost close to the baseline at year five But when medication on stage, as you can see that the cardinal symptoms still respond to it but become less less beneficial, but the gait and the balance group once pass the two years they can even getting worse, particularly on the STN group But GPi probably will not get worse until five years after So it means that, you know, the axial symptom can graduate losses and then fed to the DBS as time goes particularly on medication assets And the study was supported by a bunch of other summaries study as well, I will not cover detail here

but that’s the overall impression So now, why it’s so difficult to treat it axial symptoms? Most likely because axial symptom is controlled by non-dopaminergic mechanism, Cholinergic as such as some study And so far our medication and targeted dopaminergic medications So then how we deal with this axial symptoms, what’s new or relatively new? There was one study published in Tucson a by a French group proposed that low frequency stimulation is around 60 hertz issues Some people say 80 most people use 60 hertz compared to high frequency stimulation, which is the usual stimulating frequency around 130, anywhere between 120 to 180 They found a low frequency stimulation improve the freezing gait in those patients who have DBS about two to five years at all for medication states and our study also support the disorder and found that even in some acute stimulating patients frequently still play a role And then we move on did a randomized study and then we found a not only low frequency stimulation controlled freezing gait in those people with gait refractory to high frequency stimulation We also found this low frequency duration in this population can improve or reduced aspiration Even though about 15% of the patient They found that the tremor slightly getting worsening under low frequency stimulation but aspirations more an issue please engage more in the issue because of these two symptoms are the most important symptom associated high morbidity and mortality patients Parkinson’s disease, and so far there’s no good treatment for it So, we also found that that it has long term benefits as well particularly for the freezing gait even though as time goes, the beneficial effects are gradually reduced So then, who should try low frequency stimulation, you know? High frequency stimulation should still be the mainstream treatment We did a review paper and summarize all this published data (indistinct) group as well and we found that low frequency stimulation should be trying patient with freezing gait, refractory to looting high frequency stimulation But trauma can be worse than about nine to 15% of patients under low frequency information So then your question is the What about another important symptom swallowing function? We recently did a systemic review on the effect of DBS on swallowing function And we found that STN DBS and the usual stimulation frequency can have beneficial effects and no effect or detrimental effect While low frequency can have beneficial effects on suspicion with freezing gait, as mentioned GPi DBS could have a beneficial effect or no effect but no detrimental effect on swallowing function in PD So, the fact that DBS on the swallowing function is pretty much consistent with the meta analysis data from the gait and balance because this is not a surprise, even though this is the first systematic review, the swallow issues because they both belong to axial symptom So then why the low frequency could happen in some patients? It’s probably because it’s a stimulus the another targeted PPN, pedunculopontine nucleus, which is very close to the STN, as you can see here, and also their atomic and theological connection between these two targets based on the reported by other study group So overall conclusion, low (indistinct) DBS, high frequency stimulation was very well on motor complicated, wearing off, dyskinesia and medication refractory tremor NPD patients working on majority of the patients And low frequency can be try only in this patient presented with axial symptom refractory to use your high frequency stimulation And that hand trauma can be worse in about nine to 15% of patients on the low frequency stimulation And the DBS can only be also be tried in patient

with early a motor fluctuation As you see the early (indistinct) showed the improvement in quality life and possibly even in those moments patient with that motor complication, even though that’s the largest study this (indistinct) but there’s so far there’s no direct effect a non-motor symptoms so far, such as cognitive dementia, issues of costliness some type of symptom motor symptoms such as hallucination, proper shoe job, secondary to medication overdose, then DBS, cognitive STN can indirectly improve the symptom So are they any already new developments? One of them as a stimulation of post ceramic area PSA, increasing the CCI Chordoma instead of fibers for a better control tremor ’cause we mainly focus to the FDA approved (mumbles) VIM and STN GBS But there’s another one called the post STN (indistinct) include a cZi Let’s took a amplified look at this area This is called a (indistinct) area, (indistinct) Zi So NYSERDA and also prelim mystic radiation area Basically, it’s about a two millimeter below the VIM If you look at the actual plan of the brain, it’s a posterior to the subthalamic nucleus and lateral to the red nucleus So why this is important because this is the area where the fibers from basal ganglia and fibers from a cerebellum, both the area is involved in degeneration, the modulation trauma that emerged in that small area that’s why there’s still, this area has to mean stimulating the fiber become very efficient, you use a prior a little energy can have a big beneficial effect with possibly less side effect So, this is based on the review paper and the effect of GBS in this area and also supported by a recent randomized blinded evaluation compared to DBS in that area versus the best in medical therapy impatient with PD ended they found that the trauma controller is much better in DBS group and more than 90% So, this target could be a potential new one for better controlled trauma, possibly with less side effects based on the review And another exciting thing is the directional DBS when targets are so small as I just showed you precision and direction are crucial This is the STN targets As you can see that this is a traditional lecture that the DBS electrode, usually they contend four content, you can pick up either one to stimulate and because the only one target on one level, when you stimulate a private stimulation, you stimulate that area you want and also on (indistinct) you may also stimulate the area you don’t want that can cause side effect and also that wouldn’t waste the energy because you still in large area even though some areas unnecessary for you to stimute And this is a director stimulation as you can see, on one level, you can have three context, you can choose one of them or you can choose two of them, you can choose three of them, you can apply different policies for energy you can put more on here or more on the other side because the critical needs and also you can stimulate the several contacts at the same time to pass the clinical needs So that gives you much precision stimulation and also reduce potential reduce the unwanted the stimulation side effects, and also because it’s a precision stimulation to energy is less so you save the energy Even though nowadays, energy probably is a lesson issue because you have a rechargeable battery as well That’s part of another development So another new development still ongoing as adaptive or (mumbles) DBS The future has closed and adaptive to individually DBS patient And basically as individual as needed stimulation

