All posts in Managing HD

Fatty Acids

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Today in the U.S., we are commonly instructed to lower our fat intake because word is out that fats are bad. Low-fat, non-fat, and even “fake fat” food products dominate supermarket shelves. Consumers typically fear fat in any form. However, not all fats are bad. In fact, some types of fats are actually necessary for life and health and should not be eliminated from the diet. This chapter examines the different types of fats, as well as the effect that these fats can have on the brain. In addition, this chapter reveals how optimizing the amount and type of fat in the diet may help combat Huntington´s disease (HD).

Saturated vs. Unsaturated Fat^

The whole of issue of fat in the diet has become very confusing, mainly because there are so many different types of fat. Essentially, there are two broad categories of fat: saturated fat and unsaturated fat. These two types of fat differ in their chemical structure. Saturated fatty acids (the building blocks of saturated fat) have no double bonds (a particular kind of chemical link between adjoining molecules) and this lack of double bonds means that there are no gaps in the fatty acid chain: it is packed with CH2 molecules. Unsaturated fatty acids (the building blocks of unsaturated fat), on the other hand, have double bonds and these double bonds break up the string of CH2´s and create gaps within the fatty acid chain. See figure 1 for a depiction of the difference between saturated and unsaturated fatty acids. We will explore how this difference in chemical structure affects how different types of fat interact with the body below.

Saturated fats (meats, butter, dairy products) are solid at room temperature, whereas unsaturated fats (vegetable oils) are liquid at room temperature. Due to their difference in chemical structure, saturated fats and unsaturated fats exert different effects within the body. Because saturated fatty acid chains have no gaps, they are able to pack together very tightly. When these tightly packed saturated fatty acids enter the bloodstream, they increase levels of “bad” cholesterol known as low-density lipoprotein (LDL) cholesterol and clog arteries. In comparison, unsaturated fats do not increase “bad” cholesterol and, in fact, are able to increase levels of “good” cholesterol known as high-density lipoprotein (HDL) cholesterol. HDL is able to grab LDL and escort it to the liver where it is broken down and eventually removed from the body. Thus, by increasing levels of HDL, unsaturated fats are able to protect against the damage done by saturated fats. Since heart disease is a leading cause of death for people with HD, it is especially important to keep the heart healthy and limit intake of saturated fat. (For more information on the many complications of HD, including heart disease, click here.) And as we will see below, there are even more reasons than heart disease for people with HD to be conscientious about the types of fat that they consume.

Trans fat^

Because saturated fats were shown to be so unhealthy, food manufacturers decided to start using more unsaturated fats. The problem is that unsaturated fats spoil quickly. Food manufacturers solved this problem by putting unsaturated fats through the process of hydrogenation, which essentially alters the chemical structure of unsaturated fats and makes them more solid and long-lasting. However, when unsaturated fat is hydrogenated, a new fat called trans fat is produced. Fried foods, doughnuts, cookies, and crackers all contain high levels of trans fat. Trans fat rarely exists in nature and has been shown to be toxic to the body. Not only does it increase levels of “bad” cholesterol, it also decreases levels of “good” cholesterol. Thus, it has no redeeming qualities within the body and, as will be discussed later, it can worsen HD symptoms.

The relation between fat and nerve cells^

Nutrition is an integral component of our daily life routine and it has the potential to modulate brain health and function. Although it may at first seem strange, fat is essential for brain development and maintenance. In fact, about two-thirds of the brain is composed of fat, which may come as a surprising statistic. Where is all that fat? It is found in two places associated with nerve cells themselves. First, the protective covering of nerve cells called myelin is 70% fat. More importantly, the membranes of nerve cells are made of a thin double-layer of fatty acid molecules. After the body breaks down fat from the diet into fatty acids, the brain then uses these fatty acids by incorporating them into its cell membranes. Nerve cell membranes are extremely important because their composition determines what is able to pass into and out of the cell. Oxygen, glucose, and the nutrients that the cell needs to survive all must pass through the membrane and into the cell´s interior. When saturated fatty acids are incorporated into normally very fluid cell membranes, they pack very tightly because saturated fatty acid chains have no gaps. Thus, essential nutrients are unable to get into the cell, making the cell less healthy and more prone to injury. In contrast, unsaturated fats can be beneficial to nerve cells because they prevent the tight packing of fatty acids in the membrane. Unsaturated fatty acids have gaps in their chains and these gaps allow for a certain amount of “fluidity.”

Membrane fluidity is absolutely essential for the optimal function of most cells in the body, but it is especially important for nerve cells. In addition to letting in essential nutrients and keeping out harmful substances, nerve cell membranes also contain proteins that act as receptors for some neurotransmitters. Neurotransmitters are the chemical messengers that nerve cells use to communicate with each other. (For more information on neurotransmitters and their role in HD, click here). In order for the receptors to be able to recognize neurotransmitters and send along the messages that they contain, the nerve cell membrane must be fluid. If the nerve cell membrane is too rigid, the receptors on the membrane become less capable of recognizing neurotransmitters and passing along messages to the nerve cell. Often, the messages contained in neurotransmitters are critical to the survival of the nerve cell. Thus, membrane composition is extremely important because it influences nerve cells´ ability to communicate with each other and, ultimately, survive.

