PADRECC NATIONAL VANTS AUDIO CONFERENCE Lewy Bodies and Dementia in Parkinson’s Disease John E. Duda, M.D. January 14, 2010 Let’s go to slide #3, the Objectives. For this talk to understand the relationship between dementia with Lewy bodies and Parkinson’s Disease with dementia. To identify recent changes in the diagnosis and management of those conditions and to understand the emerging role of neuroimaging and the diagnosis of Parkinson’s Disease with dementia and Lewy bodies. Next slide. One of the main advancements in the last decade or so of Parkinson’s Disease research and management is the understanding that Parkinson’s Disease is not just a dopaminergic disease. Many of the components of the nervous system and affected, including other neurotransmitters that include neuropinephrine, serotonin, Acetycholine and other systems and a lot of the symptoms that you get with Parkinson’s Disease are probably manifestations of dysfunction in these systems that are not dopaminergic mediated and therefore not amendable to dopaminergic replacement therapy so that they need alternative therapies. Dementia is probably one of them. Next slide. This describes the core features of the diagnosis of Parkinson’s Disease with dementia, including #1, the diagnosis of Parkinson’s Disease according to the Clean Square Brain Bank criteria and #2 is dementia syndrome with insidious onset and slow progression, developing within the context of established Parkinson’s Disease and diagnosed by history, clinical and mental examination defined as impairment in one or more cognitive domain, that is a decline from a pre-morbid level and includes deficits that are severe enough to impair activities of daily living, either social, occupational or personal. That’s often the tricky part in diagnosing PDD because motor dysfunction can obviously impaired ADL’s as well and distinguishing what impairments are due to the cognitive dysfunction rather than the motor dysfunction is sometimes difficult. The cognitive domains that are often impaired include attention, executive functions, visual special functions for the recall memory that usually improves with queuing so that if you give five items, they may not remember that, but with category or multiple-choice ques, they can often retrieve them. There are obviously other behavioral symptoms that we will talk about more that can support the diagnosis, but are not necessary for the diagnosis. Basically, these criteria develops to lay down firm consensus criteria, but also to distinguish the diagnosis of PDD from the diagnosis of Alzheimer’s Disease, which obviously relies more on a deficit in memory function. At the time, there are already existing criteria for the diagnosis of dementia with Lewy bodies and these criteria were consistent with those. Next slide. So some patients with Parkinson’s Disease will have Lewy bodies, aside with dementia will have Lewy bodies in many areas of their brain. This is just a representative, just a micrograph of a brain site that is showing the peel layer and somewhere around here would be the light matter layer. The larger dots you see on the lower part of the micrograph are Lewy bodies in a higher power micrograph and then there’s also a lot of aggregates within axons and probably dendrites that represent dystrophic neuritis. That’s what we call Lewy pathology and kind of the pathologic hallmark of these conditions. But, when you see a patient that has dementia and has this on their brain instead of the typical we see with Alzheimer’s Disease, what do you call that? Next slide. Different people called a lot of different things for many years and then in 1996, there was a consortium of experts convened to try and standardize this condition and the diagnosis of this condition. Next slide. The term that they chose was dementia with Lewy bodies. They came up with consensus criteria that they felt stated or suggested the state of the art in the diagnosis and were meant to be validated in the future. I am not going to go into these in detail there because many of them are reiterated in the follow-up set of criteria. Next slide. The validation of the initial criteria revealed some interesting things. If you look at some of the larger studies that had sufficient numbers of DLB and other dementia types to confirm the diagnosis that the sensitivities were pretty good, 79%, 90%, 100%, 84%, 95%. Some of the studies also had pretty reasonable sensitivity also, 85%, some of the studies were a little under represented with DLB patients, but then you also see other studies that had significantly lower sensitivities, suggesting that the criteria were a little too rigorous and that they should be broadened a little bit to capture some of these other patients who ended up having dementia with Lewy bodies, pathologically. Next slide. That did rise to a consensus statement in 2005, which we sometimes refer to as DLB3, but basically revised the diagnostic criteria and so let’s go through those briefly now. The central feature of course is dementia. You have to have dementia defined as a progressive cognitive decline of sufficient magnitude to interfere with