CLICK HERE-This Article In Word   This article by Dr. Shannon is now 5 years old but is still one of the best consolidated updates I've seen on Huntington's Disease before or since she presented it!  Since this was written the studies on the CoQ10 have taken place, you don't hear much about the fetal transplantation in HD today, and other exciting discoveries have taken place.    I think we should all thank Dr. Shannon for writing this article because it's obvious she cares about the families living with HD and urge her to please consider writing an update 2002! (kshannon@rpslmc.edu)   Jean   Review of Publications in the Last Year  Relating to Huntington's Disease By Dr. Kathleen Shannon  1997 Presentation by Dr. Kathleen Shannon at the General Meeting of the Illinois Chapter, Huntington's Disease Society of America, March 8, 1997. Reported by Renette Davis   People often think that medical research progresses much too slowly, especially if you're watching people that you love deteriorate. Sometimes it seems like we're not making much progress, and we agree with that. We would like things to move faster. It's important to understand that although medical research does progress slowly, there are important new breakthroughs every year which I think will snowball into the major treatment or cure for Huntington's Disease.   I looked through the literature of the last year and there are 103 major publications in the English language relating to Huntington's Disease. I culled out what I thought were the most important ones, and I'm going to go over them with you and explain why I think they're important so we can see how progress is occurring in this disease.   Clinical Features   I've divided the studies into several areas. One of them is the clinical features of Huntington's Disease. The clinical features of the disease are what physicians see and examine, how the disease begins and progresses, what kind of symptoms we see. This is important because in most of the diseases that neurologists take care of, our ratings of how severe the disease is are based on these clinical features.   How severe the chorea is, for example, how slowly the patients move, how they function cognitively is our way of measuring the disease getting worse. The reason that's important is it's going to be our way of measuring our treatment interventions, how effective they are in slowing down this worsening process or reversing the symptoms. This is a very interesting area of research and it's essential as the foundation for understanding whether our treatments work.   There were two really significant publications in the last year in this area. The first one is relevant to the interest in transplantation surgery for Huntington's Disease. It's called the Core Assessment Program in Transplantation for Huntington's Disease, or CAPIT-HD. (1)   This was the work of a group of scientists who sat down and decided how we could rate Huntington's Disease, specifically for transplantation. They also put together a scheme for evaluating patients before and after transplantation. It's important that we collect the right information so we can show whether transplantation works.   A similar publication has to do with the Unified Huntington's Disease Rating Scale. (2) Every time I come to address this group, I see more familiar faces. I am seeing a lot of people in this room professionally as well as at this kind of a meeting. People who come to Rush know that when they come to see me I have a stack of paper work to fill out. It's got little boxes and scores go in those boxes. Those sheets are then torn apart and one copy is shipped off to Rochester, New York, and entered into a database.   This rating scale is called the Unified HD Rating Scale (UHDRS) . We now have a database on thousands of people with Huntington's Disease to understand how the disease worsens. Again the purpose is to decide how to measure improvements in the disease or slowing of progression of the disease. So all that paperwork that you and I fill out when you come to see me is an important part of research in and of itself.   Nursing Home Patients   There was an interesting study by Martha Nance, who is a researcher that has done a lot of work in the clinical and genetic aspects of Huntington's Disease. (3) One of the things she looked at is what are the clinical characteristics of people with Huntington's Disease who are in nursing homes.   Understanding how they are different from other nursing home patients helps nursing homes to modify their programs to better address the needs of Huntington's patients.   She looked at all of the people in Minnesota with Huntington's Disease who were in nursing homes and found that they were young.  They averaged in their 40's. They tended to be unmarried. Some of the people who don't have a good family network to support them at home will end up more often earlier in nursing homes.   Her conclusions were: Huntington's Disease patients are different from other nursing home patients. Even though patients tended to lose weight throughout the course of the illness, patients in nursing homes tended to gain weight late in the disease.  The staff had to be adaptive and creative in order to take care of people with Huntington's Disease. Increasing their understanding of the disease might help the care that people get in nursing homes. The negative behavior, aggressiveness, etc., is a significant part of dealing with nursing home patients who have Huntington's Disease, but only in a minority of patients. They were able to deal with most of the patients without a lot of negative behavior. Motor Symptoms   Most of you are familiar with the group at Indiana University who have done a lot of genetic legwork on Huntington's Disease. Because they've done so much genetic work they have a very large group of patients.   Dr. Siemers looked at patients who had not yet developed obvious symptoms of Huntington's Disease to see if he could determine any minor changes in them before they developed the symptoms. (4)   This kind of work is important because we hope to get a treatment that will stop brain cell degeneration before people get sick. This is our ultimate goal - to find a treatment so that a gene carrier who doesn't yet have symptoms can be prevented from ever having symptoms.   