Good morning everybody. My name is Ebony Dix. I'm a geriatric psychiatrist and I'm here with Dr. Farheen and we are going to talk about collaborative approaches to managing Parkinson's disease neuropsychiatric symptoms. First I would like to just give you a little introduction of Dr. Farheen. She and I worked together at Yale and she was a fellow. She attended medical school in Calcutta, Medical College in India and residency at Case Western Reserve. As I mentioned, she did her fellowship in geriatric psychiatry at Yale School of Medicine and she's currently an outpatient attending and geriatric psychiatrist at Cleveland Clinic in Akron, General Ohio. She will be giving a majority of the slides. Interwoven will be some cases that will kind of try to tie together some of the ideas and goals of the talk. So firstly, for disclosures, I've received some honorarium for a lecture for National Council of Mental Well-Being, but otherwise we have no other conflicts of interest to disclose and the discussion of either patient cases, any mention of medications, whether they're FDA approved, off-label or unregulated will be presented here for educational purposes only. Just briefly, we're going to review the current knowledge of idiopathic Parkinson's, the epidemiology and sort of the significance of this disease and we're going to talk about the neuropsych symptoms. We could probably spend an entire day, but we're going to focus on understanding how to differentiate between Parkinson's disease neuropsych symptoms and try to differentiate between Parkinson's disease dementia and dementia with Lewy bodies. And then we're going to also use some examples from some clinical cases to sort of demonstrate the need for having a collaborative approach to care for these patients. So next I will hand it over to Dr. Farheen. Good morning, everyone. Thank you, Dr. Dix, for the introduction. Starting with the Parkinson's disease, as we all know that Parkinson's is the most common neurodegenerative disorder. Actually it's the second most common neurodegenerative disorder and it has been reported first by James Parkinson in 1817. And the etiology of the Parkinson's disease is that there's deposition of Lewy bodies and the substantia nigra, which leads to degeneration of substantia nigra and causes abnormal motor symptoms. The epidemiology of Parkinson's disease, it affects about 1% of the population above 60 years. And it's, as we can see here, it affects about two people in thousand of the population at any time. The disease prevalence increases with age and it is about nearly 1 million in US and 10 million worldwide are estimated to have the disease. So we'll be alternating between the slides. So Dr. Dix is going to speak about global burden of disease. So one thing I wanted to just bring up before we get into the rest of the presentation is that, you know, the reason why we're talking about this disease is because it's pretty prevalent and many psychiatrists are going to, you know, interact with patients in various settings. But the global burden of diseases is quite impressive. You know, there are disparities and inequities across the globe. And, you know, there was, there's been data collected to suggest that it's the fast growing neurological disorder in terms of death and disability, which of course, you know, translates to increased health care costs, increased caregiver burden. So it's becoming very internationally, I think worldwide recognized as a very common and prevalent disease. Coming to the pathophysiology, historically, it has been well established that the neuropathological finding in Parkinson's disease is a deposition of alpha-synuclein-acetylglybobodies in the substantia nigra of the basal ganglia, leading to the degeneration of dopaminergic neurons in the striatum and leading to abnormal motor control. Risk factors for Parkinson's disease includes age, which is the most important risk factor. In terms of sex, males are more predisposed for Parkinson's disease than females, and the ratio is 1.4 is to 1. In terms of genetics, first-degree relatives have more chances of or risk of Parkinson's disease, about two to three-fold increase. And other environmental risk factors like exposure to pesticides and other chemicals can also be the risk factor for Parkinson's disease. Genetically, Parkinson's disease is divided into two forms, autosomal dominant form, autosomal resis, recessive form. The autosomal, the genes responsible for autosomal dominant forms are SNCA gene, LRK2 gene, GBA1 gene. SNCA gene, the penetrance is about 90%. LRK2 gene, the penetrance is about 25 to 74%. For GBA mutation, the penetrance is very low, which is around 11 to 29%. Autosomal recessive forms, the penetration for all these three genes is 100%, and those genes are Parkin, PINK1, DJ1. SNCA gene and other autosomal recessive forms, they present at an early age, and they are classified as young-onset Parkinson's disease. The other two genes, LRK2, GBA1, can be, they are very typical presentations as late-onset Parkinson's disease. This was described in Heinzel et al. in 2019. As we discussed, historically, we know that dopaminergic neurons are involved, and there is degeneration of those neurons. But recently, it has been established that along with dopaminergic neurons, serotonergic, cholinergic, and noradrenergic neurotransmitters are also involved in neuropsychiatric manifestations of Parkinson's disease, leading to other symptoms like depression, anxiety, apathy. And in Kummer et al., which was published in 2017, they have used radio tracers and did neuroimaging and figured out that for depression, noradrenergic, dopaminergic, and serotonergic neurons are dysfunctional. In anxiety, noradrenergic and dopaminergic system has been dysfunctional. And in apathy, the neurotransmitters involved are dopaminergic and serotonergic neurotransmitters, leading to the neuropsychiatric presentations. So recently, as I said, it has been established that there is not only dopaminergic neurons involved, but other neurons which are involved in serotonin, cholinergic, and