normal, social or occupational function and then there are features including fluctuation cognition with amounts of variation in attention and alertness. Recurred visual hallucinations that are typically well formed in detail and the spontaneous features of Parkinson’s. In order to make a diagnosis of probably DLB, you need two of these core features and in order to make a diagnosis of possible DLB, you need the central feature and one core feature. Next slide. The one that changes with this set of criteria was the addition of suggestive features, including REM sleep behavior disorder, severe neuroleptic sensitivity and low dopamine transporter uptake in basil ganglia demonstrated by SPECT or PET imaging. We will go through some of these symptoms in a little more detail in further slides, but essentially in order to improve the sensitivity of this criteria, the new criteria allows one suggestive feature and one of the core features to give a diagnosis of probably DLB and you could even make a diagnosis of possible DLB in the absence of the core features. So, without hallucination, Parkinsonism or cognitive fluctuation, as long as you have a demented patient with any one of these three features, you can still make a diagnosis of possible DLB. Next slide. Both sets of criteria had supported features that lacks a diagnostic specificity to be included in the rigorous, but can support the diagnosis and the new criteria included several more that were not included previously, including many of the imaging studies that you see in the latter part of this slide, including low uptake on the SPECT/PET perfusion scan with reduced occipital activity, abnormal MIBG myocardial scintigraphy, relative preservation on the temporal lobe, structures on MRI. So, these features are supportive of the diagnosis, but not necessary for the diagnosis. So, I am not going to pretend that we are done playing the numbing clinching game, but this is a current stay of the field. We currently think of dementia with Lewy bodies as DLB, Parkinson’s Disease is obviously PD. Parkinson’s Disease with dementia is PDD and currently the main distinguishing feature between DLB and PDD is the time to onset of dementia. So that if a patient with Parkinson’s Disease develops dementia after one year of developing Parkinsonism, we call it Parkinson’s Disease with dementia or if the patient develops Parkinsonism and dementia at the same time or within one year of each other, then we call it dementia with Lewy bodies. One thing Parkinson’s Disease, Dementia and Dementia with Lewy bodies together, you get the Lewy body dementias and the Lewy body diseases in total are PDD, DLB and non-demented Parkinson’s patients. Next slide. However, if you look at an autopsy series of patients who end up having a lot of Lewy bodies in their brain, almost all of them will end up falling somewhere around this chart. So, there are some patients who just have Parkinsonism and end up getting a diagnosis of PD and some patients who just have dementia and get a diagnosis of DLB. Occasionally, you will see patients with REM sleep behavior sleep disorder and no other nerve degenerative symptoms, but they can have Lewy body pathology in their brain and then some patients with pure autonomic failure can get diagnosed with MSA or pure autonomic failure, when in reality their brain, the pathology is Lewy pathology. So, overall, the majority of patients though will have a combination of these symptoms and will either get a diagnosis of PDD or DLB. Next slide. How prevalent is Lewy body dementia? Well, it’s difficult to say with any degree of certainty, but rough estimates include a recognition that DLB probably causes 10% - 15%, possibly 20% of dementia in the general population. 25% of cases of Alzheimer’s Disease have Parkinsonism and most of them will have Lewy bodies at autopsies, so you can think of that as a form of Lewy body dementia really can ?? illnesses and then obviously PD has a large incidence of dementia, particularly with increasing age. So, if you total all of that up, there are probably somewhere around 1.5 – 2 million people with Parkinsonism and dementia that can be turned to have Lewy body dementia. Next slide. Evaluation of these patients has not advanced very much since 10 years ago. We will rely heavily on the history and physical examination and neuro psychometric testing. But, neuroimaging, I think on the cusp of becoming useful in this process and we will talk a little bit more about that at the end of the talk. Next slide. For a screening instrument, this is for Parkinson’s Disease primarily, but for screening there are several choices. Obviously, the one that most of us have used the longest and the most is the MMSE, which was developed for the diagnosis of Alzheimer’s Disease, but has been recommended as a screening instrument for Parkinson’s Disease as well in particular the same movement task force except using the MMSE, but we would argue, my colleagues at the Philadelphia PADRECC would argue that a better instrument, next slide. Would be the Montreal Cognitive Assessment, which is a similar one age, 30 item test, but we think is better