It's important to be able to find people before they become sick but you don't want to treat everyone from birth. You want to be able to find people when they're getting close to being sick.   Trying to find very minor changes in function is important. Dr. Siemers looked at almost 400 people with the gene for Huntington's Disease, none of whom were diagnosed yet, and he was able to find some very minor motor changes which we might be able to use in the future to determine when these kinds of treatments should be started.   Behavioral Symptoms   There have been a number of publications on how the disease gets worse in Huntington's Disease. We in the Huntington Study Group put together one looking at the progression of motor changes (chorea, slowness, posturing, poor coordination, falling) and cognitive changes (memory, thinking, higher cognitive processing.) (5)   One thing that we found (and another group has found this as well) is that the psychiatric symptoms don't progress in an orderly fashion. That's important to understand because if someone has a lot of psychiatric problems at one point in their illness, it doesn't necessarily mean that the illness is worse. They're just going through a bad phase. You can treat the psychiatric problems.   The psychiatric problems are not a major indicator of the disease getting worse. They come and go. Even in early Huntington's Disease, someone can have a major psychiatric problem. Someone later on may not be having psychiatric problems. So we can't really use psychiatric problems as a measure of the disease getting worse.   This is important to know, and I think can be comforting to people who are having a lot of trouble at some point. Those kinds of things are very responsive to treatment.   One of the things we're learning now that the gene test is so readily available, is that lot of people have late onset disease, which is very interesting. I have a colleague who has a patient who's in her 80's and really just started having symptoms. The disease that we thought always began with people in their 40's and 50's, we're seeing sometimes begins with people in their 60's, 70's, and 80's.   That's opened up a whole area of previously undiagnosed people who had late onset disease. They often have a negative family history and that's probably because the preceding generation had a very late onset or died before their disease started. This is a disease that we can see now even into later life. One publication was by a geriatric psychiatrist, a psychiatrist who specializes in people over the age of 65. It talked about the special needs of people in their 70's and 80's with Huntington's Disease. (6)   Cognitive Function   In the area of cognitive or memory and thinking function there was a very interesting report called "Loss of disgust. Perceptions of faces and emotions in Huntington's Disease".(7) This was a group of scientists who showed patients with Huntington's Disease various facial expressions. They wanted to see if they could interpret facial expressions.   They found that people with Huntington's Disease could interpret happiness and the kind of nice, pleasant emotions, but they had a hard time interpreting anger and fear and disgust, the more negative emotions.   I think it's kind of an interesting study and it may help people to understand that sometimes patients with Huntington's Disease can't interpret the emotion that's going on in a situation. They may not be able to read the emotion in your face, which means you have to communicate your feelings a lot more concretely. You can't rely on these subtle kinds of things that other people can interpret very well.   There's another similar kind of study looking at the ability to shift attention. (8) One problem which people with disease in this area of the brain have is that when there are a lot of competing stimuli it's difficult for them to shift back and forth. So for example, if the patient's attention is being held by something like the television set or one kind of activity, and you want to get their attention onto something else, it's very difficult for them to shift back and forth.   That causes problems like then the spouse says, "He never hears what I'm saying, he doesn't pay attention to me, he doesn't listen." It's really a problem related to this kind of brain disease that makes it difficult for them to shift attention.  So you have to kind of go and stand in front of the television and say, "Pay attention to me here, I'm telling you something." It's not something that can be helped so you have to work with that a little bit.   Neuroimaging   There are several studies on neuroimaging, brain scans, etc. These are interesting from a scientific standpoint, but also because we need to have objective reproducible ways to measure how severe the disease is. Remember that I told you we use the CAPIT-HD, and the Unified Huntington's Disease Rating Scale. These are things where a doctor looks at the patient and rates them.   It's pretty reproducible - if you do it all day you get pretty good at it. But we like to have other things. PET scanning isn't really available generally, but is used as a research tool. (9) That's one of the things that most people are using to follow a transplant patient.   There are a couple of other things which are a little bit detailed even to talk about, but are ways that we can look at certain kinds of neuro-images. SPECT scanning is one you might hear about. (10)  And there's one called Proton Magnetic Resonance Spectroscopy, which looks at the function of the brain. (11) Most of these brain scans look at how the brain is functioning rather than how it looks structurally.   Most people with HD in this room have probably had an MRI or a CT scan. That merely looks at the structure of the brain, how big the various parts of the brain are.  These newer imaging methods look at the chemical reactions in the brain. The Proton Magnetic Resonance Spectroscopy looks at chemical transmitters in the brain, like dopamine, etc. Those newer imaging methods may give us a more reliable way to measure the disease and how it's improving when we get more aggressive treatment.   