noradrenergic systems. This is a schematic representation of clinical progression of a Parkinson's disease. The y-axis here demonstrates the percentage of degenerative dopaminergic neurons, and the x-axis determines the duration of years. And as you can see here, the zero is diagnosis time, and on the left we have preceding years before the diagnosis, on the right we have years after the diagnosis of Parkinson's disease. In the preclinical stage, the biomarkers are genetic and epidemiologic biomarkers that can be used to identify the Parkinson's disease. However, in the preclinical stage, there are no signs and symptoms. This can only be identified by genetic or epidemiologic markers. The second stage is called the prodromal stage, in which there are clinical symptoms which include REM sleep behavior disorder, hyposphere, depression, urinary dysfunction, and constipation. These symptoms can vary, and they can present at any time between diagnosis time and preceding 15 years. Coming to the clinical stage, it will start during the time of diagnosis, around the time when the patient has tremors and mild motor symptoms, followed by, in five years, we can see full Parkinsonian syndrome, and in 10 years, there will be other complications of Parkinson's disease, like levodopa-induced complications, and in 15 years, we will see development of dementia and other complications of Parkinson's disease, like falls and other gait abnormalities. The slide over here also shows typical symptoms of Parkinson's disease, which include stooped posture, tremors, cogwheeling rigidity, forward tilt of the trunk, and shuffling gait or stepping gait. Dr. Dix is going to talk about this case from her experience. So I'm going to speak about briefly a case, and what I would like you to do is sort of hold on to the information that I'm giving you in this case, because in the slides after I speak, hopefully certain things will start to percolate in your mind as they pertain to this. We had a 64-year-old female with a 10-year history of Parkinson's disease. Now, she was diagnosed 10 years prior, meaning it was early onset, and yes, she had a family history. This was familial. Her older brother also had Parkinson's. She had Parkinson's disease, ADHD, and major depressive disorder with anxious distress, who presented for inpatient hospitalization on the unit that I run at New Haven for having some very bizarre behavioral changes at her independent facility. Multiple incidents of these behaviors included leaving the sink on and flooding her apartment, walking around unclothed in common areas and answering the door naked. She would spend a lot of time rearranging things in her apartment, taking apart parts of the garden at this living facility as well, and she was picking apart carpet walls, drywall, electrical panels, so on and so forth. Just very, very strange behaviors. Next slide. So on admission, her main complaint was that she's had a lot of brain fog and terrible anxiety, and that's why she felt she needed to be in the hospital. She also spoke about her motor symptoms that would sort of get worse at different periods of time, notably when she was more anxious, and during these periods of time when she would have off symptoms. She also noted some more intense muscle spasms and dystonia in her legs and feet. These were painful, and she was getting Botox injections as an outpatient for them. When she was admitted to the service, her medications are included below, and how we ended up treating this patient included a phone call to her neurologist and working with the neurologist to actually add on Antekapone to sort of help reduce the off periods, and that was like the little magic thing that worked for this woman. But I think in the next few slides, Dr. Farheen will continue to talk about some of the other symptoms that are common and that we might sometimes think could be attributed to some of the medicines our patients are taking versus the neuropsych symptoms of the disease itself. As we know, primarily Parkinson's disease, in Parkinson's disease we have motor symptoms, but non-motor symptoms are also predominantly seen, and they can be a dominant feature of this disease. They are classified as symptoms because of the autonomic dysfunction, neuropsychiatric symptoms, sleep disorders, and sensory and other disorders. In autonomic dysfunction, the symptoms that we see include constipation, nausea, dysphagia, dribbling of urine, nocturia, urinary voiding, urinary urgency, urinary frequency, excessive sweating, orthostatic hypotension, and sexual dysfunction. In neuropsychiatric problems, we have depression, anxiety, apathy, suicidal ideations, hallucinations, impulse control disorders, et cetera. In sleep disorders, most commonly we see REM sleep disorder, insomnia, restless leg syndrome, periodic leg movement disorder, and excessive daytime sleepiness. In sensory disorders, we see olfactory dysfunction, visual dysfunction, and auditory dysfunction, pain, fatigue, and weight changes. Now talking about sleep disorders, the prevalence of sleep disorders is about 60-90%, and among all the Parkinson's disease patients, 60% of the patients have REM behavior sleep disorder. This is the most specific and most common sleep disorder or prodromal stage symptom in Parkinson's disease. Out of all the RBD patients, 80% of them are because of idiopathic RBD, that is, without any cause, it is just etiologically because of the Parkinson's disease, and 20% of them are because of medications like dopamine agonist therapy and other medications like SSRI. So thorough medication assessment should be done as well for these patients. As I said, RBD is recognized as an important marker of prodromal stage of Parkinson's disease. The other common sleep disorders include restless leg syndrome and periodically movement disorder. The prevalence of restless leg syndrome in Parkinson's disease is about 15%, and the management is via dopamine agonist and gabapentinoid medications, which include gabapentin and pregabalin. The same management applies for periodically movement