because there’s a less of an emphasis of AD related cognitive impairments like memory and language dysfunction. There’s a better representation of executive dysfunctions and attention. It is free online, unlike the MMSE now, there is, as I said a total score of 30 and in the general population a score of 25 or less is indicative of at least mild cognitive impairment. Next slide. We have used this test in several investigations of cognitive impairment in our Parkinson’s Disease population here at the Philadelphia PADRECC at the University of Pennsylvania. Dr. Dan Weintraub, who you may recall from an earlier lecture in this series, spearheaded these investigations and in one of them, we took about 130 patients and eliminated those who had what we declared cognitive impairment by being less than the 25th percentile on age and sex matched MMSE scores. That left us with 100 patients and we administered the MoCA to them and somewhat to our surprise, even though their mean MMSE score was 29, 52% of those patients scored less than 26 on the MoCA, meeting predetermined criteria for cognitive impairment using that test. Now you could argue that it just may be too sensitive in a PD population, perhaps some of the motor components or some of the components that require patients to use a pencil, may be too difficult or whatever, so it requires further validation, which we will talk about in a second, but we did want to make sure that it wasn’t one component of the MoCA that was driving this determination of the cognitive impairment. Next slide. We look at the different sub scores within that test and as you can see, nearly every test revealed significant differences between the group that was declared to be cognitively impaired and the group that was unimpaired, including the more AD relative functions, as well as the PD relative functions, like visuals, facial, executive dysfunction, attention, etc. So, it was kind of a broad base cognitive impairment even in these Parkinson’s patients who are not demented because they did not have impairment of activities of daily living and MMSE scores were normally cognitively. Next slide. If you look at the factors that were correlated with the separation of cognitively impaired and cognitively intact patients and remember, these are almost all men, mostly from the VA, but there were some women from our University site. The factors that correlated with that were age, as you might expect, male, sex, a lower education and greater disease severity as judged by the Hoehn & Yahr Scale, at least in univariate analysis. In multivariate analysis, the only factor that remained significant was age. Interestingly, the last line, you can see the duration of Parkinson’s Disease did not correlate with that distinction, which is somewhat surprising, as we all normally expect that patients with longer duration of Parkinson’s Disease are more likely to get cognitive impairment, but there may be features of this study that prohibited a distinction to be seen there and we can talk about that later in this discussion if you would like. Nest slide. As I mentioned previously, the other thing we wanted to do is validate the MoCA in the diagnosis of cognitive impairment in Parkinson’s Disease, so we took the full cohort of patients, I think 131 patients and looked at the discriminate characteristics for each test in this cohort and if you look at the graph, for example, the MMSE, as a screening instrument, to get an appropriate sensitivity, you have to go to a cut off of 29 or 30, so that only patients who get a perfect score of 30 are characterized as normal cognitively, while patients who have 29 or less are screened positive as having either MCI or PDD. Obviously, there are plenty of patients who probably remember the day of the week, but with this cut off, they would require further screening for cognitive impairment, so there is a sealing effect with the MMSE that is probably unfortunate as a screening tool. In contrast, the Montreal Cognitive Assessment defined a best screening point of 26 – 27 points, with the same sensitivity of 90%, but as you can see, better specificities, with 53% correctly diagnosed and other features, so that it has better test characteristics and doesn’t suffer from the problem of having a sealing effect. It important to recognize, however, that we are not suggesting that the MoCA is used for the diagnosis of Parkinson’s Disease with dementia or MCI because if you look at the specificity of that cut off level, it’s still too low to achieve that standard, so that patients who screen positive with a MoCA we will then recommend getting further neuropsychological assessment to really clarify if it is a patient with MCI or PDD or not. Next slide. Next, I want to just talk briefly about several of the features that we see in dementia with Lewy bodies in Parkinson’s Disease dementia that are not commonly discussed in movement disorder circles. The first one and perhaps the most confusing aspect is the cognitive fluctuations. They include spontaneous impairment of alertness and concentration so that the patients may appear drowsy, but awake, look dazed and they