Studies reveal that optimal membrane composition is obtained when one consumes equal amounts of saturated and unsaturated fat. However, nutritional studies show that the average North American eats three times as much saturated fat as unsaturated fat! The addition of trans fat to the diet has made the situation even worse. Let us consider each fat in the context of our cells. Although too much saturated fat is bad, a certain amount is necessary for the optimal functioning of the membrane. On the other hand, the cell membrane has absolutely no use for trans fat. When trans fat gets incorporated into nerve cell membranes, the membranes become less capable of performing many essential functions, making the nerve cells more prone to a variety of insults.

How fat affects people with HD^

Nerve cell Communication^

Excessive consumption of saturated fat and trans fat can be particularly hazardous for people with HD. Even without any dietary influences, the HD disease process causes some nerve cells in the brain to become less able to communicate with each other, which contributes to these nerve cells losing function and eventually dying. Consuming excessive amounts of saturated fat can worsen this situation by making it even harder for nerve cells to communicate with each other via neurotransmitters. If the nerve cell membrane consists of too much saturated fat or trans fat, the nerve cell may be unable to receive messages from neurotransmitters. Often, these messages are essential for the survival of the cell. (For more information on the neurobiology of HD, click here.) Thus, it is clear that the amount and type of fat in the diet may influence the ability of nerve cells to survive. Replacing saturated fat and trans fat with unsaturated fat in the diet can enhance the ability of the nerve cell membrane to pass along necessary messages. It can also increase the fluidity of the nerve cell membrane, which makes it easier for the nerve cell to receive an adequate supply of oxygen and other essential nutrients. With the nerve cell membrane functioning as efficiently as possible, the nerve cell may be better able to deal with the harmful effects of HD. Thus, it may be possible for a person with HD to delay the onset and progression of HD symptoms simply by altering his or her fat consumption.

Oxidative stress^

In addition to negatively affecting membrane function, a diet high in saturated fat may also induce oxidative stress and decrease levels of a protein known to assist in nerve cell survival called brain-derived neurotrophic factor (BDNF). Increased oxidative stress and decreased BDNF would be highly damaging to a person with HD. When trying to combat a neurodegenerative disease such as HD, maximizing levels of BDNF is ideal because it may help combat the damage done by the disease. Thus, in the interest of maintaining levels of BDNF, one might consider limiting one´s consumption of saturated fat. In addition, keeping oxidative stress to a minimum is important for people with HD. Oxidative stress, a harmful process that injures cells and eventually causes them to die as a result of free radical damage, is thought to contribute significantly to the disease process of HD. (For more information about free radicals and HD, click here.) Although a certain amount of oxidative stress will inevitably occur due to aging, it is important for people with HD to be conscientious about not worsening oxidative stress from the food they eat. Since diet is a very controllable aspect of one´s lifestyle, limiting consumption of saturated fats is a great way for people with HD to ensure that they do not aggravate the damaging processes in their nerve cells any further. Although much more research needs to be done in this area, it seems likely that adjusting for less saturated fat in one´s diet could significantly slow down the progression of HD.

Getting the right type of unsaturated fat – essential fatty acids.^

In general, it is true that any type of unsaturated fat is better for the brain and body than either saturated fat or trans fat. However, there are many different types of unsaturated fat and some types of unsaturated fat are better for you than others. Monounsaturated fatty acids have only one double bound and thus only one gap in the fatty acid chain. Polyunsaturated fatty acids have many double bonds and many gaps within the fatty acid chain. All saturated and monounsaturated fats can be made within the body and, therefore, they do not need to be supplied through the diet. However, the body is unable to make two types of polyunsaturated fat and these must be obtained through the diet. The first type of polyunsaturated fat is alpha-linolenic acid (ALA), which belongs to the omega-3 family of fatty acids. ALA is found abundantly in flax seed (a fiber derived from plants) and flax oil, and is found in small quantities in canola oil, wheat germ, and dark green leafy vegetables such as spinach and broccoli. The second type of polyunsaturated fat that the body cannot make is linoleic acid (LA) and it belongs to the omega-6 family of fatty acids. LA is found in soy oil, sesame seeds, corn oil, and in most nuts. Because the body is unable to make these two fatty acids, they are an essential part of the diet. Hence, they are called essential fatty acids (EFA´s).

ALA^

Once the body is supplied with the essential fatty acid ALA, it can convert it into DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid). Both DHA and EPA are great at lowering one´s risk for heart disease. In addition, DHA is essential for nervous system maintenance and development. Infants who have low amounts of DHA in their diet have reduced brain development. Accordingly, human milk is extremely rich in DHA. DHA is the most abundant fatty acid in nerve cell membranes and is thought to contribute significantly to the fluidity of the cell membrane. DHA is also found in the synapses between nerve cells and is thought to greatly aid the nerve cells in sending signals to each other. The problem is that DHA levels naturally decline as one gets older. If DHA is not supplied through the diet (from consuming ALA), then the nerve cell membranes begin to function sub-optimally. Perhaps this may explain why societies whose diets are high in DHA (such as the Inuit of the arctic who eat a lot of fish, a great source of DHA) have a lower incidence of neurodegenerative disorders.

