PADRECC NATIONAL VANTS AUDIO CONFERENCE Nutritional Supplements in Parkinson’s Disease Marian Evatt, MD MS November 12, 2009 I appreciate this opportunity to speak to you about topics that are dear to my heart. When I do talks, I usually use a lot of transitions within the slides, so you will be hearing me say “[Next Slide]” quite a bit. It’s a little tough in this teleconference format, but please bear with me. [Next Slide]. Slide #3 – First, I want to give an overview of what I am going to cover in the next 50 minutes or so. I am going to start out by talking in general about vitamins and supplements then prevention and treatment of Parkinson’s Disease with regard to vitamins and nutritional supplements and include some of the current studies that are underway and then if you hit the advance, I want to briefly touch on some of the logistical nutritional issues that we encounter in the care of Parkinson’s patients. [Next Slide] -That includes weight loss, swallowing problems and, who are using diet to maximize medication effects. [Next Slide]. Then finally, of course, I will try to summarize today’s topids. [Next Slide]. Slide #4 - Why should we even both talking about this. [Next Slide]. There are three reasons. First of all, your patients are going to take vitamins and nutritional supplements. Second of all, I get questions all of the time about vitamins and nutritional supplements with regard to the Parkinson’s. Finally and perhaps most pertinent in this day and age of limited healthcare dollars, the expense is really not inconsequential. [Next Slide]. Slide #5 - A survey 120 consecutive Parkinson’s patients done by Wolfrath and Zezowitz in Florida, found that 63% of them took some kind of nutritional supplement. Over half took two or more and at least 40% took one. [Next Slide]. You will see in the pie chart, a breakdown of what were the most common supplements. Approximately half were multi vitamin supplements. A little over a third were Vitamin E supplements and then a significant minority were Vitamin C and calcium supplements. To me is some concern because the age group that people get Parkinson’s is when their calcium intake may actually need to be higher than what they are getting from their diet and taking in supplement form. [Next Slide]. Slide #6 - Now let’s look at expenditures. This data is getting old, but I think it’s still pertinent. If you hit the [Next Slide], you will see a horizontal bar rising along the left Y-axis. The Y. axis axis indicates the annual expenditure in billions of dollars for vitamins, minerals and other nutriceuticals. You will see in 1996 the green bars indicate there were at least 10 – 11 billion dollars spent for these compounds. [Next Slide]. That same year, Medicare expenditures on prescriptions were about $31 billion. About 1/3 of what we spend on prescription drugs is getting spent on vitamins and nutrition supplements. Slide #7 - Going to some more recent data on the [Next Slide] from Tan in Movement Disorders about three years ago: Looking at complimentary therapy use in an Asian and Chinese population we see ~$21.00 spent per month per patient on vitamins and supplements. [Next Slide]. This compares to about $56.00 or $57.00 to on traditional medical therapy. So, again, even outside the US, we are looking at about 1/3 of what is being spent on vitamins and supplements and yet the data sometimes is a little bit scarce to support taking supplements. [Next Slide]. Slide #8 - Now let’s switch gears and I want to look for a minute about what exactly are vitamins and dietary supplements and review cautions and pitfalls. [Next Slide]. Then I want to look at the specific vitamins and supplements that we use in Parkinson’s that have been investigated in Parkinson’s, including, Coenzyme Q10, Creatine, Gluthathione, Vitamin C, D and E. [Next Slide] Slide #9 The term vitamin was incorrectly coined from “vita” and “amine” because it was thought all vitamins were amines. [Next Slide]. Slide #10 Vitamins are organic chemicals that we humans require in small quantities to maintain normal health. Much of what vitamins are used for is converting food into energy. [Next Slide]. Slide #11 The vitamins fall into two categories, water soluble and fat-soluble. We have to include them in our diet because typically your body doesn’t make enough to support your health. There are some vitamins, including A, D and niacin that can be made from other components in the diet and of course, vitamins don’t supply calories, so we can’t live on vitamins and water alone. [Next Slide]. Slide #12 For water-soluble vitamins, Vitamin C, Biotin and the Seven B vitamins. Anything we take in excess of what we need, we essentially urinate out. [Next Slide]. Slide #13 The fat-soluble vitamins, including A, B, E and K are stored in fat. [Next Slide]. Also, they have a tendency or can become toxic. I remind patients they have to be very careful about these in