can vary on a temporal scale from hours to hours to day-to-day or week-to-week. They often include a loss of consciousness so that many of these patients will end up in the ER and it is not uncommon for me to get calls from ER or outside hospital physicians talking about the patient with loss of consciousness who has had an appropriate work up for seizures and strokes and other things that might cause that, that have been unrevealing and often I chalk that up to cognitive fluctuations. They are not epileptic as I said, as they have no EEG correlate. But, diagnosing these isn’t always easy. There are some scales to help with that diagnosis. One of them is the Mayo Clinic Fluctuation Scale. So, there’s about 15 items, Furman and Colleagues in 2005, looked at the outcome of that scale and saw which items were more likely to distinguish DLB patients from ADD patients and they actually came up with the four items that you see at the bottom here. Questions about whether out our patient is drowsy or lethargic during the day, whether they sleep for two or more hours during the day, whether their thinking is logical, unclear or incoherent and whether they stare into space. There were questions, obviously, about does their attention seem to fluctuate, but they were not found to discriminate between patients with DLB and AD, possibly because it’s hard for caregivers to differentiate that in the two different patient groups. So, you can use this scale to help and then there are other ways as well. Next slide. Other behavioral abnormalities that we see in these conditions, obviously, are visual hallucinations, which are usually well-formed people or animals visualized. They can occur early in the course of the illness as opposed to Alzheimer’s Disease. They obviously are more common in patients with poor eyesight and sometimes it’s difficult to differentiate the illusions and visual hallucinations, but from a therapeutic standpoint, it may not matter that much. Delusions are also common. Delusions are misidentification, so they don’t know who their spouse is or they think they are someone else. Persecution or paranoia, phantom boarders, abandonment, they are all not uncommon delusions seen in these conditions. Next slide. As I mentioned before, there was a previous lecture in this series about neuropsychiatric manifestations of Parkinson’s Disease by Dr. Weintraub and I think he went over a lot of these aspects. There obviously are mood changes in DLB and PDD, apathy and Amotivational states, aggression, nocturnal issues, but I am not going to go into those in any more detail at this point. Next slide. One other interesting component is REM Sleep Behavior Disorder, which is a kind of parasomnia that involves acting out violent dreams. They are usually, the patient is being chased or attacked or they are attacking someone else during REM sleep so that they mostly occur in the latter part of the night, early morning. They involve shouting, kicking, punching and often to the point of hurting themselves or their bed partners. One key component is that when they wake up they should remember the dream, which helps to differentiate from some other parasomnias. Fortunately, they respond well to low dose clonazepam, sometimes at .5 milligrams at bedtime. Next slide. So what else do we do for these patients, especially for the cognitive components? Next slide. In order to understand the management, it is important to keep in mind this interesting analysis from Nick Bohnen that came out in 2003, wherein he described the acetyl cholinesterase activity by functional imaging in the brains of patients with Alzheimer’s Disease, Parkinson’s Disease and Parkinson’s Disease with dementia and if you look in many areas of the cortex, the dark bars are Alzheimer’s Disease, the gray bars are Parkinson’s Disease without dementia and the light bars are Parkinson’s Disease with dementia. As you would expect, in every area there are reductions in acetyl cholinesterase activity in Alzheimer’s Disease patients, but then in several areas of the brain, including the cortical areas on the bottom, there are even greater reductions in Parkinson’s patients without dementia and the highest reductions are Parkinson’s Disease patients with dementia. So, as we often think of Alzheimer’s Disease as a cominergic mediated dementia, Parkinson’s Disease and Parkinson’s Disease with dementia has even more reason to believe that. Next slide. So, with that in mind, we are very helpful that the Central Acting Cholinesterase Inhibitors like MODERATOR IS UNINTELLIGBLE, Rivastigmine would be very beneficial in this group and the reality is that it is probably more to what we have seen in Alzheimer’s Disease. There are some patients that get modest improvements in cognition. It can help with hallucinations and other behavioral problems. There are some problems that believe it can help with gait problems, although I think that has yet to be proved. It does, I think, clearly help attention, not in a significant portion of patients, so that the medications, they may work better in this population than in Alzheimer’s Disease. Some people think the reason