based on electrophysiological, biomarker or wearable sensor markers detected by the brain and the brain know when I should turn on the DBS or which DBS, which part, which program or should I just shut it off For example, you know, as I mentioned that if the low frequency helps the axil symptom freezing gait and then when patient walking, they can turn on the low frequency and when the patient sitting, the rest of the trauma become problem and then that that usually to trauma respond better to high frequency stimulation and they can shut off low frequency stimulation and turn on the high frequency stimulation when the patient is not walking when the patient is sitting and resting So and this allow to having a more precision or accurate estimation is unneeded basis and also will reduce the side effect Again also in the energy saving, but this was still ongoing but I think the future is a closed and adaptive So let me quickly share with you some real video from clinical from I/R So this is a patient in participation with a resting tremor This is a video recording I/R as you can see the patient developed resting tremor now we we hit the sweet spot better action DBS, determine immediate stop, right? Now when we stop the DBS the trauma, immediate return as you can see here It shows that you know DBS is very effective in trauma control and other (indistinct) way to know And then, this is the patient (mumbles) freezing gait on the usual 130 hertz hospital stimulation the stimulation improve or other symptom, particularly (muffled speaking) parkinsonism and dyskinesia However, the patient as you can see, has freezing gait, particularly when she turned around, feels like the feet is stuck, is rooted to the floor as you can see, right And now we turn to low frequency 60 hertz, that also improve the speed and the swirl And as you can see, he’s state become much better Even now when she could turn There’s no freezing So this is a patient (indistinct) study as you can see that lutein 130 hertz, she has a little bit of aspiration This is a patient with a significant freezing gait And then we switch to 60 hertz You can see that You can see there’s no aspiration the candidate here is left over from the previous study as you can see here It’s not a desperation So the overall conclusion as a DBS is very effective under routine condition on control selective motor symptoms in various stages of Parkinson patients, mainly motor fluctuation dyskinesia, medication refractory tremor And in some patients, medication overdose with side effects And also not only effective impatient with later complication, but also impatient with early complication And some studies also show that even patient with that complication can be also beneficial, particularly on tremor, even though that’s still part of the data And also new development provide more precise stimulation like a directional DBS and energy setting, with a better control of symptom and better quality of life and the future will expect a personalized in need of stimulation That’s pretty much all I’d like to share