disorder in Parkinson's disease as well. Other sleep disorder that can be seen in Parkinson's disease is excessive daytime sleepiness, which could be because of dopamine agonist therapy, and the way you treat is by lifestyle modification and to treat the other nocturnal disorders and to evaluate the medications, see if they are on any sedating medications like dopamine agonist or any other medications like Seroquel, which can be eliminated and the excessive daytime sleepiness could be treated. Other treatment includes bright light therapy, exercise, weight promoting agents like modafinil, armodafinil, methylphenidate, caffeine, and sodium oxybate. The other neuropsychiatric disturbance is insomnia, which is a significant amount seen in Parkinson's disease. The causes of insomnia include motor symptoms, neuropsych symptoms, nocturia, other sleep disorders, cramps, pain, medications that can keep the patient awake. In terms of medications, they include dopaminergic medications, which can cause both sleepiness during the daytime or it can cause insomnia. So both are the side effects of dopaminergic medications, so we just have to be careful using these medications and make sure that patient is not having these side effects with the dopaminergic medications. Other medications which can cause insomnia include MAO inhibitors and imantadine. How do you evaluate the sleep insomnia in these patients is getting a very thorough history, doing a physical exam, maintaining a sleep diary, and may also perform polysomnography. You do need to distinguish it from circadian rhythm disorders and RLS, which is restless leg syndrome. Treatment includes assessing and treating the contributing factors, CBT-I, bright light therapy, exercise medications like melatonin, and DORA, which is dual orexin receptor antagonists. These have been studied to be effective in Parkinson's disease. In REM sleep, coming to REM sleep behavior disorder, the prevalence is about 60% of the patient populations of Parkinson's disease. The pathology is similar as alpha-synuclein deposition in the brain as Lewy bodies, same as Parkinson's disease. Treatment of RBD includes melatonin and clonazepam. You can start with melatonin at three milligram and increment it by three milligram every week, and the highest dose of melatonin that can be used for RBD is about 18. The effective dose is six to 18 milligram. And other medication that can be used if melatonin is not working is clonazepam. You can start with 0.25 and go up to one milligram, and the effective dose is between 0.5 and one milligram. And for RBD, as I said, you need to make sure that the patient is not having side effects of dopaminergic agonists or other medications who are notorious for causing RBD is SSRIs. So you need to make sure that they are not having the side effect from SSRIs as well. Dr. Dix is going to talk about this case now. So for case number two, we have a 75-year-old male with Parkinson's disease, depression, anxiety, presenting for inpatient admission for failure to thrive. Also has a medical history of some chronic medical conditions. Essentially, the wife reports his depression has worsened over the last few months. He's become more apathetic, hasn't showered for several weeks, nor has he left the house to attend doctor's appointments. He just won't get out of bed except to eat or go to the bathroom. Whenever I encourage him to shower or leave the house, he says, I can't. Wife also notes that he's now stopped taking most of his medications, including carbidopa levodopa, resulting in worsening of his Parkinson's disease symptoms. So initially, the thoughts are that you have this patient with Parkinson's disease and a comorbid major depressive disorder. Are these symptoms related to his underlying depression, or are these symptoms related to his Parkinson's disease, which potentially may be progressing now, especially since he stopped his carbidopa levodopa? An additional point is some of the apathy that's being mentioned here, very large overlap between apathy and depression, and sometimes very difficult to distinguish in Parkinson's disease patients. Now, talking about anxiety, it's more common in Parkinson's disease, and it can occur as a comorbid disorder along with depression. It's seen in about one third of the patients, and prevalence is about 31%. Etiology is multifactorial, and it must be differentiated from akathisia. Anxiety is also associated with lower quality of life. The neuropathology includes neurodegeneration of dopaminergic, neurodegenergic, serotonergic pathways. The neuroanatomy that is involved in anxiety disorders in Parkinson's disease is the same as in generalized anxiety, which includes the fear circuit, the limbic corticosteroidal thalamocortical circuit as well, which plays a parallel role in anxiety and fear as in generalized anxiety disorder. Anxiety disorders in Parkinson's disease includes generalized anxiety, OCD, trauma, and stress-related disorders. These are very common in Parkinson's disease. Social anxiety is also known to be very common because patients may be very conscious or concerned about their physical symptoms and may be socially withdrawing and may be in a depression as well. They may also have a fear of disease progression, institutionalization, and caregiver burden as well. They may also be anxious about the high risk of falls, which is very common in Parkinson's disease as well. Management of anxiety includes lifestyle modification like improvising the diet, nutrition, improvising the sleep hygiene, and also exercise. Other management includes using SSRIs and SNRIs in Parkinson's disease, like Lexapro, Sertoline, or Effexor as SNRI. The use of benzodiazepine is discouraged because of their side effect profile. In terms of therapy, we can also use CBT, mindfulness, and desensitization as well. Apathy is one other neuropsychiatric symptoms of Parkinson's disease. The prevalence for apathy is about 17% to 70% of those with Parkinson's disease. Apathy is defined as a state of reduced motivation that manifests as a reduction in goal-directed