they got approved in the first place was because there were some contamination of the AD chords with Lewy body dementia patients, but they are certainly worth a try. Rivasitgmine is the only FDA approved treatment for Parkinson’s Disease dementia. Although, I think it is worthwhile trying the other medications as well in the VA, MODERATOR IS UNINTELLIGBLE, but I do have patients, some, who failed to get any significant benefit with Sedenapizle or Galantime and I have switched them to Rivasitgmine and some of them have its use and benefits. So, it’s worth trying more than one if they fail because lack of efficacy. It’s probably not because of side effects. The role of Memantine in the management of these conditions is a little more unclear. Their original study, suggesting that it could exacerbate the psychosis and one fairly well conducted double MODERATOR IS UNINTELLIGBLE, that really didn’t quite answer the question. Some of the pinpoints from that and some were not. So, it justifies a larger study, but really hasn’t answered the question regarding the use of Memantine in this population. Next slide. Regarding the management of the movement disorder in these patients, it becomes the balance between alleviating the motor symptoms and worsening the neuropsychiatric symptoms because a lot of the medications that we use as adjunctive therapies for Parkinsonism, including Dopamine agonists, anti-cholenminergics, and to a lesser extent, COMT inhibitors and MAO-B inhibitors can worsen the psychosis hallucinations and deliria, so that management is often optimal with cinematic mono therapy, which is usually what we try to do here at the Philadelphia PADRECC. Next slide. Regarding the management of the neurobehavioral symptoms, even in Alzheimer’s Disease, there is no FDA approved agents or the management of agitation and psychosis, depression. As you may expect, depression, we use the same medication that we use for depression in the other elderly population. Psychosis is managed with atypical antipsychotics and we will talk a little bit more about that in a minute. And then, the usual mood stabilizers and anti-convulsions are adjunctive therapy in addition to atypical antipsychotics for the management of agitation in these patients. Next slide. There are some concerns about the safety of antipsychotics in this elderly population, as I am sure most of you know, the FDA put out a public health advisory in 2005 suggesting that patients on these drugs did have a 1.6 – 1.7 fold higher death rate compared to placebo, which were caused by heart conditions and infections, so it wasn’t entirely clear how they were related, but it did kind of select out atypical antipsychotics. So, later the same year, Wang and Colleagues looked at the conventional antipsychotics and realized that they are just as likely, if not more likely, to have a higher risk of death, so it’s important that when discussing the management of these symptoms with your patients that there is this advisory from the FDA for a possible higher risk of death, but it’s still a low risk, obviously, and most patients would much prefer to take that risk and attempt to control the psychosis and the other behavior symptoms in these patients. Next slide. Regarding the different atypical antipsychotics, there is a bit of a relationship between D2 potency and extra parietal symptom effects, so that Clozapine seems to have the lowest incidence of exacerbating Parkinsonism. Quetiapine is probably second best and then the others come in somewhere below that. Although, I have had plenty of patients on Olanzapine and Risperidone, who have had significant worsening of Parkinsonism, who have switched to Quetiapine in particular and have seen some benefits. So, it’s certainly worthwhile trying to switch patients from those medications to Quetiapine if necessary, which has really become our first line of therapy because of the need for regular monitoring of Clozapine therapy. But, Clozapine does work the best and so, if you still are having problems with Quetiapine, it is worth trying. Next slide. In a study from Gerald Freeman and Stuart Factor, they looked at several of the atypical antipsychotics and as you can see, Quetiapine had as good or better improvement in psychosis in Parkinson’s Disease patients with a significantly less incidence of worsening of Parkinsonism. So, there are some data to support the use of that medication in this condition. Next slide. In summary, Quetiapine and Clozapine have become the first line agents for the management of psychosis. These patients will often respond to doses, which are much lower than commonly used for schizophrenia, so it’s highly recommended to start very low and go slow in the titration of these agents because we often find that they will respond to what some psychiatrist would be homeopathic doses of these agents. We do want to strenuously avoid typical neuroleptics to prevent neuroleptic sensitivity reactions, which are defined as some amounts of sedation, increased confusion, rigidity and immobility with substantial reductions in survival, often leading to a fatal outcome within days to weeks. I have