with you this morning I hope it is helpful I guess you might have lots of questions to ask I’m more than happy to entertain and discuss your moment Just bye for now I’ll get back to you in minutes Thank you again very much And including thanks to my DBS team (lighthearted music) Hello, everyone I’m so excited to be here with y’all this morning again Thank you so much for taking time to join us and also thank APDA (muffled speaking) this wonderful event I hope the talk is informative I’m sure you would have a lot of questions well So this is a special Q&A session That’s why we’re here, I’m here Please feel free to ask as many questions you might have And I’m more than happy to answer Let’s (mumbles) start First question from anonymous Does a DBS become less effective over time or well, it just continued to be calibrated? So this is a great question A lot of patient asked me the same question DBS very effective, particularly for the cardinal symptom The core symptom, a motor symptom of the parkinsonism, including bradykinesia, which is slowness in movement, resting tremor, and stiffness with its more specific assemblages This cardinal symptom continue to be responsive to the DBS based on the meta status analysis data review a systemic review studies and also large studies larger population in larger center so far a good response has been ported over 10 years or longer for a lot period So the second question is it possible to wait too long to get a DBS? I think, yes or no, I think it’s if it waited too long and because DBS is mainly improve your quality of life will not alter the disease progression So in that sense whether you said earlier or not, (mumbles) not to study the the disease because it’s not a disease modifying therapy But on the other hand, DBS can dramatically improve the quality of life So earlier, as long as you fit the criteria should be recommended And also, if you waited too long, then comorbidity could have become a more of an issues Because you needed to have a good general health condition to target to the surgery, even though it’s not that big of surgery, but still, you know, waiting too long is not good for the safety of surgery and complication, and also Most importantly, the quality of life So, particularly, given the current evidence is it just covered We have early stim study showing that the earliest in early stage less than two years when you develop a motor for exploration dyskinesia can have significant improved quality of life So I think that’s another reason we have evidence we have rational to support that once you fit this criteria, you should be considered taking this procedure, but eventually it’s also a discussion between you and your mood disorder because it’s also certain cases needed to be individualized And then another question from anonymous is, if I don’t have a good response to levodopa, what are my options? Yeah, this is a good question There’s a couple of possibilities there One possibility is whether you really have a diagnosis of idiopathic Parkinson’s disease because so far Parkinson’s disease or the response to the DBS well, but not either, Parkinson mimics For example, if you (indistinct) disorder, such as a progressive supranuclear palsy or motor system atrophy, at an early stage of disease, they will look like Parkinson disease,

but in fact they’re not So that’s a reason when we talk about the criteria, we also talk about (indistinct) four year disease course because that would increase your level of diagnostic confidence So that’s one possibility Another thing is maybe it’s a really advanced stage, the response to medication may not be great, or maybe add a comorbidity, a limit at the for motor assessment So you need to visit a mood disorder specialist to do a thorough evaluation But here I have to point out that if your trauma does not respond to medication, still, the trauma is a very good indication to get a DBS because DBS would have a good a therapeutic effect in controlling trauma, regardless of whether your trauma respond current medication or not That’s an exception So what is involved with DBS and maintenance? Maintenance not really much, because it was implants, they’ll actually implant your brain It’s like a permanent appraisement there The only thing is that the battery can be drained and for whatever reason, usually, the battery lasts about three to five years depends how much energy used in a program And nowadays we have also this rechargeable battery so they can last a very long time, nine years, 15 years, or even 20 years So it’s a resting issue The other thing is that in some patient after surgery, they found that it itch on the surgical side, but then try not to scratch it, if you scratch, you can cause skin aggression and then cause skin infection So other than that, if you have suspect any other (muffled speaking) or any questions about DBS feel free to contact mood disorder specialist to get a future presentation Another question from anonymous, if I’m having problem with cognition, would I still be a good candidate for DBS? Good question In general, we would like to have we will patient to have a good cognitive status for multiple reason, one of the major reasons as some studies suggest that the cognitive function in certain cognitive domain such as visual mode, processing speed, verbal phrase, et cetera, can be affected to certain degree more so, by doing STN, DBS and GPi, even though other study later on in (muffled speaking) data found that deficit from that as a minimum more and also the difference between two target the discrepancy in terms of cognitive function is also minimal So in general we would like to have a good or reasonable cognitive function And also that’s another thing for the quality of care as well So, another question is also from anonymous I had my first DBS in June 2014 and my second one in September 2015 My question is, how long should I expect the first DBS to last? I think this is the very common concern from patient they got a staged DBS at two different sides to two different time and as I also covered in first answer to the first question, DBS for the cardinal symptom has long to benefit reports paper can show the more than 10 years so far also Although one year difference will not show significant difference in terms of benefits still long-term there to enjoy it And even though the axil symptom, the speech swallow balance can be an issue particularly as time goes Why is that? Because it’s probably involve some non dopaminergic mechanism as well, such as called (muffled speaking), et cetera, as we covered in our talk Another question, what percentage of your DBS patient experience no decrease in developer in tech? I had the DBS two and a half years ago Okay This is a good question A lot of people think that the purpose of DBS

is to reduce the medication that’s not true The proper DBS improve the quality of care no matter what How do you, okay? Yeah, so I think is the quality care is a major thing So what we matter Where is the question? Okay, time for flies I hope I can answer more question but we only have 15 minutes Feel free to contact after session anytime we are available here And again, thank you so much for joining us and I hope you continue to enjoy the rest of the program Take care, bye, bye (lighthearted music) – Hello, everybody