behavior. This needs to be distinguished from depression as well. For depression, as we know, there is a different DSM-V criteria, and that needs to be well-established if the patient is having apathy or depression. In apathy, we may see emotional indifference, reduced reactivity, reduced activity, and loss of interest in the world, loss of interest in people around them, and lack of concern for others as well. So however, apathy and depression can coexist, but it is also important to distinguish these two symptoms. The pathophysiology of apathy in Parkinson's disease includes disruption of dopaminergic neurons, or the projections between the frontal cortex and ventral tegmentum. The listed scales are used to assess the apathy, which includes WHO Well-Being Index, Neurasthenia Scale Detect Apathy Severity, Lilly Apathy Rating Scale, while Starstein Apathy Scale as well. Treatment of apathy includes dopaminergic medications, that is dopamine agonist therapy that we use for Parkinson's disease, and acetylcholinergistase inhibitors, which have been well studied in the management of apathy, like rivastigmine, which can be helpful in treating apathy as well. Next symptom as a neuropsychiatric symptom of Parkinson's disease is fatigue, the prevalence of which is around 50%. Now Dr. Dix is gonna talk a little bit about apathy. Yeah, so this slide is mostly just informational about the different domains of apathy and some of the potential ways to treat apathy in certain individuals. As you can see, methylphenidate, which is a psychostimulant, is sometimes used to help treat apathy and fatigue. That's treatment refractory in Parkinson's patients. Other neuropsychiatric symptoms, which are also seen in Parkinson's disease, include impulse control disorders, which include binge eating disorder, pathological gambling, compulsive shopping, or abnormal sexual behaviors. Etiology of these disorders could be idiopathic or it could be because of the dopamine agonist therapy. So these symptoms have to be monitored while the patients are started on dopamine agonist therapy. At the same time, patients have to be counseled about these risks of these side effects and being monitored during subsequent visits because these may be causing significant ramifications in their personal life and cause severe impairment in their functioning as well. The risk factors for these impulse control disorders include men and those with certain personality traits like impulsivity, novelty seeking, anxiety, and depression. Younger patients are also a risk factor for impulse control disorder. Smoking and taking high doses of dopamine agonist for a long duration can also cause these disorders. Management consists of down titration of dopamine agonist therapy and also using CBT and careful management of worsening of motor symptoms. Other important point here is dopamine dysregulation syndrome which could be a combination of dopamine replacement therapy coupled with individual risk factors for the particular patient and Parkinson's disease pathology that can cause this addictive syndrome. And the clinical features of this dysregulation syndrome is a combination of addictive behavior as previously I talked as impulse control disorder and other component is mood fluctuations. So in this syndrome you'll see two components that is mood fluctuations and addictive behavior that could be in form of gambling or compulsive shopping or any other sexual behaviors. Management consists of again the same as down titration of dopamine agonist therapy and fractionation of levodopa therapy. Levodopa can also be given intrajejunally. You can also treat this dopamine dysregulation syndrome by deep brain stimulation in refractory cases. Other important syndrome to be considered includes dopamine agonist withdrawal syndrome which results from rapid down titration of dopamine agonist or withdrawal of dopamine agonist suddenly. The clinical symptoms include fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, psychological symptoms like anxiety, depression, dysphoria, panic attacks and suicidal ideations. It can also manifest as generalized pain or as well as drug cravings. Now talking about depression in Parkinson's disease, the prevalence of depression in Parkinson's disease is very high which is about 38% and it can occur in combination with or as comorbidity as with anxiety disorder. The pathophysiology is poorly understood. However, it is considered to be multifactorial and as discussed before, the neurotransmitters involved are serotonergic receptors, noradrenergic receptors, acetylcholine receptors and dopaminergic receptors that may be involved in the presentation of depression in Parkinson's disease. And the severity of symptoms of Parkinson's disease is in correlation with severity of depression. As Parkinson's disease progresses and worsens, the severity of depression can also worsen. It has been positively correlated. Now talking about the scales that can be used to assess the depression in Parkinson's disease which include Hamilton Rating Scale for depression, Beck Depression Inventory, Hospital Anxiety and Depression Scale, Montgomery Asperger Depression Rating Scale, Geriatric Depression Scale. These all scales can be used to assess the depression in Parkinson's disease. Management includes symptom severity to assess the symptom severity and to see what kind of effect it is having on patient's quality of life. If it is very minimal and not disturbing to the patient, then you don't wanna start any medications. But if it is impairing their lifestyle or their personal or professional life in any way, then you wanna treat it with selective serotonin reuptake inhibitors or SNRIs which is serotonin noradrenergic receptor inhibitors, TCAs or myob inhibitors. SSRIs are most commonly prescribed to manage depression in Parkinson's disease and the choice of SSRI is dependent on the side effect profile and you also have to make sure that there is no drug-drug interactions with other medications that the patient is on. Other treatment for depression in Parkinson's disease