particular. [Next Slide]. Slide #14 - Now, what is classified as a dietary supplements is actually defined by our lawmakers. In 1994, they passed the Dietary Supplement Health and Education Act. [Next Slide]. Slide #15 - What they say is anything that is labeled as a dietary supplement, [Next Slide] can contain one or more vitamins, minerals, herbs or botanicals (note: they specifically excluded tobacco for obvious reasons), as well as amino acids. [Next Slide]. They can be ingested in multiple different forms, tablets, capsules, liquid, but they are not to be represented as a conventional food source or some kind of sole meal item or diet. [Next Slide]. Slide #16 - Here, I have an example of Coenzyme Q10 to show when these products are advertised, they are often have very broad speaking claims. They may say “improve heart function, support heart performance,” but you will notice with the asterisks that there’s always a statement that “these statements have not been evaluated by the FDA and so it’s not intended to cure, treat or prevent any disease.” If you a patient brings in a bottle from which a supplement is supporting to treat, prevent or cure a disease, it is illegal and it should be reported to the FDA. One of the things that I am constantly reminding patients these products are regulated, similar to foods. They are not as strict as drugs. [Next Slide]. Slide #17 - Unlike drugs, they are not pre-approved for safety or efficacy. There are some special categories called Special Nutritionals, (for example, infant formula,) which may be geared toward the more vulnerable, population and therefore, may be more tightly regulated. [Next Slide]. Slide #18 - The other thing that I think is worth just reminding people of is some of the dietary intakes are based on the amount of intake in the diet that minimizes the deficiency. It’s estimated average requirement for a vitamin or supplement is. [Next Slide]. The RDA is that amount, which will keep 97% - 98% of us out of deficiency state for that vitamin. [Next Slide]. As you increase the intake of that supplement or vitamin, there’s a limit of that amount at which more than 1% - 3% of us may risk toxicity. [Next Slide]. Slide #19 - If we look at the data from Anderson, (who looked at various food groups, fruits, vegetables, meats, etc. and risk for Parkinson’s) ,for various food groups and food containing Vitamins A, C, D or iron, there did not appear to be any decreased risk of Parkinson’s. [Next Slide]. Vitamin use in general was not related to Parkinson’s risk, however, there might have been a trend of increased risk with increased intake of Vitamin A supplements. [Next Slide]. The other thing is there did appear to be some increased risk with increasing intake of foods containing animal fat and interestingly enough, (which I will get back to in a few minutes,) Vitamin D. [Next Slide]. So, in conclusion, their findings supported previous findings that suggested high animal fat intake may increase your risk of Parkinson’s, but there was no association of past intake of most food groups and Parkinson’s risk. [Next Slide]. Slide #20 I am going to switch gears again and just do a quick review of oxidation and neuroprotection. I like this B.C. comic because I think it’s useful in this context that oxidation can be sort of like “brain rust”, if you will. [Next Slide]. Slide #21 On this slide you see graphic that I think is very helpful in viewing what we think happens with Parkinson’s. With normal aging, there is a decrease in the dopamine production and in the numbers of dopamine-producing cells. However, what we think happens in Parkinson’s is that certain factors, including diminished trophic support, increased immunological stimulation, genetic predisposition, increased exposure to toxins, that may accelerate the aging process by increasing oxidated stress. [Next Slide]. Slide #22 This slide shows that in the body, the normal balance is upset in Parksinon’s and there’s an imbalance between antioxidants and pro-oxidants, so you get oxidative stress. [Next Slide]. Slide #23 This slide shows tables from a report from a group investigators that came together to formulate a list of compounds that were promising neuroprotective agents and might be appropriate to Parkinson’s. [Next Slide]. You will see at the top of the slide that of the four top candidates, two - Coenzyme Q10 and Creatine - were identified for the “short list” to be investigated and actually are currently in clinical trials right now. Also, if you look at some of the other drugs identified, they include Vitamin C and [Next slide} you will see red lines underscore caffeine and folates are other nutritional compounds that may be under future investigation. [Next Slide]. Slide #24 I also want to mention because I am going to talk in a minute that Vitamin D has been shown to regulate several of the factors along the pathway that we think generate or are in the pathogenesis