My name is Rebecca Gilbert,

I’m Chief Scientific Officer at APDA And today I will be discussing medical marijuana and Parkinson’s disease This is a topic that many people really want to know a lot of information about And there isn’t a lot of information out there And so I’d like to provide today the connections between medical marijuana and Parkinson’s disease and the information that we may find helpful to be able to think about this product and how it may help people with Parkinson’s disease So before we begin, just wanna be clear that this presentation and really any presentation at this conference is not an endorsement of any treatment This is solely designed to educate you and to be able to have a discussion, an educated discussion with your neurologist or movement disorder physician because all treatment decisions are going to be a collaboration between you and your neurologist or movement disorder physician So let’s begin with the basics about marijuana and medical marijuana Medical marijuana is derived from a group of plants, known as cannabis And cannabis is a genus of plants that when ingested, can exert numerous different effects on the brain and the body And this is because cannabis contains hundreds of different chemicals We also know that cannabis, when ingested, can cause a high, which means that it causes a euphoric feeling in the body And this has led to the potential for abuse of this particular plant But it turns out that anecdotally, over the years users of cannabis found that it would help certain medical problems such as chronic pain for example, and this has led to efforts to create medical marijuana, which is purified chemicals from the cannabis plant to be used at specific doses in order to produce a specific medical result And primarily there are two chemicals within the cannabis plant that are purified for this purpose And these are THC and CBD THC and CBD are shown here on this slide THC is a psychoactive chemical So it is part of the chemicals responsible for that high feeling CBD however, is not psychoactive and is not responsible for that high Medical marijuana typically consists of purified combinations of THC and CBD in different ratios So one could have only CBD, sometimes only THC but often a combination of the two And another variable and how medical marijuana is dispensed is that it can be dispensed in various forms So there are liquids, pills, nasal sprays, powders, all sorts of ways of ingestion of these different chemicals So how does THC and CBD work? And why do they have effects on the body? So it turns out that THC and CBD mimic particular chemicals that are found within our bodies, and they bind to receptors that are found in our bodies and these receptors are known as endocannabinoid receptors The natural chemicals that binds the endocannabinoid receptors and the receptors together, composed this system called the endocannabinoid system or the ECS The ECS in our bodies regulates many functions including mood, pain, memory and appetite And so I have a little schematic down at the bottom of this slide, where in the natural state, we have ECS receptors in our bodies and in our brains And we have our natural eigenes, our natural chemical within our bodies, and they bind and together they form biological responses If one has ingested either THC or CBD, this mimic can interact with the receptors as well and cause similar reactions And so that is what our cannabis chemicals are doing Now, it is unfortunate that the system in our bodies was named the endocannabinoid system, because it implies that somehow this natural system had cannabis in mind when it was formed And of course, that isn’t the case

This is a natural system that has nothing to do with cannabis But it turns out that cannabis at some products of cannabis can interact with this natural system in our bodies I wanna emphasize I want this to be a real important take home message of this talk And that is that there are many medication used in Western medicine that are derived from plants So that is not at all a unique property of medical marijuana And each of the medications that are have been derived from plants that are now used in our medicines were studied in clinical trials and approved for use by the FDA based on those clinical trial results So being a plant does not get you out of this process by which a medicine is approved for use The reason we have this process this clinical trial process is because we want to know if the medication really works And we want to know if there are side effects that are problematic, or there are adverse effects of these medicines that we need to know about And we will only get that information through properly design clinical trials And so medical marijuana should be treated like any other medication and undergo the clinical trial process What we know anecdotally and for people who take it, that medical marijuana can of course have side effects, much like any other medication, again, medical marijuana being treated like any other medication, we have to be very conscious of the potential side effects And the side effects are not that surprising They could be sleepiness, confusion, psychosis, even difficulty concentrating, apathy, or a lack of interest in things, mood changes, gait and balance, all things that are problematic for everyone and specifically for people with Parkinson’s And other potential side effects, nausea, hypotension or low blood pressure, diarrhea, dry mouth Now this of course doesn’t mean that everyone who takes these products will get all these side effects, but something to consider in the process of understanding medical marijuana Other things to know is that the effects of THC and CBD may be prolonged in those with impaired liver or kidney function, something else to be wary of And what we always need to highlight is that as people age, they are more prone to side effects in general, or this particular medication and other medications and so we have to be even more careful about side effect profile in people as they age Another thing to remember is that medical marijuana can interact with other medications So if someone is on other medications for other medical problems, we want to consider that as well Having settled that medical marijuana is used in Western medicine for specific indications because the clinical trials do support the use of medical marijuana for these diagnoses, certain types of childhood epilepsy syndromes, chronic pain and chemotherapy induced nausea And so clinical trials have been done for these particular entities So there’s use of medical marijuana for these entities There is not the same level of evidence for Parkinson’s disease, and certainly more clinical trials are needed One could hypothesize that medical marijuana may be helpful for certain elements of Parkinson’s symptoms, for example, tremor, or dyskinesias, possibly stiffness or rigidity When the body is too tense to shaky moving too much medical marijuana may be able to calm that down, potentially insomnia and ability to go to sleep Medical marijuana may be helpful for that Dystonia or twisting of an arm or a leg, that can be painful pain in general weight loss These are all symptoms that are problematic in Parkinson’s disease and may find some relief in medical marijuana However, each of these symptoms will need to be evaluated with a clinical trial In addition, as we’ve mentioned before, THC and CBD can be dispensed by a different delivery systems, as we mentioned, in different doses and at different ratios And we do not know the optimal delivery system dose or ratio for any of these symptoms So there is a lot of information that’s missing I’ll receive questions frequently What is the best dose of CBD for my pain? We don’t know What is the best dose of of THC CBD for my tremor? We don’t know We don’t know if it’s effective We don’t know what the specific type that should be given and so there’s a lot of information missing