includes myob inhibitors. When you're using myob inhibitors, you have to make sure that there is no serotonin syndrome involved because there is a risk of serotonin syndrome when you're combining dopamine agonist medications along with myob inhibitors. TCA medication which is tricyclic antidepressant can have a potential advantage in promoting sleep in individuals who suffer with insomnia and this has to be carefully monitored as well because TCAs have anticholinergic side effects and daytime somnolence, especially in the elderly population. Depression in Parkinson's disease is associated most commonly with female patients, patients carrying the GBA1 mutation and this is associated with freezing of gait, apathy, anxiety, and fatigue. Now let's talk about psychosis in Parkinson's disease which is also very prevalent in Parkinson's disease patients and the prevalence is around 43 to 63% which is very high and it increases as the disease progresses. It is associated with poor quality of life, disability, caregiver stress, decline, hospitalization, institutionalization, morbidity, and mortality. In 2007, National Institute of Neurological Disorders and Stroke and National Institute of Mental Health has proposed a unified Parkinson's disease rating scale which includes the presence of at least one psychotic symptoms to assess the psychosis in Parkinson's disease. And again, similar like depression as the prevalence increases as the duration of the Parkinson's as the disease progresses. The risk factors include duration and severity of illness and cognitive impairment. Anecdotally, it has been observed that there has been an association between Parkinson's disease psychosis and the use of dopaminergic therapy, that is dopamine agonist therapy and the duration of treatment as well. Psychotic symptoms are most potently seen with the use of dopamine agonists. This is a brief overview of unified Parkinson's disease rating scale that is used for the assessment of psychosis in Parkinson's disease. It has three components. Component one includes assessing the mentation, behavior, and mood. Component two, it assesses the activities of daily living. Component three, it assesses motor symptoms of Parkinson's disease. Now coming to treatment of psychosis. So we need to identify the psychosis first and then treat it. Many people who have Parkinson's disease may have very mild visual hallucinations or other very mild paranoia or very mild symptoms of psychosis and they may have insight about it and it may not be causing them any distress. So what you do in that case is just wait and watch and you don't give them any antipsychotic medication. But you have to see if it is interfering with their functioning in personal life or in their quality of life, then you may want to treat the psychosis. And the treatment includes using medications like rivastigmine, which has been established to have good efficacy in treating the psychosis of Parkinson's disease. Clozapine and pimvansirine can also be used. Pimvansirine has been FDA approved for management of, FDA approved for the management of psychosis in Parkinson's disease. Other atypical antipsychotics which have been studied include Seroquel, Quetiapine, Olanzapine, Zypraxa, Risperidone as well. And you need to use these medications with caution because of the side effects that these medications have. The NICE guidelines also proposed that, in 2017, also proposed the low dose Seroquel and Clozapine as the best medications for treating the Parkinson's disease psychosis. However, in clinical practice, currently Quetiapine is very commonly used, but again you have to make sure the patient does not have any other comorbidities and does not have any side effects. Cognitive impairment in Parkinson's disease. It is very heterogeneous in terms of its presentation, severity and progression and in terms of the domains which involves. It has a negative impact on the quality of life of the patient. In idiopathic Parkinson's disease, a cognitive impairment ranges from MCI, that is mild cognitive impairment, to dementia. But does not have necessarily, has to progress linearly as well. 40% of the patients have cognitive impairment at early stage of dementia, early stage of Parkinson's disease. 80% of the patients have dementia at the late stage of Parkinson's disease. MDS, that is Movement Disorder Society Task Force has reported MCI in Parkinson's disease as prevalent as 27%. In Parkinson's disease dementia, cognitive impairment presents one or more years after the presentation of Parkinsonism. Whereas in Levy Body Dementia, cognitive impairment presents before Parkinsonism. The features of cognitive impairment in Parkinson's disease dementia includes the impairment of executive functioning, that is decision making, planning, problem solving, maintaining or shifting attention, and inhibition of habitual responses. There is visuospatial impairment as well. Impairment in attention, bradyphrenia, that is psychomotor slowing can also be seen in cognitive impairment in Parkinson's disease. Mild to moderate memory problems, internally cued behavior as well. Risk factors for cognitive impairment in Parkinson's disease include age, severe motor disability, male sex, visual hallucination, postural instability, gait disturbance, bradykinesia, and poor response to levodopa. Treatment of cognitive impairment in Parkinson's disease. It includes medications like Donapizil, which is an acetylcholesterase inhibitor. You start with five milligram once daily for four to six weeks and then increase it to 10 milligram daily if well tolerated. The other medications that are used for treatment includes Revastigmine that is available as oral medication and also as patch. Revastigmine oral can be started as 1.5 twice daily for four weeks, then increased to three milligram twice daily and the max dose that can be given as six milligram two times daily. Revastigmine is also available as a patch because of the GI side effects that oral Revastigmine has. The patch comes in the form of 4.6 milligram as 24 hours for four weeks and