CAG Repeats   There are a lot of interesting developments in the genetics of Huntington's Disease, mostly because over time we're just getting more and more genetic samples to look at. We're learning more about the genetic mutation and how it's reflected in the clinical disease. One very interesting article had to do with the intermediate length repeat. (12)   We know that the genetic defect underlying Huntington's Disease is an expansion of a normal kind of genetic pattern. That genetic pattern involves three chemicals called cytosine, adenine, and guanine (or CAG) which are in the genetic code. Those three chemicals code for an amino acid or building block that goes into a protein.   We've known since 1993 that everyone with more than 40 repeats would get Huntington's Disease unless they died early for some other reason, and that no one with fewer than 30 repeats would get Huntington's Disease, no matter how long they lived. Somewhere in the middle was the 30-40 repeat range and we couldn't always predict what happened to those in the 30-40 repeat range.   It's a very small percentage of the total number of tests that would actually fall into that category. Because we've done so many tests now, we're getting a lot more in that category and so we're learning about that intermediate repeat length.   This was a study called "Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington's disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats." They had 178 people with intermediate size Huntington's genes, and they looked to see if those people developed Huntington's Disease.   They found that there were 7 people who had 36 repeats who did have Huntington's Disease, so you can get Huntington's Disease if you have 36 repeats. But not everyone with 36 repeats develops Huntington's Disease. They even had a man who was 95 years old and had 39 repeats who didn't have Huntington's Disease. He had no clinical signs at all.   This study helps us know a little bit more about this grey area.   In other words if you have 36 or more, there is some chance of getting Huntington's Disease, although it's not 100 percent. If you have 40 or more, it's 100 percent chance of getting Huntington's Disease, and if you have 30 or less, it's still a 0 percent chance. We are finding people in this intermediate range who do have Huntington's Disease.   The more work that's done on this, the better able we are to under-stand what would make someone with 39 repeats not get Huntington's Disease and what would make someone with 36 repeats get Huntington's Disease. There must be some other factors that determine in this intermediate range who gets Huntington's and who doesn't. Whether that's some other gene, or whether you're a man or a woman, or who knows what, understanding that will help us understand what's going on, even with people who have repeats over 40.   There's been kind of a long standing debate in the Huntington's Disease community about the importance of the actual number of repeats over 40. The Huntington Study Group has come out rather strongly on this, saying that since there isn't a strict correlation between the repeat length and what happens to you, other than the fact that you get Huntington's Disease, the actual number isn't important.   All you need to know is more than 40 equals Huntington's Disease. What that number is, whether it's 41, 42, 43, 44, doesn't really matter. There are some people who say that it must matter because the size of the repeat is important, so there's still a lot of controversy about that. We're learning more about that as well.   We've known for a long time that if you have 60 or more repeats, you have juvenile Huntington's Disease. So certainly in the way upper range of the repeat length that's a very early onset and much more aggressive disease than in the lower limits of the abnormal gene length.   Most studies which try to correlate age of onset and disease pro-gression with repeat length, find that there is a correlation. The longer the repeat length, the earlier the disease age of onset and the more rapidly the disease progresses.   The problem is that most of that effect is accounted for by the very long genes. In other words, there's a very powerful correlation with age of onset and aggressiveness of the disease in the 60, 70, 80, or 90 repeat length mutations, and it's not a very powerful correlation in the 40 to 60 range.   In one study they looked at 42 repeats and found that patients' age of onset ranged from 29 to 69. Again it's important to understand why the same mutation would cause a different disease in two different people.   Is it the effect of another gene? Does it have something to do with general health? Does it have to do with gender? Does it have to do with what you eat or how you exercise? It will be important to identify the factors which determine age of onset in two different people with the same genetic mutation.   There are a number of studies on that. (13, 14) It's important to under-stand that the individual number still is not felt to be important. In fact, when my lab does the test, I don't even get the number. I get more than 40, less than 30, or 30 to 40.   Someone looked at the correlation of psychiatric symptoms and CAG repeat length, and there was no correlation at all. (15) That just re-inforces what I told you earlier, which is that psychiatric disease is something that comes and goes, and isn't really related to the severity of the disease at any one time like the other symptoms are.   Negative Family History   One publication was on patients who have a negative family history. (16) At most large Huntington's clinics, about 10 percent of the people who present to the clinic have no family history of Huntington's Disease. Sometimes it's a mysterious family history, like a parent who went missing somewhere along the way, or other family members who haven't kept in touch.   But there are a number of patients who do not have a family history. People used to have a real hard time diagnosing them because they didn't want to introduce a disease into the family that was a hereditary disease if there was no evidence of the disease in the preceding generations. I know from personal experience, there were people that I was convinced had Huntington's Disease who had been carried along by their neurologist for years because the neurologist was afraid of saying Huntington's Disease when there was a negative family history.   