And we need clinical trials to evaluate all these permutations Now, why is it so difficult to get information about medical marijuana? And that’s of course, because federally medical marijuana is illegal And that is, of course, a major obstacle to doing research on medical marijuana, because you cannot get money to do federal money to do the clinical trials that are necessary And so the Parkinson’s community is advocating to ease federal restrictions on medical marijuana research This is very important to move the field forward And there are many bills that have been introduced already in Congress in their various levels of stages of going through the the bill process, and hopefully, we will make some headway on that front to ease the ability to get information about medical marijuana Despite the fact that federally medical marijuana is illegal, many states have made it legal Now this dichotomy is a very interesting legal situation And it’s obviously a work in progress Here is a map of the United States And it’s color coded based on where the different states are in there legalization of marijuana The green states, marijuana is fully legal, which means it is legal recreationally and medically In red, it’s prohibited completely, recreationally and medically The blue states however, have keep forbidden medical marijuana recreationally but to allow it on some level medically Now, there is a tremendous amount of variability between state to state and what is allowed even within all the states that are blue For example, there are some states in blue that only allow CBD formulations for medical marijuana and some states that allow the combination THC and CBD This is important because there are some maps that you might see that differentiate between the states that only allow CBD from the states that only allow that allow both THC and CBD and maybe color coded differently So this map includes any medical marijuana all is colored blue Within those blue states, as I mentioned, the laws governing medical marijuana vary significantly Most require some sort of certification for use by a physician, and many require registration with the state Some require issuance of a medical marijuana ID card Another difference between states is whether they list Parkinson’s disease as a qualifying diagnosis to obtain medical marijuana Some do, some don’t Some list chronic disease as a large category of disease that may allow you to obtain medical marijuana, and Parkinson’s disease may fit under that broad category of chronic disease Let’s turn to the actual data that’s available that looks at medical marijuana for PD I’ve mentioned a number of times that we do not have a lot of data, but we do have some So let’s look at the data that’s available and see what we have to make any decisions or make our understanding of medical marijuana NPD more complete Now, as you probably know, there are different types of clinical trials Two big categories of clinical trials are here on this slide, survey-based trials and open label trials A survey-based trial would be a type of trial where a larger group of people are given a list of questions, perhaps about their medical marijuana experience, what they use it for, what type of medical marijuana they use, and what the results are And those results are tallied Now surveys trials are certainly very interesting They give us some insight into what people are doing in their homes It gives us some insight into whether what they’re doing they perceive as helpful, and it gives us some information about what to study in the future What it doesn’t do is allow us to really obtain information that we can generalize to everyone because there is a lot of variability and what people will report, what people report is not validated And so it is not data that can really be used to justify acceptance of a medicine for everyone An open label trial is a bit more rigorous in that situation and medicine is actually given to a patient that researcher,