then you can increase it to 13.3 milligram for 24 hours if tolerated well. Other medications that can be used includes Galantamine that can be started at eight milligram daily as an initial maintenance dose and can be increased to 16 milligram daily. Memantine, which is an MDA receptor antagonist can also be used and that can be started as five milligram as BID dosing and increased to maximum of 20 milligram per day as tolerated. Now let's talk about Levee Body Dementia. So in Levee Body Dementia we have two disorders which include Parkinson's Disease Dementia and dementia with Levee Bodies as well. They both come under the umbrella of Levee Body Dementia and the common neuropathology is about deposition of alpha-synuclein deposits as Levee Bodies in the substantia nigra. It can present with wide range of cognitive, neuropsychiatric, sleep, motor and autonomic symptoms. There is an impairment of attention, executive and visual perceptual functions as mentioned before in both Parkinson's Dementia and dementia with Levee Bodies. Now let's talk about the overlap between Parkinson's Dementia and dementia with Levee Bodies. The overlapping symptoms include rigidity, akinesia, cognitive impairment, frontal executive dysfunction, visual constructive impairment, mild language impairment, mood disturbances and REM sleep behavior disorder. The dissimilarities, I'm just gonna go about it very briefly, include majority in dementia with Levee Bodies there is a deficiency of attention more compared to Parkinson's Disease Dementia. Tremors are less frequent in DLB. Hallucinations in DLB are more as in the form of visual hallucinations in DLB compared to Parkinson's dementia. Onset of dementia is earlier in Parkinson's dementia as we discussed before. Orthostatic hypotension occurs more common in DLB. Frontotemporal associated cognitive subsets more severe in DLB. Cognitive decline is faster in DLB as well. The other more frequent symptoms of DLB includes delusions, visual hallucinations, and attentional fluctuation, which is more prevalent in DLB compared to Parkinson's dementia. Treatment of Parkinson's dementia. The only drug currently FDA approved for Parkinson's dementia is rivastigmine, which is an acetylcholesterol inhibitor. However, memantine NMDA receptor antigenase can also be used as second line for the treatment of Parkinson's dementia. Delirium is also one of the neuropsychiatric manifestation of Parkinson's disease, and it has to be managed accordingly. So concluding, Dr. Dix is gonna talk about the conclusion. Okay, so in conclusion, the neuropsychiatric manifestations are common and devastating. If we review back and think about case one, where we had my patient who was a 60-something year old female with early onset Parkinson's and very bizarre behaviors at her independent living facility, which can probably be categorized as sort of impulse control type behaviors, but also some of the dopamine, it relates not just to dopamine withdrawal, but I think it was dopamine sensitivity. Some of the behaviors where she was repetitively and almost chronic, almost OCD-like type behaviors are something that's called punding, I learned, and can be seen in patients with Parkinson's. Again, we've seen apathy, depression in the second case. Was that a case of worsening depression? Was it a case of worsening Parkinson's disease? Neuropsychic symptoms, or was it a case of dopamine withdrawal because we stopped taking our carbidopa levodopa? And also in that case where the individual, the 76-year-old man, was just not getting out of bed, not showering, not taking care of himself, and the wife would say, he just won't get out of bed. He says, I can't. It turns out that he was not only very, very anxious and self-conscious about his tremors in public, but he also had a slight bit of paranoia, which we ended up having to treat with a low-dose antipsychotic. He was afraid that he was going to be arrested if he left the house. So this man didn't leave the house or shower for weeks. It was very sad. And I think the moral of the story is these are complex patients with complex symptoms and a collaborative approach with a multidisciplinary team, including psychiatrists and neurologists, and is essential for assessing and managing these symptoms and to hopefully mitigate the resulting negative impact on the patients, their families, and society. I think the last but not least, the moral of this lecture is Parkinson's disease is not simply a movement disorder. There are, as you heard, many, many neuropsychiatric symptoms that present, and oftentimes as prodromal symptoms. There are times when patients present with features that we can't really figure out. Is this Lewy body dementia or is this Parkinson's disease dementia? And so it's very complex, requires multidisciplinary collaborative approach. And overall, this is an increasingly prevalent neurological disease, not only in the United States, but globally, and as we have seen, the data is showing that the global burden of diseases is quite high, and as the population is aging, we'll only continue to do so. Well, thank you all for your attention. I apologize for not being able to show you the remaining slides with our references because of our lack of power, but we can open up to questions now. Thank you. In one of the initial slides, you had the reason for the anxiety you had is like the dopamine and the norepinephrine system, but don't you think the serotonergic system is also quite involved in the anxiety? And also in the patient that you talked about, the 60-year-old female that came in with the anxiety, you are saying that you used the bupropion and the lorazepam, don't you think the bupropion would be worsening the anxiety in that patient? Great question. So this was a patient who was placed on bupropion and lorazepam by a nurse practitioner, her psychiatric nurse practitioner, prior to hospitalization, unbeknownst to her neurologist. And that's part of probably the first part of the problem. And the neurologist kept adjusting her carbidopa levodopa. She kept feeling like her anxiety