of Parkinson’s, including Vitamin D can decrease oxidated stress, down regulate the L-type CA channels that may have a role in the pathogenesis of Parkinson’s. It will up regulate neurotrophins and up regulate tyrosine hydroxylase, which is the rate-limiting step for catecholamine, including dopamine synthesis. [Next Slide]. Slide #25 I want to focus for a minute of intake and risk of Parkinson’s for some specific compounds. [Next Slide]. Slide #26 There was an article about seven years ago by Zhang et al in neurology, where they looked at almost 80,000 women in the nurse’s health study that were followed for about 14 years and almost 50,000 men in the health professional study and of these, about 371 cases of intimate Parkinson’s were identified. If you looked in this study, they had been perfectly collecting dietary intake using food frequency questionnaires. They again, did not find any association with multivitamin use in risk increased or decreased of Parkinson’s. Nor, did they find any evidence for Vitamin, E, C or in the diet or supplement with regard to risk. They did find Vitamin E from foods to have a decreased risk of subsequently developing Parkinson’s. Also, people who ate nuts five or more times a week, compared with about once a month, appeared to have a diminished risk. [Next Slide]. Slide #27 - The suggestion that food intake of Vitamin E may reduce risk led to the possibility of trying Vitamin E and a neuroprotective treatment for Parkinson’s. One thing I will note is that the amount and dietary vs. supplemental Vitamin E may make a difference, as amy the form of Vitamin E - we are going to come back to that concept in a minute. [Next Slide]. Slide #28 We will look at Vitamin C with regard to Parkinson’s. Vitamin C is the most potent antioxidant in circulating it’s plasma, however, it has to be transported in the brain and when later looked Vitamin C levels in Parkinson’s patients in controlled subjects, there were no differences in the brains of these two cohorts. It makes sense then that dietary intake did not show any benefit in preventing Parkinson’s in Zhang and other studies. [Next Slide]. Slide #29 I do want to note that even though Vitamin C is a water-soluble antioxidant that promotes an array of functions such as wound healing, prevention of anemia, etc. [Next Slide]. The RDA is not very high. It’s maybe 75 – 90 milligrams a day, a little more if you are a smoker, but in large doses vitamin c can cause toxicity, including diarrhea and stomach upset. [Next Slide]. Slide #30 We are going to turn back to Vitamin E, which you will remember a fat-soluble vitamin made by plants. There are two forms, tocopherols and tocotrienals and when you look at Vitamin E supplements sold in stores, you can often find two different forms. One is a synthetic form that is much less expensive, it’s called “dl-alpha-tocopherol” and then there’s the natural form, called “d-alpha-tocopherol” Often Vitamin E supplements are sold in a capsule containing fat because the fat increased absorption when the vitamin is taken on an empty stomach. [Next Slide]. Vitamin E, like Vitamin C is an antioxidant and because Parkinson’s is due in part to excess oxidated stress, [Next Slide]. Slide #31 It has been looked at in studies of dietary and supplement intake and this is analysis of the study looking at Vitamin E from dietary sources, not including supplement sources. [Next Slide]. The vertical line shows the null hypothesis, basically equal risk with increased or decreased intake. [Next Slide]. With the exception of Anderson and perhaps the Schneider study where the point estimates were above one, so that suggested an increase risk of Parkinson’s from Vitamin E intake. [Next Slide]. Most of the study fall to the left of that vertical study, like the De Rijk study and then if you look at the Pooled estimate, you will see it circled, which suggests that high dietary intake may be protected. [Next Slide]. That leads to the question of supplementing Vitamin E help slow the progression of Parkinson’s. [Next Slide]. Slide #32 As it turns out, they are actually conflicting results with this regard. The first large study that was published was the Datatop study in 1989, which was a placebo-controlled 2x2 factorial design looking at Vitamin E supplements and selegiline in 800 patients. DATATOP did not show any benefit in terms of Parkinson’s progression. A study published a few years later that was much smaller by Fahn, in 20 patients, did show benefits. [Next Slide]. Slide #33 - It is probably worth looking at some of the possible explanations. It may be dose, it may be the form of supplement, it may be a combination of the vitamins or it may be timing. [Next Slide]. The dose in the DATATOP study was 2,000 IU, versus in Fahn’s study, it was significantly higher with 3,200 IU. [Next Slide]. Also, the DL form has about half the biologic activity of the D form and so it is possible