Dr. Nance, who's in Minnesota, looked at people who have a negative family history but came to her clinic. About 83 percent of them turned out to have Huntington's Disease.   Most of the people who look like Huntington's Disease but don't have a family history in fact can be demonstrated to have Huntington's Disease based on genetic testing.   She found that the people with the negative family history were more likely to have an older age of onset. As I mentioned before, maybe their other family members would have died of something else before they were old enough to develop the disease, and that might be an explanation for why they had a negative family history.   Before medical care got so good people tended to die earlier, so if you had a disease with age of onset at 65 in your family and you died at 67, you might not have lived long enough to have a diagnosis.   Genetic Fitness   There was an interesting article about genetic fitness, (17) which is how well a genetic abnormality will survive into the subsequent generation. Many dominantly inherited diseases affect your ability to reproduce or your desirability as a mate. Families with inherited genetic diseases often kind of dwindle out.   We've known for a long time that this is not true in Huntington's Disease.  Genetic fitness, or the ability to reproduce and have generations of family members, isn't affected by the disease. In fact, there are several publications which suggest that at least in the old days, before 1920, people with Huntington's Disease had more children than people without Huntington's Disease.   That's changed a little bit now with increased understanding of the genetic defect and the ability to check your gene carrier status. This mutation has carried on for centuries simply because it doesn't affect your ability to reproduce, and because it starts so late in life it doesn't affect your ability to find a mate. So people get married and they have children and the disease will continue until we find a cure.   Preimplantation Genetic Testing   There was an article about preimplantation genetic testing. (18) This is a very high tech way to reproduce and make sure you don't have any offspring with Huntington's Disease. It is test tube fertilization for a person with Huntington's Disease, who still wants to have natural children but doesn't want any chance of their children inheriting the gene.   They take the sperm and harvest an egg and they fertilize it in the test tube. Then they can take a little piece of the developing embryo and do a genetic test on it. They usually will make six embryos at a time. They test them all and they find one or more that don't have the Huntington's gene and then they put those back in. Then you have a baby and you're sure that baby won't have Huntington's Disease.   It's a kind of alternative for people who aren't willing to have prenatal testing and then abort any gene carrying fetus. A lot of people aren't willing to do that. So this would be another alternative for people who don't want to use prenatal testing and abortion as a way of insuring that their children won't have Huntington's Disease.   It's very expensive. It sounds expensive and it is. I don't know of any successful pregnancies yet, but it's something that's possible. It's also possible to do that for the person who doesn't know if they have the Huntington's Disease gene and doesn't want to be tested. That person could have preimplantation testing and make sure that the embryo doesn't have the Huntington's gene. They don't have to be told whether they have the Huntington's gene.   Effects of Genetic Testing   There have been several studies about what happens psychologically to people who get genetic testing. One of them looked at patients who had a negative result and patients who had a positive result. (19) They looked at psychological factors before and after. Mostly patients who come in for testing are people who would rather have a positive result than not know. That's basically how people decide to go in for testing, because they need to know for sure.   What happens to them after they're tested is that they mostly feel a sense of relief that they know now. Patients who get a positive result tend to get depressed, because now they know what deep inside they didn't want to know. People who have a negative test result also get depressed. It's usually a little bit later. The reason they get depressed is what's called survivor guilt.   The analogy is that you're on a plane and sitting next to you in the seat is a little child or a nice person. The plane crashes and you walk off the plane but the person in the seat next to you doesn't. You feel guilty that it wasn't you. It's even more of a factor because the people in the other seat on the plane in this case are your siblings or your nieces and nephews. There's this survivor guilt that we've known about for awhile.   This recent study looked at 53 people tested for Huntington's Disease. They looked at anxiety and depression before the test and after the test. They found that patients who got a good result weren't as anxious any more and people who got a bad result were the same. It didn't make them worse and didn't make them better.   They also found that reproductive decisions were actually altered by the test. People who got a positive test result were less likely to go on and have children than people who had a negative test result. There's been a lot of discussion in the literature about whether genetic counseling has any effect on reproductive decisions in the Huntington's community and this suggests that it does.   Brain Cell Degeneration   Probably the most interesting work continues to be trying to define the mechanism of the brain cell degeneration in Huntington's Disease. We know the gene that causes Huntington's Disease.  We have found the protein that the gene makes and named it huntingtin. Huntingtin is spelled with an i instead of an o. That's just convention in genetics. When you find a protein you name it after the disease but you put "in" at the end.   