LA^

The other essential fatty acid, LA, is converted to GLA (gamma linoleic acid) within the body. GLA eventually leads to the production of prostaglandins, which are molecules that help regulate inflammation and blood pressure. (For more information on essential fatty acids and inflammation, click here.) While LA is termed “essential,” it is not entirely good for the body. In fact, Americans tend to consume way too much of it. This overconsumption is a problem because it turns out that both ALA and LA compete for the same enzymes to produce their final product. In other words, if there is too much LA, then the enzymes will be busy converting LA into GLA and there will be no enzymes left to convert ALA into DHA. (For more information on how ALA and LA compete for enzymes, click here.)Thus, a balance of ALA and LA is essential for proper health. Studies show that the optimal ratio of LA to ALA is somewhere between 2:1 and 1:1. It is estimated that the ratio of LA to ALA for most Americans is around 20:1. This imbalance makes sense because typical foods such as cereal, eggs, poultry, bread, and baked goods are made from oils rich in LA. Foods rich in ALA are much harder to find. Often, dietary supplementation may be needed in order to get enough ALA.

In addition to consuming enough ALA, humans must be able to absorb it. Findings suggest that an inadequate intake of vitamin E results in decreased absorption of ALA. Thus, some experts suggest that vitamin E supplementation may be useful in conjunction with ALA supplementation.

As mentioned earlier, nerve cell membranes are critical in terms of maintaining the safety of the nerve cell. Not only are they responsible for letting in essential nutrients and expelling harmful substances, but they also help nerve cells communicate with each other. Thus, in a person with HD, it is especially important for the nerve cell membranes to be operating optimally because it can greatly aid in the survival of the nerve cells. DHA, a product of ALA, has been shown to keep nerve cell membranes operating at an optimal level. It stands to reason that if a person with HD obtains adequate amounts of ALA and fixes the skewed imbalance of LA to ALA, he or she may be able to prolong the life of his or her nerve cells, and this too would likely delay the progression of the disease.

A wrap-up on fatty acids and HD^

Fats play a significant role in the brain. Specifically, the amount and type of fat one consumes directly affects the composition of nerve cell membranes. The composition of nerve cell membranes is especially important for people with HD because it has the potential to protect the nerve cell from damage. Too much saturated fat or trans fat in the diet leads to stiff, rigid membranes and a loss of membrane fluidity. In addition, too much saturated fat and trans fat alters the shape and size of the nerve cell membrane, which ultimately makes it so that the nerve cells are less able to communicate with each other. By replacing saturated fat with unsaturated fat in the diet, a person with HD can help his or her nerve cell membranes to function as efficiently as possible. Furthermore, certain types of unsaturated fat are more beneficial than others. In particular, the essential fatty acid (EFA) called ALA, which leads to DHA as described above, is the most abundant and perhaps most important in the brain. Because ALA competes with LA, one must limit one´s consumption of LA in order to ensure adequate amounts of ALA.

In short, the research reviewed in this chapter indicates that a person with HD should strive to reduce the amount of saturated fat and trans fat in his or her diet and to increase the ratio of ALA to LA in his or her diet in order to ensure the optimal functioning of the nerve cell membranes. Better functioning membranes means healthier nerve cells and having healthier nerve cells may well postpone the onset of HD symptoms.

Research on essential fatty acids:^

Vaddadi, et al. (1999) examined the effect that essential fatty acid (EFA) supplementation can have on the symptoms in people with HD. In the study, there were 17 HD patients who all showed clinical signs of HD, such as chorea. Genetic testing confirmed that these 17 patients did indeed have HD. During the study, the patients were told to stick to the same routine and continue taking the same amounts and types of medication. Randomly, nine of the subjects were assigned to the treatment group and they were given capsules that contained essential fatty acids. The other eight subjects were assigned to the control group and they received placebo capsules that did not contain essential fatty acids (this group was used to compare to the group receiving treatment). The study was designed to last two years and the patients´ symptoms were assessed at the beginning of the study and at six-month intervals. Their symptoms were assessed using two Huntington´s disease rating scales.

After twenty months, the study had to be stopped on ethical grounds because it was clear that the treatment group was receiving a significant benefit from the essential fatty acid capsules. The subjects in the treatment group improved in motor skills and functional performance while the subjects in the control group deteriorated. The results indicated an actual improvement over the starting measurements for the treatment group and not merely a slowing of deterioration. Of the nine subjects in the treatment group, only one subject did not improve over baseline. Much of the separation in results between the two groups occurred during the first six months of the study, indicating that it does not take long for the effects of essential fatty acid supplementation to be seen. However, the study did have a few shortcomings. The sample size was small and the effect of any earlier treatments that the subjects may have tried is unknown. Also, the study was terminated early so the long-term benefits of essential fatty supplementation are unclear. The study also does not indicate how high a dose is required to produce an effect. Clearly, much more research needs to be done in this area.

Clifford, et al. (2002) looked at how essential fatty acid (EFA) supplementation affected a mouse model of HD. These specific mice have an HD-like allele and they develop late-onset nervous system deficits in a manner similar to the motor abnormalities of HD. The mice were randomly divided into two groups: a treatment group receiving a mixture of fatty acids and a control group receiving a placebo. Through mid-adulthood, mice in the control group experienced progressive shortening of stride length and complications in movement ability. These deficits were either not evident in the mice in the treatment group or were significantly decreased. The findings of the study indicate that early and sustained treatment with essential fatty acids may be able to protect against motor deficits in mice that have an HD-like allele, and thus may also be able to protect against motor deficits in people with HD.