had some personal experience with these and they do happen, so while they are rare, it’s really a shame to have patients be admitted to an outside hospital, get a single dose of Haldol and then end up never recovering from it. It’s something that we are trying to gain more recognition of in the field, particularly with geriatricians and primary care doctors and the like, to try and avoid that unfortunate complication. Next slide. The last section is the calmest section on the role of imaging and how I think in the not traditional future, imaging will impact our diagnosis and management of these conditions. Next slide. Whenever you talk about imaging of dementia, obviously, the medial temporal lobe atrophy comes to mind and people have looked at AD, which you typically see in Alzheimer’s Disease is medial temporal lobe atrophy and in this study by Tam and Colleagues, the rating scale that they propose is shown here, so that the top image shows a normal medial temporal lobe at the camp entorhinal cortex. Then each successive picture shows a more highly atrophy medial temporal cortex and looking at groups of controlled patients, Parkinson’s Disease, PDD, DLB and AD, you can see that while AD had the greatest degree of atrophy, the other Lewy body dementias also had significant atrophy compared to control, but interesting in this cohort, PD patients in DLB and PDD patients were not significantly different, suggesting that when they do get medial temporal lobe atrophy, they get it at an early stage, even before they manifest through dementia. Next slide. Others have looked at structural MRI changes in PD, dementia and DLB and even MCI in Parkinson’s Disease and suggested that there are changes on a group setting between these conditions. On an individual basis, I think we are still far from finding any sensitive and specific changes that will really help us on a day-to-day basis at the clinic. These studies are ongoing Next slide. Diffusion Tensor Imaging is obviously a problem to the foreign in Parkinson’s Disease research because of the possibility of using it as a diagnosis of Parkinson’s Disease. But, people have also looked at it in the diagnosis of Parkinson’s Disease dementia. This study, actually looked at 12 non-demented PD patients and 13 controlled, but it’s important to recognize that they defined dementia with the MMSE and had a MMSE score of 29, so that by our calculations about half of those patients would probably have cognitive impairment greater than the controlled subject. So, whether or not it’s a truly cognitively intact cohort is up for debate. Even in that group, they were able to show differences in Fractional Anisotropy, particularly in the medial frontal cortex, the right superior longitudinal fascicilus and left corpus callosum, the right singular drivus, so that as you call this modality assesses in integrity of white matter tracks, it specifically MODERATOR IS UNINTELLIGBLE, so it does seem to be a connection between the frontal lobes and other areas of the brain, which is consistent with the early frontal executive dysfunction that we see in Parkinson’s Disease. But, again, at least today, I don’t think there’s anything about these imaging studies that will allow us to determine, to be useful in the diagnosis of Parkinson’s Disease with dementia or dementia with Lewy bodies on an individual basis. Next slide. One other intriguing neuro imaging methodology is spearheaded by David Eitleburg, looking at patterns of spatial covariance in FDG-PET studies. He developed a pattern called the PDCP, which was developed by training computer to recognize the spatial pattern differences between a group of PD demented patients and a non-demented cohort and in 2008, he did this study where he applied that pattern to patients with multi-domain MCI PD, single domain MCI PD, normal cognition PD and normal and was able to show that even in these non-demented patients, you could see basically significant changes in the expression of the spatial covariance pattern within these groups. Again, not quite yet at the level where you it could be useful on an individual basis. Next slide. However, I think the modality that is closes to being translated to use in the clinic is Amyloid Deposition Imaging by SPEC and PET scanning, the most commonly used so far is the Pittsburgh compound of B, which recommends Amyloid Deposition, and as you can see in this picture, patients with Alzheimer’s Disease have dramatically increase uptake of this agent in the cortex in regions where Amyloid Deposition occurs compared to healthy aging, but also, patients with Parkinson’s Disease, dementia and dementia with Lewy bodies show uptake at least in the subset of cases compared to patients with non-demented Parkinson’s Disease. Next slide. Another group compared patients with these different diagnosis, AD, DLB, PDD and non-demented PD and showed that there are some patients shown on the bottom that have cortical PiB uptakes consisted with healthy control levels. So, these groups with non-demented, all of the patients with non-demented PD, some of the patients with PDD and some of the patients with DLB did not