We know that the protein is bigger than the one made by the normal gene. The Huntington's gene makes a bigger protein and it's bigger because it has too much glutamine in it. Remember each CAG codes for a building block of protein. CAG codes for glutamine and there are too many CAG repeats so your protein has too much glutamine.   What we don't understand is why does a big protein with too much glutamine cause your brain cells to die. That's still the missing piece in the puzzle. There have been a number of research projects looking specifically at that. There are several ways to look at it.   One way that's being done a lot is by creating rodents with the Huntington's gene. There is no naturally occurring Huntington's Disease in any animal besides man, so you have to make it. One way we've always made it is we've injected a poison into the brain, but that's not natural. It's not how the disease occurs.   A better way is to try to make animals, or genetically engineer them, to have Huntington's Disease. That's been done in several cases now. It's called a knock-in. Another thing you can do is a knock-out, where you take the gene out. They've done that as well. What happens if you take the gene out, so there is no huntingtin protein made, is that those animals don't survive to be born. They die as embryos.   So the huntingtin protein is something very important. You can't live without it. We know you have to have it to be born and to live. What we don't understand is how the bigger huntingtin protein, the abnormal huntingtin protein, causes the brain cells to die. For that we use knock-in mice. You put the Huntington's gene into the mouse so now it has too many CAG repeats where it used to not have too many.   They're just starting to successfully make mice that now have chorea, behavioral changes, etc., like Huntington's Disease, using knock-in. This is really important because it provides a way to study treatment interventions in a more naturally occurring form of the disease, rather than what we've done before which is to take a poison and inject it into the brain to cause degeneration of the brain cells that mirrors Huntington's Disease. Right now people are just reporting that they're able to do this. (20)   The next step is to see if you can prevent brain cell degeneration in these mice who you've given Huntington's Disease to. To get back to the mechanism of how this very large glutamine rich protein causes degeneration, there are several theories now. This protein seems to be sticky. It tends to stick to other proteins in the cells. You can think of it as kind of gumming up the machinery.   That seems to make the brain cells more vulnerable to things occurring in the brain which can damage brain cells. In other words, your brain cells have a natural protection against dangerous chemicals, even chemicals which occur naturally.   When you have the huntingtin protein, the big sticky form of the protein rather than the nice small, not sticky form, your brain cells become more vulnerable to chemicals.   We think they're more vulnerable to excitatory chemicals. The way brain cells communicate one with the other is that they send chemicals from one cell to another cell. There are two basic kinds of chemicals. There are inhibitory chemicals which then suppress the action of the cell and there are excitatory chemicals.   Excitatory chemicals are important and they're normal, but if your brain cells are weak, they can be dangerous. Excitatory chemicals can excite the brain cells to death if they're too vulnerable, if they're not protected from the effects of too much excitation.   The reason we think this is happening is that we've known for a long time that if you inject excitatory chemicals into the brain, the brain cells will die. If you inject it into a specific location you can make the animal look like it has Huntington's Disease.   People with Huntington's Disease don't seem to have too much excitatory chemicals. They have the same amount of excitatory chemicals as people without Huntington's Disease. It's just that their brain cells (and only in a specific location) appear to be more vulnerable to that excitatory chemical. This is probably the most important area of research because these are the kinds of things we can use to find medications to combat Huntington's Disease.   For example, there's a potential that the weakened brain cells in Huntington's Disease could be strengthened. The thing that people are looking at most closely is Coenzyme Q10, which people can actually buy in the health food stores. It is a chemical that can strengthen brain cells and make them less vulnerable to excitatory chemicals.   The problem is that in order to get the dose of Coenzyme Q10 that you need to have strong brain cells, you would have to rob a bank because it's really expensive. It's about 10-30 times the dose that's available in the health food stores. Anyone who's bought Coenzyme Q10 in the health food stores knows that the dose you can buy there is already expensive.   One of these studies (21) has shown that high doses of Coenzyme Q10 are well tolerated in Huntington's Disease so that will be useful for study. In fact one part of the Care HD protocol, which many of you may have heard about, involves uses of these high doses of Coenzyme Q10.   The other thing that we've learned is that you can give medicines which block excitatory chemicals. Remember I told you that people with Huntington's Disease don't seem to have too much excitatory chemicals, but that their cells are more vulnerable to the excitatory chemicals. If you can give a medicine that blocks excitatory chemicals, you may be able to prevent those brain cells from dying.   The medicine that we're looking at is called Remacemide. One of the studies is a small study looking at whether Remacemide is well tolerated in Huntington's Disease. (22) In fact, it is well tolerated. This is an investigational drug. It's not available anywhere except under protocol.   The Care HD protocol is a study where some patients get a placebo, some patients get Remacemide, some patients get Coenzyme Q10, and some patients get both Remacemide and Coenzyme Q10. They are then followed with the Unified Huntington's Disease Rating Scale and other measures over a two year period to see whether those treatment interventions, either one or both of them, slows down the progression.   