For further reading^

  1. Aiguo, W. et al. “The interplay between oxidative stress and brain-derived neurotrophic factor modulates the outcome of a saturated fat diet on synaptic plasticity and cognition.” European Journal of Neuroscience. 2004; 19(7): 1699-707.
    This is a technical scientific article that explains how a diet high in saturated fat can lead to oxidative stress and decreased levels of BDNF.
  2. Clifford, J.J. et al. “Essential fatty acids given from conception prevent topographies of motor deficit in a transgenic model of Huntington´s disease.” Neuroscience. 2002; 109(1): 81-8.
    This article is fairly easy to read and it describes the study in which a mouse model of HD that received essential fatty acids showed improvements in motor abilities.
  3. Vaddadi, K.S. et al. A randomised, placebo-controlled, double blind study of treatment of Huntington´s disease with unsaturated fatty acids.” Neuroreport. 2002; 13: 29-33.
    This article is of medium difficulty. It describes the study in which essential fatty acid supplementation was examined among HD patients.

-D. McGee, 04/27/05

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Curcumin, the Curry Spice

For many years, people around the world have been preparing their meals with an Indian spice called curry. Although most people who eat curry probably do so simply because of its pleasant taste, some current research suggests that the spice may actually have another important characteristic: it may be helpful in combating the effects of some neurodegenerative diseases. According to research on Alzheimer’s disease (AD), the disease-fighting effects of curry come from a compound called curcumin, which is a component of turmeric, the yellow spice that is used in most traditional curries. This chapter gives an overview of curcumin’s beneficial effects on AD and suggests possibilities for how curcumin may affect Huntington’s disease.

How Curry Relates to the Epidemiology of Alzheimer’s in Humans^

Scientists first became interested in studying curcumin when they looked into some statistics about the prevalence of AD in India, where curry is eaten in large quantities. In India, a relatively small proportion (1%) of people age 65 and older have AD. Additionally, in comparison to their American counterparts (who eat significantly less curry), Indians aged 70-79 develop AD one-fourth as often.

Although these data indicate that there is something special about Indian people with regard to AD, the many factors involved in the disease (which may involve a variety of things like genetics, exposure to certain toxins, eating things besides curry, etc.) make it inaccurate to state that curcumin is definitely the cause of India’s low prevalence of AD. However, the fact that curry (and thus, curcumin) is much more common in the Indian diet than the American diet does demonstrate what is called an inverse correlation between the use of curry and the prevalence of AD; that is to say, higher average amounts of curry intake are associated with lower prevalences of AD.

Having recognized this inverse correlation between curry and AD, scientists were able to take the research one step further. Interested in finding out whether or not curcumin might have a causal effect on combating AD, researchers turned to rodents (mice) as experimental animals in which to study the effect of curcumin on nerve cells. What they found in this research is discussed in the next section.

The Effects of Curcumin On the Cells of Rodents with Alzheimer’s^

The process through which Alzheimer’s disease degrades nerve cells is believed to involve three things: inflammation, oxidative damage, and most notably, the formation of beta-amyloid plaques. In order to understand how curcumin combats AD, we will look at its effects on each of these three phenomena.

Inflammation^

On a short-term scale, inflammation is a very helpful event: it is the body’s way of protecting itself from foreign invaders. However, over an extended period of time, inflammation can actually be quite harmful. (For more info about inflammation, click here.) One of the ways that AD degrades nerve cells (and thus results in the manifestation of the disease’s symptoms) is by causing chronic inflammation in the central nervous system. For this reason, populations that exhibit prolonged use of certain nonsteroidal anti-inflammatory (NSAID) drugs like ibuprofen have been shown to have a reduced risk of developing the symptoms of AD. However, while ibuprofen significantly reduces the amount of inflammation in the central nervous system, its prolonged use has dangerous side effects like gastrointestinal, liver, and kidney damage.

Curcumin is a natural NSAID. For this reason, in mice models of AD, it was shown to reduce the levels of inflammation in the brain by about 60% (as measured by the reduced presence of a certain indicator of inflammation). An added benefit of curcumin is that it appears to be far less toxic than most drug NSAIDs. If further research confirms the safety of the substance, its use may become an alternative to drug NSAIDs for combating AD.

Oxidative Damage^

Like Huntington’s disease, AD can also increase the number of free radicals that nerve cells produce. Over time, this increased number of free radicals leads to oxidative damage, which can degrade nerve cells. In comparison to untreated mice with AD, mice with AD that were treated with curcumin had significantly reduced levels of free radicals. Thus, the oxidative damage that AD caused to the nerve cells of the curcumin mice was far less than the damage to the untreated mice.

Beta-Amyloid Plaques^

The most prominent characteristic in the brains of people with Alzheimer’s disease is the presence of beta-amyloid plaques. These plaques are basically an accumulation of small fibers called beta-amyloid fibrils. The plaques can be found in the spaces between nerve cells, and in addition to being a tell-tale sign of the disease, their presence is believed to contribute greatly to the neurodegenerative process of AD.

The levels of beta-amyloid in AD mice that were given low doses of curcumin were decreased by around 40% in comparison to those AD mice that were not treated with curcumin. In addition, low doses of curcumin also caused a 43% decrease in the so-called “plaque burden” that these beta-amyloids have on the brains of AD mice. Surprisingly, those AD mice that received high doses of curcumin did not show any decreases in beta-amyloid levels or plaque burden in comparison with untreated mice. While the exact reason for this finding is not yet clear, the results of it are intriguing: low doses of curcumin were actually more effective than high doses in combating the neurodegenerative process of AD.