but in an open label trial patients know that they’re receiving the medicine there’s no placebo or group that does not receive the medicine And so a person cannot really fully evaluate whether the medicine is helpful for them, because they understand that they received the medicine and that can influence their, the results of how they feel when they take the medicine There have been five clinical trials of Parkinson’s disease and medical marijuana that were conducted in the most rigorous fashion and those are placebo controlled So some of the participants get the treatment, some do not Randomized, which means the participants are randomly assigned to either receive the treatment or are in the placebo group and don’t receive the treatment and double blinded, which means that neither the participant nor the research staff know who is in the treatment group and who is not And so let’s look at the trials that have been done So Here I’m gonna show you a bunch of tables I do not expect anyone to really read every word, I’m just gonna give you a general overview of the trials that we have available in our literature The first table looks at the patient survey type trials, and there have been five over the years And as you can see the sample size that’s the third column varies quite significantly to very small to very large to 454 patients In general, these patients surveys again, looked at patients who taken medical marijuana and their own and what results they’ve had in their symptoms And, for example, the first trial here in 2004 This patient survey shows that these patients did report improvement in their motor symptoms of PD The second trial showed that over 50% showed benefits in their mood and sleep, a smaller percentage showed benefits in their motor symptoms The third showed 77% reported benefits in their pain The fourth, also improvement in their non-motor symptoms and reduction of their prescribed medication And the last decreased complaints of falling stiffness and tremor, decrease in pain, sleep improvement of mood In general, patients who take medical marijuana their own and then report back what it does for them in general feel like it is helpful And again, this is important information, we wanna capture it but it is certainly not enough information for us to then say this works for everyone The next two tables are open label trials and again these are trials in which the medication is given to a group of patients and then the results are tallied And there is no placebo group that patients all are very aware that they’ve received the medicine and the researchers are aware that they’ve received the medicine And in general, this type of trial that isn’t a placebo group is not considered a rigorous trial because patients who are aware that they receive a medicine tend to do better and this has been established in trial after trial And so we are a little bit wary of jumping from an open label trial to saying this is an efficacious medicine But of course, it is interesting to capture and to report that these results have been received Again, these trials are very small, these trials are much smaller than the survey trials Here we have between five and 22 patients that were tested, and various results are logged And again, overall, there is a trend to improvement There are some trials that did not show improvement in the results that they expected But most of the open label trials do show some level of improvement from the medication received Let’s look at our most rigorous trials Our randomized placebo controlled trials And there were five as I mentioned, and in general, these trials have some mixed results Well, what we must note here is that our sample size again, the number of people that receive the medication is very small, it ranges between four and 24 So very small groups And so these are not the numbers that really enough for FDA, for example, to come and say this is a medication that is effective for everyone Just as comparison medication trials that do lead to approval of medication have hundreds or thousands of patients in them So we’re quite far from the numbers that are really required for approval of a medication but it’s definitely a start And these five trials looked at various results, various outcomes And again, as I mentioned, there is a bit of variety in what the different trials showed, the first trial showed

a reduction in levodopa-induced dyskinesias, severity and duration The second trial, however, did not show an improvement The third trial, again did not show an improvement And the last two do show improvements The first, the one in 2014, showed improvements in quality of life with 300 milligrams of CBD And the last one was an interesting trial where they gave 300 milligrams of CBD powder and looked at anxiety and tremor in a simulated public speaking test, and showed that in a randomized, placebo controlled way, there was improvement in the group that received the CBD And so to summarize, patient survey and open label studies tend to demonstrate that medical marijuana has benefits in PD, but this type of data is not sufficient to approve a medication for use Results of these five randomized control trials showed mixed results, they were small But definitely, some were suggestive that some forms of medical marijuana are helpful for some symptoms, and definitely intriguing and pushes us to really need to know more and to perform larger clinical trials to get that information So the bottom line, more work needs to be done to determine if medical marijuana is useful, what it is useful for and which formulation is best In the meantime, based on what we know already, there is enough to have a discussion with your healthcare provider to discuss whether this is something that you may wanna pursue, even if not all the information that we want is available And please discuss this and of course, all your medical decisions with your physician And now of course, we are looking toward the future to see what other clinical trials are available potentially people listening to this talk may be interested in joining a clinical trial to further our knowledge about medical marijuana and Parkinson’s So there are three that are listed in ClinicalTrials.gov, right now ClinicalTrials.gov is a list pretty comprehensive list of all the clinical trials that are available throughout the world And we have three here that are looking at this impacts of medical marijuana and Parkinson’s The first is looking at cannabis oil for pain in Parkinson’s disease, the second looking at tolerability and efficacy of CBD on motor symptoms in Parkinson’s, and the third is looking at nabilone Nabilone is a synthesize cannabinoid, so it’s not derived from the plant but it is made in the lab to mimic a cannabinoid And it’s looking at that chemical for non-motor symptoms in Parkinson’s disease And so this is a start, few more trials to help us gather the information we need to make informed decisions about our patients I have listed here all the references of all the different clinical trials that I mentioned And on that note, I want to thank everybody for listening And I want to once again encourage everybody, to educate yourself to take this information to your doctor, and to make informed decisions about your medical care Thank you so much for listening today (lighthearted music) Hi, everyone Thank you so much for listening to the talk on medical marijuana and Parkinson’s And now we’re gonna try to answer some of the questions that have been coming in The first question from anonymous is, is there any evidence that marijuana interacts negatively with levodopa? To my knowledge, there is no specific evidence that the to interact and poorly So I do not think that’s going to end up being a major problem in our giving up medical marijuana to people with Parkinson’s The next question from anonymous is, is there a difference between CBD oils and lotions and something you would take orally? I am not aware of the ability of CBD to be absorbed through the skin There may be a literature on this and I just don’t know So I do not want to comment on how a CBD is absorbed through the skin My guess would be that CBD taken orally would be a more powerful way of getting CBD into the system then using the oils So my guess is that the oils would not be really what we’re talking about here that we’re really talking about either internationally or orally,