was worse with her off symptoms. And in fact, what ended up happening is I increased her Welbutrin during the hospitalization, added Entecapone after speaking with her neurologist. The Entecapone helped to reduce the off periods because it was very obvious when she was just about to get her next dose of carbidopa levodopa, she was on five times daily immediate release, a controlled release at nighttime, and then the extended release three times a day, so a lot, right? But the Entecapone helped to reduce the off periods and she ended up doing better. So it was sort of like this in-between of depression and anxiety, which one was making which worse for this patient. There's always concern, but I think in the inpatient setting that was the beautiful thing about being able to really watch and slowly adjust medications as needed. Did this go out? Yes. Okay. We're just doing questions now, so it's okay. Are we done? Yeah, you can, please. One more. I'm Joe Simpson, San Antonio. I've done ECT most of my career, and we know that ECT will definitely improve Parkinson's. Is there any chance that it could become a more useful tool? I had the impression it may even tend to reverse the course, which nothing else does. Just a question. I certainly hope so. I do a lot of ECT, and I've had patients with Parkinson's disease have really great results in both their depression and some of their motor features. I think the problem that I've sort of encountered is that my colleagues don't necessarily think that ECT is for Parkinson's. ECT is for Parkinson's disease motor symptoms, right? So we use it for depression, catatonia, but I think that it really could be a fantastic modality of treatment and much more readily available than DBS or palatotomy, I think, so. Well, I mean, does it actually, do you think it tends to reverse the course? I mean, I wouldn't get it myself if I had a heart. Well, reverse the course of like the depression. I don't think it can necessarily reverse the course of the, you know, right. But I did have a very, very, really, really good outcomes with patients with Parkinson's disease and depression. But of course, with other medical comorbidities, it can be very difficult to just cure everything, right? Okay, thank you. Thank you very much for your presentation. And I would like to ask you about the use of bupropion as an antidepressant for depression because you didn't recommend it as first-line choice treatment. And I was wondering if there is any reason for that. First line, I personally don't have any problems with bupropion. I think with the patient case that I mentioned, she also had co-existing ADHD, so the bupropion was good for that. I've used bupropion in patients with Parkinson's, especially those getting ECT. It kind of helps with the seizure threshold. And, you know, I think there's some controversy, however, because of the dopaminergic aspects of, if it could potentially in some people, perhaps, you know, make maybe anxiety or psychotic symptoms worse. So it really, it's gonna be very dependent, I think, on the person. Thank you. Yeah, this is Dr. Ramana Rao from India. Do you have any strategies for the prevention of Parkinson's disease, especially pharmacologically as well as lifestyle modifications? Especially rosacelizaline is a drug that is available in India. It's supposed to, you know, slow down the degeneration of the negrostatial pathways. Any comment upon that? And also the role of the lifestyle modifications, especially physical exercise in the reduction of the symptoms of, especially the motor symptoms, cognitive symptoms, lifestyle modification, prevention. I have a really good case from my residency program of a patient with Lewy body dementia who was living with a caregiver. And it was not a good situation. And I was able to advocate for this man to get out of that situation. He lived in his own apartment. And he did boxing for Parkinson's disease every week and was able to really, you know, his cognition, his motor symptoms really, you know, they were kind of very mild and limited. So I really do believe it could be just an outlier, but boxing for Parkinson's is very, very important. All the exercise programs that exist. I don't know if we can absolutely 100% prevent Parkinson's disease from occurring. And I do think that especially with the use of psychiatric medications that can cause drug-induced Parkinsonism, there's that small percentage of folks who have the idiopathic Parkinson's unmasked. But I think diet, exercise, and life, yeah. And sleep. Sleep, I shouldn't, I should practice what I teach. Rosacelizine, the drug which we use, yeah, Rosacelizine. Any experience with that? Yeah, I've used Rosacelizine and Tecapone. I've had really good responses with Rosacelizine. But not necessarily prevention. And I'm not sure, I don't know if there's data to use it to see how it might slow progression. I think there have been data about once a disease has been established that you can use Rosacelizine, but I don't know about the data about prevention using Rosacelizine as prevention for Parkinson's disease. But to your question, lifestyle modification certainly can be very helpful. But Rosacelizine, I have not read about it. And maybe there is, but we are not sure about that as prevention. Hello, Alan Anderson, Tucson, Arizona. Jerry, a psychiatrist there. So thanks for bringing this to this meeting because it's a very important issue of managing the neuropsychiatric aspects of Parkinson's disease. I also want to make a comment. I appreciate the updated info. A lot of clinicians still don't realize that cognitive impairment is very common. In fact, you mentioned up to 80%. And some people even say it's because some Parkinson's patients die before they get dementia. And I want to make notice of that because the most recent Alzheimer's Association 2023 facts and figures still cites an old percentage of around 30 or 40%, which is just not true. So thank you for that. But I do have a question about whether there's any true, good studies that look at light therapy for sleep disturbance because