How this Alzheimer’s Research May Affect Huntington’s Disease^

Although research to confirm such a notion is just now getting underway, the results of the Alzheimer’s study suggest that curcumin might well be helpful in combating other neurodegenerative diseases like HD. Despite the differences in the fundamental “cause” of each disease – HD is believed to be a purely genetic disorder, while AD is believed to have both genetic and environmental components – the damage to nerve cells in each disorder is strikingly similar. Thus, because curcumin combats the phenomena that contribute to neurodegeneration in AD, it is fair to suggest that the substance may possibly be capable of combating similar phenomena in HD.

Just as in Alzheimer’s, inflammation and oxidative damage play a strong role in the neurodegenerative process of HD: oxidative damage (also known as “oxidative stress”) helps to degrade nerve cells in the basal ganglia and cerebral cortex; chronic inflammation in the brains of people with HD is believed to play a significant role in the progression of the disease. ( For more info about inflammation, click here.) As shown previously, curcumin was able to reduce inflammation and oxidative damage in mouse models of AD. Although it is possible that the pattern of inflammation in the brain and the severity of oxidative damage may be different between AD and HD, if they are even slightly similar in the two disorders, then one would expect curcumin to also have a positive effect on combating HD.

Despite the harmful effects of inflammation and oxidative damage, beta-amyloid fibrils (which make up beta-amyloid plaques) have won the most attention among researchers and the general public with regard to AD. Similarly, despite the harmful effects of other phenomena that contribute to neurodegeneration, the most attention among researchers and the general public with regard to Huntington’s disease is devoted to huntingtin protein aggregation. The attention paid to beta-amyloid fibrils and huntingtin protein aggregation is not unjustified: in addition to being telltale signs of their respective disorders, these two phenomena may be key players in the neurodegenerative process. For instance, some researchers believe that substances which inhibit huntingtin protein aggregation will also be found to inhibit the initial structural alteration of the huntingtin protein, an alteration that is believed to start the entire disease process in HD. But there is another discovery that could have potentially profound effects on the research underway for both of these diseases: based on their ribbon-like structure and the mechanism by which they are created, huntingtin protein aggregates are quite similar to beta-amyloid fibrils. Given this discovery, it is possible that substances that decrease the presence of beta-amyloid fibrils may do the same with huntingtin protein aggregates, and vice-versa.

As of this writing (June 2004), research on the effectiveness of curcumin in combating huntingtin protein aggregation has just gotten underway. Should curcumin prove to decrease huntingtin protein aggregates as well as it did beta-amyloid plaques, this would be a true triumph in HD research. However, while this possibility is certainly a source of intrigue, it is important to note that not all substances that are proven to decrease beta-amyloid levels have shown the same effectiveness with huntingtin protein aggregation. For instance, the compounds thioflavine T, gossypol, melatonin, and rifampicin, all of which are believed to decrease the presence of beta-amyloid, had little or no success in inhibiting huntingtin protein aggregation. On the other hand, Congo Red and thioflavine S, which are also believed to decrease beta-amyloid, did effectively decrease huntingtin protein aggregation. Thus, while the similarities between beta-amyloid fibrils and huntingtin protein aggregates make us hopeful that curcumin can decrease the aggregates, current research on curcumin and HD will have the final say.

A closing remark: This section lacks definitive answers about how curcumin affects HD for one reason: the research simply has not yet been done. As the studies that are currently underway produce results, and as potentially more studies are begun, we will learn a great deal about how curcumin affects HD.

Uncertainties in How the Animal Research Relates to Humans^

The AD mice study mentioned in the above sections prompts us to offer some cautionary notes about directly applying results from mice to humans:

First, the AD study tested curcumin by splitting the mice into three groups: one group received a low dose of curcumin, another group received a high dose, and the third group received no curcumin at all. Curiously, comparing the low-dose group and high-dose group, low doses of curcumin actually appeared to combat neurodegeneration in AD better than high doses. While the reason for this finding is not yet fully understood, the results do tell us something important: just because a substance is helpful does not mean its helpfulness is increased with every increase in dosage. In fact, increased or prolonged dosages of an initially helpful substance can actually be harmful. In the ibuprofen study mentioned above, for example, gastrointestinal, liver, and kidney damage resulted from the prolonged use of otherwise helpful ibuprofen.

Second, it is also important to keep in mind that mice, of course, have significantly smaller bodies than humans and may metabolize substances differently than we do. Thus, despite its apparent safety in animal studies (for example, one study on mice used 83 times the normal amount of curcumin, and still produced no mortalities), one should always exercise caution when using a new substance (medicinal or natural) to treat a disorder. And as always, for advice about treating disease, it is important to consult a physician.

Clinical trials should soon be underway in order to establish the safety of using curcumin to combat AD in humans. If future laboratory and animal studies suggest that curcumin holds promise for combating Huntington’s disease as well, then clinical trials to test its safety and effectiveness in HD would also be needed.

For further reading^

  1. Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, Lehrach H, Wanker EE. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6739-44. PMID: 10829068 [PubMed - indexed for MEDLINE]
    A technical paper that describes the effectiveness of certain compounds in decreasing the amount of huntingtin protein aggregation in HD.
  2. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. . J Neurosci. 2001 Nov 1;21(21):8370-7. PMID: 11606625 [PubMed - indexed for MEDLINE]
    A technical paper that discusses how curcumin affects the nerve cells of Alzheimer’s mice. This is the paper on which the majority of the chapter was based.
  3. Scherzinger E, Sittler A, Schweiger K, Heiser V, Lurz R, Hasenbank R, Bates GP, Lehrach H, Wanker EE. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington’s disease pathology. Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4604-9. PMID: 10200309 [PubMed - indexed for MEDLINE]
    A technical paper that discusses the similarities between huntingtin protein aggregates and beta-amyloid fibrils.