look that they had extra burns of Amyloid in the brain. But, then there were some patients with PDD and DLB that were showing levels in the same range as patients with Alzheimer’s Disease, suggesting that there probably are different cohorts of patients in these groups, some of which have common in Alzheimer’s Disease pathology and some were MODERATOR IS UNINTELLIGBLE, which is fairly consistent with what we see pathologically. Next slide. So, in conclusion, PDD and DLB are similar disorders. They probably lie upon a spectrum of Lewy body diseases. Diagnostic screening of PD patients may be improved with the use of the MoCA and remember it’s not for diagnosis, it’s for screening. So, someone who screens positive should have further neuropsychological assessment to determine whether or not there really is mild cognitive impairment or dementia. Management requires a balance between alleviating motor and cognitive symptoms and novel-imaging techniques may soon play an important role in our diagnosis and management of these conditions. So, now we are in one minute going to open up the phone line for questions. This is Sandy Whalen, I am a nurse practitioner in Cambridge. I’m actually on my cell phone driving home from ?? and I didn’t want to miss this. What about the use of Depakote for real agitated patients? I know that when I work with the Geri psychiatrist and did some nursing home consultations, that was a drug that he utilized quite a lot. He dealt with 250 DID and that patient that was really agitated, throwing things and they typically had, well it was an Alzheimer’s unit, but they usually, who knows what kind of dementia they really had at that point because they were pretty much chair down, total assistance, but real aggressive. I agree. I think Depakote is a valuable therapy in the management of aggression in this patient population. When you get back home and you look at the slides, it is one of the things that we put on the slide for use of convulsions. I think it varies from provider to provider on how comfortable they are doing that, but as a neurologist or people tuned into the management of these conditions, I think it is certainly something to consider and even recommend if you are colleagues are not aware of the potentials of that medication. Do you have many patients that really utilize Clozarel, Clozapine because with having to have the blood tested and whatnot, all of the particulars in terms of possible RESPONDENT IS UNINTELLIGBLE, I never really found it to be a favorite. So, as I tried to suggest in the presentation, we do use Clozapine. I think it’s a second line agent if, number one, Quetiapine is not successful in controlling the psychosis, Clozapine and obviously, there are issues with weekly CBC’s and everything. It obviously works well in patients in a nursing home setting, where you don’t have to worry about them coming in for blood checks, you can get those set up automatically. I think it pretty clearly is the best medication for that indication. So, if everything else fails, I think it is worth a try. Other questions? Relating also Depakote, I guess it is being used as a mood stabilizer, right or helping the patient like that? Yes. But how about the tremors, because Depakote can give a tremor. Not a big one, but I have seen a lot of people. That’s true. I worry because RESPONDENT IS UNINTELLIGBLE. . . I have had patients who have essentially exaggerated physiologic tremor and even Parkinsonism induced by proic acid. As with the management of most of the symptoms in these conditions, it becomes a balance between controlling the cognitive neuropychiatric symptoms and the motor symptoms. Sometimes patients and/or caregivers will tolerate a little exacerbation of tremor in order to control agitation and other neuropychiatric manifestations. So that if it happens, you know that that’s a possibility. Thank you. Thanks for bringing up that important point. This is Dr. ??? from Sioux Falls. My question is about treatment for the movement disorder in dementia and Lewy body. RESPONDENT IS UNINTELLIGBLE. . .so how high of a dose you would try RESPONDENT IS UNINTELLIGBLE. So, as with typical Parkinson’s Disease, non-demented Parkinson’s Disease, as you know, there’s really no upper limits to cinimate therapy. I think some patients, however, will not respond no matter how high you go. So, a general rule of thumb that I have is that if I try patients on 900 – 1,200 milligrams of cinima a day and I don’t see any benefit, I will probably stop there and stop fairly quickly, so that you can determine if it’s possible after slow titration, you may not really notice the difference between or the benefits that cinima is giving. So, I will titrate them off fairly fast and see if they get worse. If they don’t get worse after being 900 – 1,200 milligrams, then I categorize them as patients who are unlikely to benefit from dopaminergic replacement therapy and I don’t try anything else because I have not come across any instances where a patient will fail cinima and respond to something like a dopamine agonist. Thank you. Good question. John, this is Jay in Portland. You didn’t talk