obviously that's a very commonly thing that I even use in some of my dementia patients. But, and I'll just mention it, if you move to Tucson, Arizona, you don't actually have to buy a light box because we hardly have any clouds there. So you can actually get all the light from the sun. But any knowledge of any studies? So there have been few studies for the use of bright light therapy in depression for Parkinson's disease. But I don't think we have documented that in the slides. Yeah, and I'm more referring to for the sleep disturbance. Again, there's good data about using morning bright light therapy for people who are having insomnia or late in the day therapy for people who are having phase advance. Yeah, that's a good question. Circadian rhythm disorders are also one of the component or neuropsychiatric manifestation of Parkinson's disease, especially in those type of sleep disorders. Bright light therapy has been studied to be very helpful. And any dose recommendations? 10,000? Oh, doses. Yeah, how long and how long do you use it? Oh, I don't know how long. Yeah, I think I've read about 10,000 lux, but I don't know much about the duration. I think you just ask them to use it as a disease progresses and depending on the other factors as well. Thank you. One last question. Good morning, congratulations. What is your experience with transcranial magnetic stimulation? Thank you. TMS has been useful in Parkinson's. I personally don't do a lot of TMS at Yale, but there are places that do. I found that unfortunately when patients come to me, they are so sick that they need to be hospitalized so sick that they need to get better much faster than TMS can do for them, so that's why we go for ECT. But it certainly is something that if a patient's able to and there's access, I think that it can be helpful. But again, the studies vary. There are plenty of people who end up with treatment-resistant depression after TMS or even ECT and then go on to get deep brain stimulation. So it really will, it kind of depends. Corinne Sabatini, I'm a geriatric psychiatrist based in Canada. I have a few patients with Parkinson's and depression and dementia and I've really been struggling. The one I need to keep on maintenance, ECT, when they develop cognitive impairment due to Parkinson, then you add on the short-term cognitive impairment due to ECT, it's really hard to manage, right? So do you have any tips or tricks with how to minimize the cognitive impairment with ECT, like different uses of different anesthetics like we've brainstormed, but if you have any recommendation of your. I find the bifrontal and right unilateral approach, but also just spacing out the treatments can be very helpful. I know in Canada, usually it's twice weekly, where acute series, whereas in the States, it's three times weekly, but spreading things out even more can be important and I think also just being very clear to know the timeline because sometimes the cognitive fogginess and slowing that one might be experiencing during an acute course of treatment can also be sort of confounded by their Parkinson's medications and the off periods and just wanting to have a functional sort of bar or goal, so what is the goal for this treatment? If, for example, the patient I had with failure to thrive, I mean, he'd lost 30 pounds, he wasn't eating, he wasn't getting out of bed, he was neglecting himself, that would have been, right there, I said, well, the cognitive effects, we'll worry about it later, we need to get you better. Just a quick question, thank you for this wonderful talk. Several of the treatment slides had rivastigmine by itself and I was just curious, is there something unique about rivastigmine in those situations or would any of the other acetylcholinesterase inhibitors also work? I think many studies have studied more particularly about rivastigmine, donepizil was also studied, but I think it's depending on the tolerance and the side effect profile, rivastigmine appeared to be more useful over donepizil in some of the studies. I don't remember exactly the study, which author, because I've reviewed several articles, but rivastigmine was well tolerated over donepizil. You can also try donepizil as well, but again, based on the literature, rivastigmine was very well tolerated, that's why it has been FDA approved. And personally, if you have a patient who's on, I guess, carbidopa levodopa eight times a day, sometimes being able to put a patch on is really nice, you know, let's reduce the pill burden, but that's just my personal opinion, but I don't know if that's the reason why FDA approved it specifically for cognitive impairment in Parkinson's. Any other questions or comments? Actually, while we're on the topic of rivastigmine, is it true that it has, because I heard from one person that it was because there's the burden of autonomic dysfunction is a bit less with this medication, is this true? I think so, personally, just from my personal use of donepizil and sometimes the risks of bradycardia, just like the specific case of the patient who wouldn't get out of bed or shower, he actually had, I think, a flutter, pacemaker, was always living at heart rate of like the 50s, so I definitely don't want to give him donepizil, you know, so that could certainly, if you have someone with really severe orthostatic hypotension and you have to put them on minidrine and flujocortisone on top of it, then it makes it, and if they're not eating, donepizil can also kind of be anorexic, so. Yes, I think based on the GI and cardiac side effect profile as a response to the previous question as well, rivastigmine, again, was well-tolerated and it can be used compared to the other donepizil and it has been proved in several studies as well, that it can be safe in both from GI perspective and cardiac perspective. And any other questions? And thank you, everyone, for joining the session. Thank you.

Parkinson's disease

neuropsychiatric symptoms

collaborative care

Lewy bodies

motor symptoms

anxiety

depression

psychosis

treatment strategies

multidisciplinary care