-M. Stenerson, 6-28-04

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Cholesterol and Huntington's Disease

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Introduction

This chapter will investigate how cholesterol relates to HD. The chapter begins with a general overview of cholesterol and its role in the body. Following this, the chapter will focus on the cholesterol that originates in the brain, and on new research that looks at the relationship between cholesterol in the brain and HD.

What is cholesterol and what does it do?^

Cholesterol is a lipid molecule present in all animals. It is largely found in cell membranes, and there is a smaller amount circulating in the blood stream and stored inside cells. Cholesterol has a number of important functions. It is a key structural component of cell membranes, maintaining their fluidity and stability, and enabling important processes such as endocytosis. It is also important for the metabolism of fat-soluble vitamins, the manufacture of bile salts and the synthesis of vitamin D and steroid hormones. The synthesis of vitamins and hormones takes place in endocrine cells, while bile salts are generated in the liver.

Recently a small number of papers have shown that HD patients have altered levels of cholesterol in nerve cells. Since cholesterol plays a key role in the maintenance of healthy neurons, the disruption of normal cholesterol levels in HD patients may be a significant cause of neuron death and dysfunction.

Where does cholesterol come from?^

There are two major ways for our bodies to get cholesterol; it can be synthesized in the body, or obtained from the diet. Normally, our bodies take advantage of both methods of getting cholesterol. On average, a 150 pound person will synthesize about 1 gram of cholesterol per day and intake 200-300 milligrams through their diet.

The highest rate of cholesterol synthesis by the body occurs in the liver, although cholesterol is also made in the intestines, adrenal glands, CNS, and reproductive organs. Other cells can produce cholesterol, but typically in much lower amounts.

Cholesterol is found in all animal foods including meat, poultry, fish, seafood, eggs, and dairy. Cholesterol is not found in plants, so foods like fruits, vegetables, grains, nuts and seeds do not raise cholesterol levels. It is partly because we synthesize so much of our own cholesterol that excess dietary cholesterol is not necessary and can be harmful in a variety of ways.

In this chapter, our goal is to first provide a general review on cholesterol and its activity in the human body, and then look at its relationship to Huntington’s disease.

HDL and LDL^

Most people have heard of a distinction between two types of cholesterol: HDL and LDL. HDL stands for high-density lipoprotein, while LDL stands for low-density lipoprotein. HDL is commonly referred to as “good” cholesterol, while LDL is called “bad” cholesterol. More precisely, HDL and LDL are not simply different types of cholesterol, but rather alternative groups of lipids and proteins that transport the cholesterol throughout the body in the bloodstream. Molecules such as HDL and LDL are needed to carry cholesterol because it is a hydrophobic molecule and therefore cannot dissolve in blood and travel through the bloodstream on its own.

But if HDL and LDL are just alternative cholesterol carrier molecules, why is one considered good and the other bad? Medical studies have noted that high levels of LDL are associated with an increased risk of cardiovascular disease, whereas high levels of HDL are associated with decreased risk of cardiovascular disease.

How exactly does HDL produce beneficial effects and LDL produce harmful effects? LDL is the major cholesterol carrier in the blood and is responsible for delivering cholesterol to cells in the body. High levels of LDL cholesterol in the blood contribute to the formation of plaque. Plaque is a thick, hard deposit of fat, cholesterol and other substances that clogs arteries and causes atherosclerosis. If arteries become severely clogged with plaque, oxygen-carrying blood may not reach be able circulate around the body- which can lead to heart attack or stroke. Approximately one fourth of blood cholesterol is carried by HDL. HDL is believed to protect against atherosclerosis by carrying cholesterol away from the blood (so it cannot contribute to plaque formation) or even removing excess cholesterol from plaque already built-up in the arteries. HDL usually delivers cholesterol to the liver or endocrine cells, where it will be used in the synthesis of steroids or bile salts, and ultimately removed from the tissue and bloodstream.

Cholesterol as a Risk Factor for Heart Disease^

When our cholesterol levels are tested, they are shown in milligrams per deciliter of blood (mg/dL). The American Heart Association classifies anyone with total cholesterol greater than or equal to 240 mg/dL as belonging to a high risk category. They recommend that those with a total cholesterol level in this high range get a complete fasting lipoprotein profile done. This test measures LDL, HDL, and triglyceride levels. Triglycerides are another contributor to atherosclerosis. The target HDL level is greater than 40 mg/dL, the target triglyceride level is less than 150 mg/dL, and the target total cholesterol level is less than 240 mg/dL.