That's an important study in its own right. One off-shoot is that if we do determine that either one or both of these interventions slows down the disease progression in Huntington's Disease, the next step would be to give the drug to people who haven't shown symptoms yet to see if you can prevent them from developing symptoms.   You can see how we're inching toward a really successful treatment to prevent disability from this disease, but it goes step by step. The first step was reported in the last year that Remacemide and Coenzyme Q10 are well tolerated in Huntington's Disease. The next step is to do the study to see if they are effective and safe in large numbers of people with Huntington's Disease.   By large numbers I mean we have determined that we have to have 340 patients in this study in order to demonstrate benefit. There are statistical calculations you have to go through before you do a study to see how many people you're going to need to prove your treatment works.   That will take several years to do. Then of course after that it would be a matter again of determining how many subjects you would need in a study to look at patients who don't have symptoms yet and then enrolling them in a study to see if it's effective in preventing symptoms. It can take a long time to do this, but all the ground work is falling into place right now, so we're very close to being able to do these kinds of research projects.   One of the arguments with the animal models of Huntington's Disease is that so much of Huntington's has to do with cognitive problems - behavioral, psychiatric, thinking, and memory. The real significant source of disability in the long run has to do with these things. It's very difficult to study those things in rats. Who knows whether the rats have an emotionally bad day or an emotionally good day.   One of the studies suggested a kind of test you can do with rats, which seems to point to similar kinds of cognitive problems that people with Huntington's Disease have. (23) This is important because when we study new treatments at the animal level we'll be able to understand whether they're going to help both the behavioral aspects of the disease and the more obvious motor aspects.   Antidepressants   One of the things we've been doing is using some of the newer anti- depressants for irritability and aggressiveness. We've noticed with psychiatric patients, that irritability and aggressiveness can get better with Prozac, Zoloft, Paxil, and Effexor, which are the newest of the antidepressants, so we've started using them in Huntington's Disease. We didn't have any published studies which said that worked, but there is now a study by Neal Ranen, (24) who reported that the aggressiveness and irritability went away in two patients treated with sertraline.   The antidepressants have always been used a lot in Huntington's Disease as antidepressants. The older antidepressants had a lot of chemical effects. They weren't real selective for one chemical so they had a lot of side effects. A lot of people are scared to use the newer ones, like Prozac, because of all of the media garbage when Prozac first came out, but it's an excellent drug. The other ones that followed Prozac, like Paxil, Zoloft, and Effexor are all excellent drugs.   What makes these drugs advantageous in the treatment of brain disease of all kinds (we use them in Parkinson's Disease too) is that they are very selective for just one chemical. We know what chemical we need to adjust. These only adjust that one chemical so they don't have a lot of side effects. This particular chemical, seratonin, appears to be really important in aggressiveness and irritability. Sometimes it may require changing the dose, so someone with Huntington's Disease may receive a higher dose of Prozac than most people, but it's a perfectly safe dose.   Neuroleptics   People who know me know that I'm not a big neuroleptic fan. I'm not a big Haldol or Thorazine fan. The reason I'm not a big fan is because I think the patients often aren't bothered by their chorea as much as other people, like the doctor or family members, are. More importantly, the other motor problems in people with Huntington's Disease, like slowness and trouble with balance, can be made worse with neuroleptics.   Not only do I think they don't they provide much benefit, except for people with severe chorea, I think that they may be harming people with mild or moderate chorea by making them more slow and more unsteady, so I'm not a big fan of that.   There's a little device that looks like a Dick Tracy two-way wrist radio which measures how active you are. There was a study (25) where they gave these wrist activity monitors to people with Huntington's Disease and they sent them home for five days. Then they brought the wrist monitor in and hooked it up to the computer and it told how active they were.   They found that people with Huntington's Disease, even though they had chorea, moved a lot less than people without Huntington's Disease. That suggested that this slowness of movement really was a significant feature. Some of their patients were on neuroleptics and those patients had much more severe loss of movement than people who weren't on neuroleptics.   CNTF   I want to move on now to the topic of transplantation and other restorative treatments in Huntington's Disease. My colleague, Dr. Kordower, has been involved with research relating to this. (26) Dr. Kordower has a rodent model of Huntington's Disease (these are rats) and he injects an excitatory chemical into their brain to give them brain cell degeneration that looks like Huntington's Disease.   He puts a capsule that contains fibroblasts (these are skin cells) into the brains of the rats. The fibroblasts have been modified to produce a drug CNTF. These are cells that have had the gene to produce CNTF inserted into them so they now produce CNTF, which is not something that they ever did before, but now they do. They put the fibroblasts into a little capsule and then they implant that capsule into the brain. What the capsule does is it keeps the cells inside but lets the CNTF get out.   