they were just using the wrong form in the DATATOP study. In the Fahn’s study, Vitamin C was given with Vitamin E, so there may have been augmentive or complimentary effects of the Vitamin C with the E. [Next Slide]. I think with many of the potential neuroprotective compounds that we are looking at, it may be timing, so that once somebody develops clinical disease, trying to use neuroprotection is almost like trying to prevent the horse from escaping the barn once he is already out of the barn. If we are going to use these compounds and try to show neuroprotection, we are going to have find barns with horses in them, where the door open and yet the horse has not escaped. So, it’s possible that giving these compounds after clinical diagnosis is too late. The other thing that I think is worth pointing out is the RDA for Vitamin E is quite low compared to the doses used in the studies. [Next Slide]. Slide #34 One thing that is pertinent with regard to Vitamin E is remember the slide showed you about recommended dietary allowance or RDA and then the upper tolerable limit. [Next Slide]. Upper tolerable limit is where you start getting an increased risk of toxicity. [Next Slide]. Slide #35 After several studies had been done looking at Vitamin E and potential neuroprotectors for cardiovascular and other conditions, it came to light that there may be an increased risk of adverse events, such as death or heart failure in the participants taking the higher doses of Vitamin E. Now, when they looked at this in the studies for vitamin E in neurological disease - the DATATOP study, and a large study that showed some benefits of Vitamin E for Alzheimer’s Disease - there was not any increased risk from high Vitamin E supplements to patient w/ neurological diseases, even though, at least in DATATOP, we couldn’t show any benefit either. I think the bottom line from this is that we haven’t quite completed the Vitamin E story with regards to Parkinson’s Disease and vitamin E may have a different “therapeutic” range in patients w/ neurodegenerative diseases than in patients w/ cardiovascular and other diseases. [Next Slide]. Slide #37 - Now let’s move to Coenzyme Q10, which is not a vitamin, it’s a dietary supplement. Your body can manufacture it and it’s known to improve mitochondrial function. Now mitochondria are one of the cell components which appear to be stressed in the pathogenesis of Parkinson’s. CoQ 10 is an antioxidant and it may be important in helping preserve immune function and prevent certain types of cancers. [Next Slide]. Slide #38 - There’s been a lot of attention drawn to a couple of pilot studies of CoQ!0 in PD. Here’s one by Cliff Shults, there are kinds of neurology in which there appeared that there may be some protective effect of ?? of CoQ10. [Next Slide]. This, I chose the UPDRS total scores. Across the bottom you have the months and across the Y-axis you have the score, (increased score means worsening PD). Over time, all of the patients got worse, as expected. The top line is placebo, the middle two lines are CoQ at 300 and 600 milligrams a day and the bottom line is Co Q10 given at 1200 milligrams a day. There were 80 patients in this trial and there was a trend, although there was not full statistical significance in disability from Parkinson’s primarily. Because of these findings, there is now a larger NIH sponsored trial called the “QE3 trial”. Interestingly, even though NIH funded this trial, there was a delay in its getting started, because FDA wanted more safety data as we began to adjust the protocols and push the doses of CoQ to higher doses. [Next Slide]. Slide #39 This slide gives and overview of the design of the CoQ10 trial and it’s a phase III trial, evaluating the safety and effectiveness of CoQ foreign clinical declines in Parkinson’s early patients. It’s aiming to enroll 600 participants who have been diagnosed with Parkinson’s five years or less and have not yet started symptomatic treatment because one of the end points is progression to disability to the point that they will need to start levadopa therapy. That trial is underway. I hope that we will complete it within a short period of time. [Next Slide]. Slide #40 - The other NIH funded trial, looking at supplements and neuroprojection of Parkinson’s is the NET-PD study, looking at Creatine. Creatine was actually discovered in the 1800’s and your body can synthesize it, with most of the body’s contents stored in skeletal muscle. In the 70’s the Soviet scientist were looking at it because they might improve athletic performance and here in the states, I think it became popular with teen athletes in particular with a way to enhance their athletic performance and build lean muscle mass. There does appear to be some variation in response to supplement with Creatine and this can be altered by other factors such as carbohydrate intake, amount of physical activity, your training status and your