Cholesterol and Triglyceride Levels (mg/dL)

Optimal Near Optimal Borderline High High Very High
Total Blood Cholesterol <200 —- 200-239 =240 —-
LDL Cholesterol <100 100-129 130-159 160-189 =190
Triglyceride Level <150 —- 150-199 200-499 =500

*Information from the American Heart Association

There are several ways to lower cholesterol levels that are too high. The best methods are usually lifestyle changes. These can include dietary changes such as eliminating foods that are high in saturated fat, trans fat, and cholesterol and increasing the consumption of fruits, vegetables and grains. Exercise is also an important way to reducing the amount of cholesterol in our bodies. By exercising for 20-30 minutes each day we use up greater amounts of fats and other energy molecules that are stored in our bodies. Additionally, there are medications that help lower cholesterol. These medications usually employ one of two general strategies. They either block the synthesis of cholesterol within the bodies’ cells or they prevent cholesterol uptake in the intestine, forcing ingested cholesterol to pass through the body and never be absorbed. The best way to stay healthy is to make sure you have had your cholesterol tested and, if it is too high, to follow your doctor’s instructions for lowering it.

Cholesterol in the CNS^

The CNS contains a large amount of cholesterol, as cholesterol is needed for the growth and maintenance of myelin, as well as neuron and glial cell membranes and for the formation of new connections between cells. However, the CNS is unique in that there is no evidence that it obtains any of its cholesterol from the blood. Instead, cells in the CNS synthesize all of their own cholesterol. In fact, the rate of cholesterol synthesis in the CNS exceeds the need for new cholesterol, so that some cholesterol must move out of the CNS through excretory pathways.

It is not easy for molecules to enter the CNS. Tightly joined endothelial cells found in the capillary network within the brain prevent many molecules from moving from the blood to the CNS. This blood-brain barrier makes it unlikely that cholesterol carried in lipoproteins could reach the CNS unless there were specific transporters in the endothelial cells of the vessel walls. Currently there is no evidence that existing transporters in those endothelial cells actively uptake lipoprotein-transported cholesterol.

Relating cholesterol to Huntington’s disease^

A few studies have recently investigated the role of cholesterol in HD and have suggested that HD may disrupt the normal cholesterol homeostasis in the brain. These research articles propose that the altered huntingtin protein may cause a change in intracellular levels of cholesterol in neurons by disrupting at least two cellular mechanisms: endocytosis and cholesterol biosynthesis. Ultimately, these cellular changes may lead to dysfunction or death of the striatal neurons and reflect another pathway or mechanism by which the mutated huntingtin protein affects the cell and causes neurodegeneration.

Cholesterol Accumulation and Inhibited Endocytosis^

A study by Trushina et al. has reported that the mutant huntingtin protein inhibits a specific type of endocytosis in striatal neurons. These neurons are also shown to have strikingly high intracellular levels of cholesterol.

Mutant huntingtin has been previously shown to interact with clathrin, which is a major protein involved in endocytosis. In this study however, a different protein has been implicated in the disruption of endocytosis in HD. It has been demonstrated that the mutant huntingtin protein interacts with the protein caveolin-1 (cav1), a key molecule in a different endocytotic pathway (called caveolar-related endocytosis). The interaction of mutant huntingtin protein and cav1 inhibits caveolar-related endocytosis and also causes an accumulation of cholesterol within neurons.

Examination of mouse tissue and HD striatal cell cultures revealed the accumulation of intracellular cholesterol. Researchers found that using siRNA to knockdown cav1 translation prevents cholesterol accumulation. For more on siRNA techniques, click here. This occurred only in the continued presence of mutant huntingtin protein, suggesting that it is something specifically about the nature of the interaction between altered huntingtin and cav1 that disrupts normal cholesterol homeostasis, and not simply the lack of cav1 altogether. It was also observed that in all cases clathrin-dependent endocytosis was normal, indicating that the mechanism of cholesterol accumulation was specific to the disruption of the caveolar-related pathway.

How is cholesterol biosynthesis affected?^

In another recent paper, by Valenza et al., Huntington’s disease has been shown to decrease cholesterol biosynthesis in nerve cells. The presence of altered huntingtin in these cells is correlated with significantly lower total cholesterol mass. This was observed in mouse tissue and in cultured striatal neurons expressing a fragment of the mutant huntingtin protein.

Mutant huntingtin affects the transcription of genes crucial to cholesterol synthesis. The altered huntingtin protein interacts with binding proteins called sterol regulatory element -binding proteins (SREBPs) and prevents these proteins from entering the nucleus. These proteins usually bind to DNA and promote transcription of many different genes important for synthesizing cholesterol. Mutant huntingtin has a strong effect on SREBPs; the proteins are reduced by 50% in the nucleus of HD cells. Reduction of the SREBPs results in significantly less transcription of the genes involved in cholesterol biosynthesis, which ultimately reduces total cholesterol.

Large changes in the levels of intracellular cholesterol will eventually lead to disruption of cellular homeostasis. Research with HD cell line models has shown that the addition of exogenous cholesterol to cultured striatal neurons expressing mutant huntingtin joined to a green fluorescent protein will prevent these neurons from dying.

Implications^

Cholesterol is essential for promoting synapse formation and maintaining membrane integrity in CNS neurons. It is also a major component of myelin and important for optimal neurotransmitter release. Because cholesterol plays such a major role in CNS growth, development, and maintenance, disruptions of cholesterol homeostasis can have negative consequences. Accumulation and depletion of intracellular cholesterol in neurons are both possible mechanisms contributing to neuron dysfunction in these HD models. However, the findings are limited to HD cell models and postmortem HD tissue. This work now needs to be followed up by investigating these changes in HD patients to see whether similar dysfunction occurs.

If studies in human subjects found a similar dysfunction in cholesterol homeostasis, it might suggest that adjusting the cholesterol levels in neuronal cells could be a potential treatment for HD. Future research may aim to discover how to transport cholesterol across the blood brain barrier and whether cholesterol therapy could be one way of slowing or halting neuronal cell death in HD.