would be the way to get the CBD and but again, not something I’m 100% sure about So thank you for that question The next question, what are the next steps in researching PD in marijuana? And you know, back to really getting that data, really designing clinical trials that help us answer exactly what type of medical marijuana is needed, though saying addressing issues of dosing addressing issues of method of delivery, which delivery system there are all sorts of different formulations and also addressing symptoms So you need a clinical trial that’s designed and sort of selecting from those lists You know, what type, how much, method of delivery and then what the outcome that you’re looking at So it really is, you know, impossible to say, let’s look at medical marijuana and Parkinson’s those that medical marijuana is too big a group of different types of compounds Parkinson’s is too big a group of symptoms, you really need to pick really hone in on what exactly you’re looking at And the successful trials have done just that I’ve taken a very specific type of CBD, for example, a very specific outcome and try to really study one thing as something that that kind of makes sense of the Parkinson’s population So those are the kind of trials that we’re looking at to help us figure out this quagmire, really We have a question from Susan, she’s a really great question How would the use of medical marijuana affect a Parkinson’s patient that also suffers with cognitive problems and dementia? So here we get into a bit of trouble because as we know, every medication can have side effects and people who are elderly, people who have neurologic disease, people who have dementia are all more at risk for side effects in general than other people And so we would expect that side effects for medical marijuana would follow that pattern as well And so it would be much more fraught, to be considering medical marijuana for somebody with who already has cognitive problems and dementia than somebody who may be looking for something for a more specific symptom, maybe tremor or insomnia, who doesn’t have a whole array of other issues And so I would be very wary of going down that path or even thinking about medical marijuana for somebody who has a more complex picture with the cognitive piece as well We have a question from anonymous How can we people with Parkinson’s and caregiver help move marijuana research forward? So that’s a great question Short of finding a trial to participate in and I did at the end of the talk mentioned three, but I did not mention is that they’re in all parts of the world One is in Toronto, one is in Austria, I think one of them Colorado So if you don’t happen to live in one of those areas, it probably will be difficult to join a trial You can always be talking with your physician about potentially new trials that are being publicized and need participants So keeping your ears out for opportunities to participate in clinical trial research is of course, one way to do it Another way is to contact your Congress, people, your representatives in Congress, the Senate and the House of Representatives, and to say, you know, there there’s multiple ways of engaging with your elected officials, you can send emails and all sorts of things very easy these days And say I want there to be federal lifting up federal restrictions on medical marijuana research and make making your voice heard in that way And that will help us move the field forward because there’ll be federal money that can support these medical marijuana trials Anonymous also asked the question, it seems it’s CBD can treat a lot of elements How can one drug help so many different things? Fantastic question And that, of course, is really the crux of this issue Medical marijuana has gotten this aura around it that it is panacea for every element And of course, it’s not it’s the plant and the plant doesn’t didn’t figure out how to solve humanity’s problems And so I agree with you 100% It is absolutely impossible, that CBD is going to be the savior that some think it is So what we’re trying to do here is exactly is precisely