genetic muscle fiber type distribution. The other thing to keep in mind when patients ask about whether they should take it, is that it may reduce the effect of some other important vitamins, including A, D, E and K and it can have some liver or kidney toxicity, so I generally don’t recommend that people take it unless they are in a clinical trial or being monitored on a regular basis by their primary care physician. The NET-PD study, which hopes to finish up by 2014 is aiming to enroll about 1,500 patients at 52 centers. The difference between this trial and the QE3 trial is that patients can have been treated, although less than two years and again, they should have been diagnosed within the last five years. [Next Slide]. Slide #41 - I want to turn now and go back a little bit to that paper that paper that I highlighted by Anderson, which suggested that increased PD risk was seen with increasing intake of foods containing Vitamin D. [Next Slide]. Slide #42 - This is interesting to me because this hypothesis paper by Newmark and Newmark really got me into looking at Vitamin D with regard to Parkinson’s Disease. What they suggested was that chronically inadequate Vitamin D intake may contribute to the pathogenesis of Parkinson’s. [Next Slide]. Slide #43 - I do want to remind people that Vitamin D is critical for maximizing calcium absorption and on this graph you see the difference in calcium absorption over about a 10 – 12 hour period with normal versus sub-optimal of Vitamin D. [Next Slide]. Slide #44 - This is showing that most of our Vitamin D comes from sun exposure or UVD exposure in the skin where Vitamin D is made. A small amount comes from eating oily fish, such as tuna, salmon or mackerel, as well as fortified foods like milk and orange juice. Very quickly in the liver, this is converted to 25-hydroxyvitamin D. 25-hydroxyvitamin D is the storage form for Vitamin D. It has a half-life of two to three weeks. So, similar to the glycosylated hemoglobin for glucose control of the previous one or two months, 25-hydroxyvitaminD reflects your vitamin D status Vitamin D over the previous one to two months. [Next Slide]. The circulating form of Vitamin D is varied tissues including kidney and I put the brain in since that it what I am most interested in, is converted by the activating enzyme (1a-hydroxylase) to the active form of Vitamin D, 1-25-dihydroxyvitamin D. This has a much shorter half-life. [Next Slide]. When it binds to Vitamin D receptors in the various tissues, the active forma performs autocrine and paracrine functions. [Next Slide]. Slide #45 - Specifically, in the central nervous system, both the activating enzyme as well as the Vitamin D receptor are widely distributed with the highest being found in the substantia nigra and hippocampus. Both areas that are of interest to those of us who study neurodegenetive diseases, [Next Slide] and [Next Slide]. Vitamin D, as it turns out I will remind you, is involved in regulating [Next Slide] neurotrophins. Neurotrophin expression and neurotrophins, function sort of as fertilizers for the brain. They help promote not only differentiation and survival of such dopaminergic cells. They may increase certain types of neurotransmitters. Vitamin D may decrease toxic free radical generation and also plays an important roll in calcium regulation. [Next Slide]. Slide #46 I am going to turn to some geography and epidemiology of Parkinson’s, which support the possibility that Vitamin D could have a role in Parkinson’s. Of course, the further away from the equator you get, the more likely that you are to have low Vitamin D levels. This is shows data from Kurtzke in 1988, in which they used Census data and death rates to demonstrate that across the northern tier states, prevalent of Parkinson’s seem to be consistently higher than in the southern tier states. They looked at all ages, those above 65, white versus non-white. [Next Slide]. Slide #47 - This is data from a research database that we have here at Emory that we call the CRIN. Stands for Clinical Research in Neurology. What we did, we looked in our database starting with its inception and picked every fifth Parkinson’s patient in the database until we got to 100. We then randomly selected non-relative matched on age, gender, state of residence APO gene type, who either had Parkinson’s Disease or were healthy controls in the database. Interestingly what we found is the prevalence of Vitamin D in sufficiency was significantly higher in the Parkinson’s patients than in the AD or healthy control population. [Next Slide]. Slide #48 - The other interesting thing that we noted was that there did not seem to be the usual seasonal variation that we would expect with regard to Parkinson’s and we did not find an association with duration of symptoms, using that as a surrogate for disease severity. So, it may be, it does appear that there may be something different. [Next Slide]. Slide #49 If we look at Vitamin D levels in the general population, we have NHANES data that looks at persons over 60 and in 8 foot walk test, which is simply how long it takes for a person to walk 8 feet between sub-optimal to optimal levels there’s about a ¼ of a second improvement in their walking speed. Similarly in the sit to stand test, which looks at how long it takes somebody to stand up and sit down five times in a row, there’s about a second difference between those participants with a sub-optimal level compared to those with an optimal level. [Next Slide]. Slide #50 - Those data suggested that it was worth looking at Vitamin D as an intervention in Parkinson’s patients with low Vitamin D to determine whether a black hole, the standard dose, that is to the medicine dose of 600 units daily, compared to a much higher dose of almost 7700 units daily, made a difference in either motor or non-motor symptoms of Parkinson’s and that study is currently ongoing. [Next Slide]. Slide #51 I want to finally turn in our list of vitamins and supplements to Glutathione, which is a naturally occurring antioxidant Tripeptide with three amino acids and it’s been noted in neuropathological studies that it’s marketably reduced in the SN and early Parkinson’s and it correlates amount of reduction of Glutathione correlates with disease severity. One other thing that is unclear about Glutathione, how it affects the blood brain barrier. [Next Slide]. Slide #52 - Many patients come into our clinic asking about the Glutathione treatment that they have seen on the Internet and there was up to this year a single clinical trial of nine patients in Italy that was an open label trial, which you have to be very careful about in Parkinson’s because we have seen tremendous and long lasting placebo effects in other studies, which used twice daily infusions for thirty days. They did see an improved Parkinson’s rating scale that in fact was comparable to that if using levadopa, the gold standard treatment for Parkinson’s and the benefits tended to lapse over two to four months after ceasing infusion. Of interest, 2 out of the 9 patients had significant side effects, formed thrombophlebitis at the infusion site. [Next Slide]. Slide #53 - This was published by Hauser and Kelly, the results of a pilot 12-week trial that was double blinded in placebo controlled in 21 patients. 10 patients got IV placebo and 11 patients got 1,400 milligrams of IV Glutathione in a three times a week dosing regime. There were no treatment related withdrawals and adverse events were similar in both treatment groups. [Next Slide]. Slide #54 - Here I chose the picture of the UPD activity of data living sub-score. There really wasn’t significant difference that was evident between the treated and the placebo group. [Next Slide]. Slide #55 - Just to review where we are, we have talked about what are vitamins and dietary supplements. We have looked at some of the specific vitamins and supplements with regard to Parkinson’s. [Next Slide]. I want to now go into the practical issues with regard to nutrition and diet in Parkinson’s. [Next Slide]. Slide #56 - The three biggies that I would say are weight loss, swallowing and maximizing medication effects with diet. [Next Slide]. It has become evident that weight loss may actually precede the diagnosis of Parkinson’s by as much as two to four years and this occurs despite an increase in energy intake. Now, one might say well, Parkinson’s patients are smelling as well, so maybe they are just not taking as much, but the data argues otherwise. The other possibility is could because of increased rigidity or tremors, could they be having a dyskinesia later on in the disease. Could this just increase their energy requirement and finally, could they have trouble swallowing? [Next Slide]. Slide #58 – With regard to swallowing function in PD, there may be a subtle behavioral pressure for Parkinson’s patients to eat less or to eat more slowly. Poltulska published a study of 18 patients and three non-Parkinson’s control subjects. The Parkinson’s patients were mild. There H&Y score was only a 2.1, which meant they didn’t have any balance troubles. Over half had complaints of dysphagia and all of them had some kind of abnormality on their video fluoroscopic study. [Next Slide]. Slide #59 - The other topic with regard to diet that we often get asked about in clinic is the concept of manipulating diet improved medication effectiveness. If you will remember, Levadopa is actually an amino acid. Amino acids come from brain break down of food and particularly large neutral amino acids from food intake may compete with Levadopa to “A” get across the gut well into the blood stream and more importantly, “B” get across the blood stream, across the blood brain barrier, into the brain. So several years ago, there was this concept of the protein redistribution diet that came into being so that people would