much between the correlation between the pathology and the clinical features. I didn’t want to put anybody to sleep. It obviously, as you know, is a big interest of mine. This is more a clinical conference with people of various degrees of expertise, but do you have a specific question you are interested in? I was just interested in if these patients come to pathology, how good is the clinical prediction that they are going to have diffuse Lewy bodies and the patients that really present early, do they also have a fair amount of Alzheimer’s changes as well? Two good questions. There have been a couple of confirmed studies, mostly out of New Castle that suggest that if you use these criteria, use them fairly rigorously, the specificity is pretty good. I think where some people argue that they are not so good is in the sensitivity. So, there will be patients who come to autopsy and end up having diffuse Lewy body disease who have not manifested the DLB ?? type or PDD type during life. There also, incidentally, a significant number of people with diffuse Lewy body disease who have no manifestation of neurodegenerative disease with either dementia or Parkinsonism. I think if you use these criteria, they are fairly specific, so if they have visual hallucinations and dementia and Parkinsonism, they are probably going to have diffuse Lewy bodies, but there are not insignificant number of patients who have typical Alzheimer’s Disease or other types who also have it. Sorry, I forget the second part of your question. The second part was about also having Alzheimer’s changes. Well, permanent Alzheimer’s pathology is something that I am interested in as well and I think it’s pretty clear from the pathological and imaging studies that there are cohorts of PD, dementia patients who have significant burdens of, particularly Amyloid pathology. You know, if there’s a recent study with only three patients, but showing PiB uptake and a diffuse plaque pathology and that’s mostly what we see pathologically is diffuse plaque, rather than the MODERATOR IS UNINTELLIGBLE, and less ?? pathology, although, I must say that several of the autopsy cohorts have shown a 25% - 33% of patients with ADD and DLB who also have enough plaque in tango pathology to make a confident diagnosis of Alzheimer’s Disease. In the early patients, I think it’s less common. As we discussed, patients with PD who get it at an older age are more likely to get demented and I think that goes the other way around as well. Patients who get PD at an early age are less likely to have Alzheimer’s Disease pathology, at least, unless they live for 40 years like they sometimes do. So, I refer you also to Glenda Holiday’s papers that have kind of looked at this and showed that there’s a big affect of age and people who get PD when they are older, pathologically are somewhat different from people who get PD pathologically who are younger. Thank you, John. Yes, you said some interesting things earlier about the latency between the onset of movement disorder and dementia in Parkinson’s versus Lewy body dementia. Could you say a little more about that? Yes, sure. I probably should have made that more clear in the slides, but by the consensus criteria, both for DLB in 2005 and the Emery Movement Disorder Task Force paper for the diagnosis of Parkinson’s Disease with dementia, we have settled upon the recognition that one of the main distinctions between those two diagnostic categories is the delay between the onset of Parkinsonism and the onset of dementia, so that patients who have dementia probably had Parkinson’s Disease for a long time before getting demented, we call Parkinson’s Disease with dementia, while patients say get demented first and later develop Parkinsonism or develop Parkinsonism and dementia at the same time or within one year of each other, then we call them DLB. The criteria basically say whatever is appropriate for the given patient in the clinic is fine to use, but for research purposes, those are the distinctions that we use. So, there are some patients with dementia with Lewy bodies who will never develop significant Parkinsonism and obviously it would be inappropriate to call them Parkinson’s Disease with dementia at this point. This is Sandy again, I have a question. Do you see any higher incidents of Lewy body dementia or Alzheimer’s or Parkinson’s with the Vets who have suffered TDI? So, we may get cut off, but the question was is TBI a risk factor for Parkinson’s Disease dementia and DLB and I think that the jury is still out. We have some data, but not enough. I think obviously the data supporting TBI is a risk factor for Alzheimer’s Disease plays into the equation because I think the common Alzheimer’s pathology is a prominent component of the reason that Parkinson’s Disease patients get demented and DLB patients are manifested DLB, so I think it probably is, but we really don’t have adequate, well conducted prospective studies to answer that question authoritatively. Thank you. END OF CONFERENCE. PADRECC National Vants Audio Conference Lewy Bodies and Dementia in Parkinson’s Disease John E. Duda, M.D. January 14, 2010 Page 15