attack what exactly what you’re saying meaning take that general notion in society that medical marijuana is a cure all and break it down and say we have to study each aspect individually and figure out whether or not it is true that that CBD could help that particular symptom So, you know, for example, sleep problems, tremor, et cetera and break it down and study it in a clinical trial and look at the outcomes and figure out whether or not CBD helps that particular thing And so yes, you need to be very rigorous in this type of research And I your point is very, very well taken and I think that’s a great point to emphasize to anyone listening today There’s a question about getting the list of references, which I assuming we should be able to do But we do need to know who you are to be able to get to send you those references So, perhaps I will talk to our technical back end and see if we can figure out how to get you the list of references that you can download yourself Anonymous also asked Does having used marijuana typically exclude you from being able to participate in clinical trials in general? I do not think that that would be an issue at all I have never seen use of medical marijuana as a exclusion criteria for a clinical trial So I, of course, every clinical trial is gonna be different, but I would not think that would exclude you from many clinical trials I have a note here from one of the conference organizers that if you send an email to APDA STN so that would be [email protected], you can request a copy of the slides, you can get a copy and you’ll be able to see those references Okay, we have another great question from anonymous If I have severe problems with my gait, should I avoid medical marijuana? So again, this is very similar to the question about cognition, people who have worse than problems with their thinking, would that be a reason to avoid medical marijuana and I was hesitant in saying that somebody with cognitive problems should be considering this because it does add a huge layer of complexity, very similar to somebody with a gait disorder because, again, medical marijuana and all medicines can have side effects One of the side effects can be imbalanced or general unsteadiness, and so if there are these additional, more complex features of the Parkinson’s disease, then we would be more wary about the side effects as well So yes, so somebody who has a more complex picture would be give it a little bit more thought about whether this is a road trip to go down or not So I agree with all those people sending in comments, that side effect profiles that’s have to be strongly considered What I should say just to clarify the the comment about how can CBD you know, sort of be the panacea and help everything What we do think is that medical marijuana is going to be a drug or is it a drug that sort of calms down nerves and so anything where the nerves are revved up so there’s a lot of tremor or there’s a lot of insomnia and you can’t sleep or there’s a lot of twisting of muscles in pain, there’s a nerves that are overexcited medical marijuana potentially could sort of ease that and take the burden off of that most super excited nerve So that’s where the list that CBD may help or medical marijuana in general may help comes from it sort of all the aspects of Parkinson’s that are too, where the nerves are too active So no one could imagine that CBD or medical marijuana in general helps those symptoms in which the nerves are too revved up Not so much that it’s a fantasy of everything, but it may be a fantasy of overactive nerves, and maybe a way to think about it So on that note, I am being asked to wrap up our Q&A session I wanna thank everybody again for listening for participating in our Q&A and participating in this

Midwest Congress in general And now you’re gonna be returned back to the main event So thanks so much again for listening (lighthearted music) – Hello, I’m Scott Hunter, Vice President Sales and marketing at Amneal Pharmaceuticals We are very excited to be part of this incredible event, and we’re confident it will provide a great spirit of community education and inspiration for people living with Parkinson’s their care partners and families At Amneal, our team comes to work every day with all of you in our minds and hearts We are passionate and dedicated to our work in Parkinson’s disease Again, we are so glad to partner with you today in this event and wish you the very best (upbeat music) – And this concludes the Third Annual Midwest Parkinson’s Congress Hello, I’m Roger Halleen, the president of the American Parkinson’s Disease Associations Midwest Chapter And on behalf of everybody at the American Parkinson’s Disease Association, the Greater St. Louis Chapter and Midwest Chapter I would like to thank you for joining us today And it has been a true honor to bring you this educational event to the Parkinson’s community Every day at the APDA, we provide sport, support and education and research to help everyone impacted by Parkinson’s, live life to the fullest We are excited that we are able to share all of our wonderful knowledgeable speakers with you today And we hope that you have learned something new and feel that you have gained some knowledge that you can take away from this educational congress I would like to encourage you also to visit the APDA website and take advantage of all their educational material and other educational webinars on that site However, this would not be possible without the support of our sponsors And I would like to thank the sponsors at our championship and their champion sponsors, the James Addison Bates Foundation, and the JCA Charitable Foundation I would also like to thank our collaborators sponsors, ACADIA Pharmaceutical, Amneal, Emerson Hendrick Motors, and Kyowa Kirin I hope that during this Congress you were able to visit their sponsors resources booth to learn more about how they support Parkinson’s and the Parkinson’s community Once again, thank you so much for joining us today

And we hope to see you again soon at our APDA Optimism Walk Please check our website for more information on these walks Thank you (upbeat music)

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