eat lower amounts of protein during the day when they wanted to move around and it would interfere less with their levodopa getting into their brain where it was needed and then in the evening they would consume the remainder of their daily requirement. Unfortunately, what I find is people often misinterpret as a low protein diet and of course, people with kidney disease need to have their recommended amounts of protein to maintain normal health. As I explain to patients, if you don’t get enough protein, you will start using up your own body stores of protein that is your muscles. Now, another approach that was published in 1991 in a small study of 9 patients by Berry, is a so-called balanced carbohydrate to protein ratio is 5 to 1. They show that mobile performance is better. However, I find that these types of manipulations are very difficult unless you have a nutritionist or dietician who understands the concept and is willing to work with the patients and do a lot of feedback with them. So, these are things that are not impossible to achieve, but do require a heavy hands on approach if you will. [Next Slide]. Slide #60 - We covered what are vitamins, what are some of the specific vitamins and supplements with regard to PD. We talked a little bit about weight loss and dietary measures. We’ll just go ahead and sum up everything. [Next Slide]. Slide #61 - With specific vitamins and supplements, there’s not any particular vitamin that stands out yet. Vitamin C, there was no suggestion of benefit. With Vitamin E, theoretically, it may help, but the clinical trials have been disappointing. There are questions regarding toxicity, although we have not seen any in the trials that have been done so far. So, I think, as I said before, that question with regard to Vitamin E in Parkinson’s has not yet been answered. [Next Slide]. Slide #62 - If you look at CoQ10, the pilot study was promising, we have the QE3 trial underway and so far, thankfully, it appears quite safe. With regard to Vitamin D, I think that the results are intriguing, there’s a little bit of back and forth as to what that role may be and I could talk a whole hour on that, but there’s some other basic science data that may be conflicting as well. And then Glutathione has no known toxicity, we don’t yet have any evidence that it is helpful. [Next Slide]. Slide #63 – “Vitamin troubles” to quote from E.B. White’s Stuart Little, sums up the concepts can be quite confusing and I think at the end of the day, [Next Slide]…. Slide #64 - The big thing to tell patients is dietary supplements, including vitamins are not regulated, they may have interaction and toxicities of which we are unaware and while many have theoretic uses, we don’t have good proof yet. So, at the end of the day, a balanced diet is really the most important aspect of managing Parkinson’s. [Next Slide]. Slide #65 - I am going to stop here and will be happy to answer any questions. I just had a question of some of the studies that have been done in, I’m sorry I’m Ann Richardson, from the Connecticut VA, with some of the studies with the high dose Vitamin E, did they have any of the adverse reactions with increased risk for bleed in the population study? You know, I can’t recall Ann about bleeding. I know in Alzheimer’s population that occasionally, in clinical practice certainly, if somebody is taking ?? units a day of Vitamin E, occasionally, they will have bleeding of their gums and then you will have to cut back the dose, but I don’t recall specifically any significant adverse reactions. This is Dr. Gross calling from Salsbury VA in North Carolina. I wanted to know if you had any specifics regarding. . . Uh, oh, it cut off. Are you still there? Is the caller still on? I think we lost Dr. Gross. Any other comments or questions? Go ahead if you have a question. I think there may have been some problems with the volume during the call and if anybody has any questions, I am in the VA address system and you are welcome to email me. Dr. Evatt you are on the Microsoft Outlook, so people can reach you that way and I will go ahead and wrap things up and if we do get a question in the meantime, we can take that, but I would like to remind the audience to please complete your registration and evaluation process by November 24th to get credit for attending this audio conference. Thank you to everyone for listening today. Your interest in movement disorders . Our next PADRECC EES session will be January 14th, the topic is Lewy Body Disease. It will be presented by Dr. John Duda from the Philadelphia PADRECC. Before I close, are there any other questions out there? All right, well let’s wrap it up for today and thank you very much Dr. Evatt for your time and for putting this together. Thank you. Goodbye everyone. END OF CONFERENCE. PADRECC National Vants Audio Conference Nutritional Supplements in Parkinson’s Disease Marian Evatt, MD MS November 12, 2009 Page 1