They have implanted these capsules into the brains of the rodents and then have given them an excitatory chemical to try to make their brain cells degenerate. This capsule protects them so their brain cells don't degenerate. This is a very interesting technology.   They are almost ready to study this in people. Now remember this is different than Huntington's Disease. This is poison induced Huntington's Disease in a rat. It's kind of a leap to naturally occurring Huntington's Disease, but the animal data is strongly suggestive enough that people are willing to look at it for the very earliest trials in humans.   We live in America, which is the greatest country in the world, but it takes longer to get approval to do these things in America, so the first studies are probably going to occur in France.   There are two companies, Regeneron and Medtronics, which I think you've all heard about because there was a big press release. Medtronics is the manufacturer of a pump, an FDA approved device, and Regeneron is working on another form of CNTF. It's a similar but slightly modified form of CNTF which would be given through a pump into the brain.   They would implant the pump under the skin, fill it up with CNTF, and it would pump this chemical into the brain. The last time I talked to them, they were about 18 months from the first studies in humans. They've done work in animals and found the same kinds of things that Dr. Kordower has found about CNTF preventing brain cell degeneration. This is a new way of thinking about working on degenerative diseases and we're talking about a couple of years until human trials.   Transplantation   Dr. Kordower and I had an article that came out this year (27) called "Neural transplantation for Huntington's disease." This was just a review of all of the basic science information and suggestions for how clinical studies should be done for transplantation.   Lastly, there was a very interesting article that looked at when in the fetal development the cells first become useful for transplant. (28) This is a really important area because you need to know when to harvest the cells from the fetal brain so that they'll grow.   This has been more of a problem for Huntington's Disease than for Parkinson's Disease because they're a little more advanced in fetal transplantation for Parkinson's than for Huntington's Disease. There are groups that have transplanted Huntington's patients with fetal cells that were outside the range where they could survive. They have not taken cells from fetuses that were the right age, so they could not possibly have successfully grafted those people.   It's very important for people to define how old the fetus should be in order to get the best cell survival. In Huntington's Disease the cells don't even appear in the fetus until about seven weeks after fertilization.   This study also took these cells at seven weeks, transplanted them, and then looked to see how long it takes before they start becoming integrated into the brain. This is important because in order for transplantation to work in any degenerative disease, the first thing you have to have is cell survival. The cells have to live. If they die you haven't done anything. They have to develop into brain cells and integrate with the existing brain cells and communicate with the existing brain cells.   What they found in this study was it takes months before they mature and integrate with the existing brain cells. This is extremely important because when you read on the Internet that all of the patients in a transplant study were better within two weeks, you should say to yourself, "Well, that's not possible."   It's not possible that their improvement in two weeks was related to brain cells maturing and integrating with the brain. We will not know how well fetal transplant works until at least a year after the transplants have been done.   It'll take at least six months for the cells to mature, make any connections, and then there will be kind of a progressive change. The analogy with Parkinson's Disease, where as I said we're much further along with transplantation, is that the improvements with Parkinson's Disease don't occur until six months. Then they start off gradually and very gradually accumulate over time.   The more you understand about this the more critical you can be of the science that gets to the Internet and the media. Realize that the people who do this kind of research want to help the patients;  that's why they're doing it in the first place. But sometimes the desire to help can cloud scientific objectivity.   So when you read this literature about miraculous treatments occurring and causing effects within two weeks, just be careful consumers. Understand that there's good science which suggests that can't be from a transplantation effect. It must be something else. Who knows what.   Dr. Shannon then read the HSG Position Statement on Experimental Surgical Treatments in HD as a final part of the presentation. (See http://www.lib.uchicago.edu/~rd13/hd/hsg.html for a copy of the statement.)   References (1) Quinn, N., Brown, R., Craufurd, D., Goldman, S., Hodges, J., Kieburtz, K., Lindvall, O., MacMillan, J., Roos, R. "Core assessment program for intracerebral transplantation in Huntington's disease (CAPIT-HD)." Movement Disorders, 1996, Vol 11, Iss 2, pp 143-150.   (2) Kieburtz, K., Penney, J.B., Como, P., Ranen, N., Shoulson, I., Feigin, A., Abwender, D., Greenamyre, J.T., Higgins, D., Marshall, F.J., Goldstein, J., Steinberg, K., Shih, C., Richard, I., Hickey, C., Zimmerman, C., Orme, C., Claude, K., Oakes, D., Sax, D.S., Kim, A., Hersch, S., Jones, R., Auchus, A., Olsen, D., BisseyBlack, C., Rubin, A., Schwartz, R., Dubinsky, R., Mallonee, W., Gray, C., Godfrey, N., Suter, G., Shannon, K.M., Stebbins, G.T., Jaglin, J.A., Marder, K., Taylor, S., Louis, E., Moskowitz, C., Thorne, D., Zubin, N., Wexler, N., Swenson, M.R., Paulsen, J., Swerdlow, N., Albin, R., Wernette, C., Walker, F., et al. "Unified Huntington's disease rating scale: Reliability and consistency." Movement Disorders, 1996, Vol 11, Iss 2, pp 136-142.   (3) Nance. M.A., Sanders. G. "Characteristics of individuals with Huntington disease in long-term care." Mov Disord, 1996 Sep; 11 (5): 542-8.   (4) Siemers, E., Foroud, T., Bill, D.J., Sorbel, J., Norton, J.A., Jr., Hodes, M.E., Niebler, G., Conneally. P.M., Christian, J.C., "Motor changes in presymptomatic Huntington disease gene carriers." Arch Neurol, 1996 Jun; 53 (6): 487-92.   (5) Zappacosta, B., Monza, D., Meoni, C., Austoni, L., Soliveri, P., Gellera, C., Alberti, R., Mantero, M., Penati, G., Caraceni, T., Girotti, F. "Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease." Arch Neurol, 1996 Jun; 53 (6) 493-7.   (6) Shulman, K.I., Lennox, A., Karlinsky, H. "Late-onset Huntington's disease: a geriatric psychiatry perspective." J Geriatr Psychiatry Neurol 1996 Jan; 9(1): 26-9.   (7) Sprengelmeyer, R., Young, A.W., Calder, A.J., Karnat, A,. Lange, H., Homberg, V., Perrett, D.I., Rowland, D. "Loss of disgust. Perception of faces and emotions in Huntington's disease." Brain, 1996 Oct; 119 (Pt 5) 1647-65.   (8) Georgiou, N., Bradshaw, J.L., Phillips, J.G., Chiu, E. "The effect of Huntington's disease and Gilles de la Tourette's syndrome on the ability to hold and shift attention." Neuropsychologia, 1996 Sep; 34 (9): 843-51.   (9) Weeks, R.A., Piccini, P., Harding, A.E., Brooks, D.J. "Striatal D1 and D2 dopamine receptor loss in asymptomatic mutation carriers of Huntington's disease." Ann Neurol, 1996 Jul; 40 (1): 49-54.   (10) Harris, G.J., Aylward, E.H., Peyser, C.E., Pearlson, G.D., Brandt, J., RobertsTwillie, J.V., Barta, P.E., Folstein, S.E. "Single photon emission computed tomographic blood flow and magnetic resonance volume imaging of basal ganglia in Huntington's disease." Archives of Neurology, 1996, Vol 53, Iss 4, pp 316-324.   (11) Taylor-Robinson, S.D., Weeks, R.A., Bryant, D.J., Sargentoni, J., Marcus, C.D., Harding, A.E., Brooks, D.J. "Proton magnetic resonance spectroscopy in Huntington's disease: Evidence in favour of the glutamate excitotoxic theory?" Movement Disorders, 1996, Vol 11, Iss 2, pp 167-173.   (12) Rubinsztein, D.C., Leggo, J., Coles, R., Almqvist, E., Biancalana, V., Cassiman, J-J., Chotai, K., Connarty, M., Craufurd, D., Curtis, A., Curtis, D., Davidson, M.J., Differ, A-M., Dode, C., Dodge, A., Frontali, M., Ranen, N.G., Stine, O.C., Sherr, M., Abbott, M.H., Franz, M.L., Graham, C.A., Harper, P.S., Hedreen, J.C., Jackson, A., Kaplan, J-C., Losekoot, M., MacMillan, J.C., Morrison, P., Trottier, Y., Novelletto, A., Simpson, S.A., Theilmann, J., Whittaker, J.L., Folstein, S.E., Ross, C.A., and Hayden, M.R. "Phenotypic Characterization of Individuals with 30-40 CAG Repeats in the Huntington Disease (HD) Gene Reveals HD Cases with 36 Repeats and Apparently Normal Elderly Individuals with 36-39 Repeats." American Journal of Human Genetics, v. 59, no. 1, July 1996, p. 16-22.   (13) Brandt, J., Bylsma, F.W., Gross, R., Stine, O.C., Ranen, N., Ross, C.A., "Trinucleotide repeat length and clinical progression in Huntington's disease." Neurology, 1996, Vol 46, Iss 2, pp 527-531.   (14) Nasir, J., Goldberg, Y.P., Hayden, M.R. "Huntington disease: new insights into the relationship between CAG expansion and disease." Hum Mol Genet, 1996; 5 Spec No 1431-5.   (15) Weigell-Weber, M., Schmid, W., Spiegel, R. "Psychiatric symptoms and CAG expansion in Huntington's disease." Am J Med Genet, 1996 Feb 16; 67 (1): 53-7.   (16) Nance, M.A., Westphal, B., Nugent, S. "Diagnosis of patients presenting to a Huntington disease (HD) clinic without a family history of HD." Neurology, 1996 Dec; 47 (6): 1578-80.   (17) Frontali, M., Sabbadini, G., Novelletto, A., Jodice, C., Naso, F., Spadaro, M., Giunti, P., Jacopini, A.G., Veneziano, L., Mantuano, E., Malaspina, P., Ulizzi, L., Brice, A., Durr, A., Terrenato, L. "Genetic fitness in Huntington's Disease and Spinocerebellar Ataxia 1: A population genetics model for CAG repeat expansions." Annals of Human Genetics, 1996, Vol 60, Part 5, pp 423-435.   (18) Schulman, J.D., Black, S.H., Handyside, A., Nance, W.E.  "Preimplantation genetic testing for Huntington disease and certain other dominantly inherited disorders." Clin Genet, 1996 Feb; 49 (2): 57-8.   (19) Decruyenaere, M., Evers-Kiebooms, G., Boogaerts, A., Cassiman, J.J., Cloostermans, T., Demyttenaere, K., Dom, R., Fryns, J.P., Van den Berghe, H. "Prediction of psychological functioning one year after the predictive test for Huntington's disease and impact of the test result on reproductive decision making." J Med Genet, 1996 Sep; 33 (9): 737-43.   (20) Mangiarini, L., Sathasivam, K., Seller, M., Cozens, B., Harper, A., Hetherington, C., Lawton, M., Trottier, Y., Lehrach, H., Davies, S.W., Bates, G.P. "Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice." Cell, 1996, Vol 87, Iss 3, pp 493-506.   (21) Feigin, A., Kieburtz, K., Como, P., Hickey, C., Claude, K., Abwender, D., Zimmerman, C., Steinberg, K., Shoulson, I., "Assessment of coenzyme Q10 tolerability in Huntington's disease." Movement Disorders, 1996, Vol 11, Iss 3, pp 321-323.   (22) Kieburtz, K., Feigin, A., McDermott, M., Como, P., Abwender, D., Zimmerman, C., Hickey, C., Orme, C., Claude, K., Sotack, J., Greenamyre, J.T., Dunn, C., Shoulson, I., "A controlled trial of remacemide hydrochloride in Huntington's disease." Movement Disorders, 1996, Vol 11, Iss 3, pp 273-277.   (23) Furtado, J.C.; Mazurek, M.F. "Behavioral characterization of quinolinate -induced lesions of the medial striatum: relevance for Huntington's disease." Exp Neurol, 1996 Mar; 138 (1): 158-68.   (24) Ranen, N.G., Lipsey, J.R., Treisman, G., Ross, C.A. "Sertraline in the treatment of severe aggressiveness in Huntington's disease." J Neuropsychiatry Clin Neurosci, 1996 Summer; 8 (3): 338-40.   (25) Van Vugt, J.P., Van Hilten, B.J., Roos, R.A. "Hypokinesia in Huntington's disease." Mov Disord, 1996 Jul; 11 (4): 384-8.   (26) Emerich, D.F., Lindner, M.D., Winn, S.R., Chen, E.Y., Frydel, B.R., Kordower, J.H. "Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease." Journal of Neuroscience, 1996, Vol 16, Iss 16, pp 5168-5181.   (27) Shannon, K.M., Kordower, J.H., "Neural transplantation for Huntington's disease: Experimental rationale and recommendations for clinical trials." Cell Transplantation, 1996, Vol 5, Iss 2, pp 339-352.   (28) Naimi, S., Jeny, R., Hantraye, P., Peschanski, M., Riche, D. "Ontogeny of human striatal DARPP-32 neurons in fetuses and following xenografting to the adult rat brain." Exp Neurol, 1996 Jan; 137 (1): 15-25