It is interesting to note that similar defects in caveolar-related endocytotic pathways and perturbations of cholesterol homeostasis have been implicated in other neurodegenerative diseases related to HD like Alzheimer’s disease and Parkinson’s disease.

Summary^

Recent research has suggested that disruptions in cholesterol homeostasis could be important in explaining how the HD mutation causes neurodegeneration. However, cholesterol’s role in the disease is still not fully understood. It might seem strange that HD has been linked to both intracellular cholesterol accumulation and depletion. One current hypothesis is that different stages of the disease are characterized by different disruptions to cholesterol homeostasis. Future research should shed light on the connections between these different disruptions and normal cholesterol activity.

For Further Reading^

-A. Hepworth, 5/13/2007

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Complications of Huntington's Disease

Huntington’s Disease (HD) is not fatal in itself. People with HD have a shorter life expectancy and die of other life-threatening complications related to this disease. Pneumonia and heart disease are the two leading causes of death for people with HD. Additionally, HD patients have higher incidence of choking and respiratory complications, gastrointestinal diseases (such as cancer of the pancreas), and suicide than the non-HD population. Why are HD patients more prone to the above complications than the rest of the population? This chapter aims to answer that question and draw connections between the symptoms of HD and the most common causes of death (see the table below). Although researchers have not explicitly proven these links in every case, the following information hopes to demonstrate a logical connection.

Primary cause of death (in rank order) Persons (total=182) Percentage
Pneumonia
Other respiratory diseases
93
5
51.1
2.7
Myocardial infarction/degeneration (heart attack
Congestive cardiac failure (heart failure)
coronary disease
Other diseases of the cardiovascular system
5
18
11
2
2.7}
9.9}
6.0}19.7
1.1}
Unspecified Huntington’s-related causes 23 12.6
Vascular lesions of central nervous system 10 5.5
Non-vascular lesions of central nervous system (e.g. meningitis) 4 2.2
Genito-urinary diseases (e.g. kidney failure) 5 2.7
Gastro-intestinal diseases (cancer of the pancreas) 3 1.6
Suicide 3 1.6
Reed TE, Chandler JH, Hughes EM, et al. Huntington’s chorea in Michigan: I. Demography and Genetics. Am J Hum Gen 1958; 10: 201-225.

One of the chief symptoms of HD is the inability to produce coordinated movements. In the latter stages of the disease, this problem becomes more pronounced to the point that people have difficulty swallowing. Although it is so common that we hardly think about it, swallowing is actually a complex series of movements by muscles in our throat to ensure passage of food into the esophagus (gastrointestinal tract) rather than the trachea (respiratory tract). As a result of these movements, the epiglottis, a flap that acts as a valve in our throat, prevents food from entering the airway. People with HD often lack this coordination, and food will accidentally enter the respiratory tract, leading to choking. Moreover, when food particles manage to get into the trachea (the “wind pipe” leading to the lungs), instead of the esophagus (the “food pipe” leading to the stomach), the lungs can become infected and cause what is known as aspiration pneumonia.

Although pneumonia is relatively common among people in the general population, it is only fatal in about 5% of these cases. However, pneumonia is much more dangerous in people with compromised immune systems. Researchers have demonstrated that stresses imposed on a person for prolonged periods of time can severely damage the body’s ability to ward off diseases. The physical, cognitive, and psychiatric symptoms of HD add a great deal of stress to everyday life for these patients (for more information on these symptoms, click here). As a result, their immune systems are compromised and diseases such as pneumonia are therefore more likely to result in death. For instance, in a long-term study conducted from 1952 until 1979 in Victoria, Australia, researchers found that more than 51% of patients with HD died from pneumonia.

The increased physical and emotional stress associated with HD can cause other problems as well. Chronic stress has been linked to high blood pressure, increased risks for heart attacks, and tumor growth. In addition, although studies have shown that suicide is not a leading cause of death for HD patients, suicide rates are higher than among the rest of the population. This is probably due to a combination of factors, including neuropsychiatric changes induced by HD and the added stress of daily life.

Although researchers have yet to find a cure for the disease, people with HD can take measures to prolong their lives. For example, extra care should be taken when eating to prevent choking and pneumonia caused by food going the wrong way. Regular exercise and sleeping in an elevated position can reduce the risk of respiratory infections. Patients can also maintain a healthy diet and reduce or eliminate other risk factors for heart disease, such as smoking and alcohol, from their lives.

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Couple Relationships and Huntington's Disease Testing

Huntington’s disease presents unique psychosocial issues due to its late onset and hereditary nature. One of the major issues of course is stress, which can come from many sources and has many effects (for general discussion of stress and HD, click here. A major source of psychosocial stress associated with HD comes from predictive testing which became available in the United States in 1993.

Extensive research has focused on the person undergoing predictive testing, with a good number of studies reporting that the tested person’s benefit from the knowledge of their genetic status outweighed their post-test psychosocial distress. However, less research has focused on the psychological impact that predictive testing may have on those at risk for HD and their partners, family and friends. This research is important because HD affects many more people than just the person who has it. Moreover, the hereditary nature of the disease can also lead to difficult questions about reproduction and about the possibility of other family members having the disease.

Fortunately, researchers are now focusing more of their attention on predictive testing and its effects on the couple relationship. In the remainder of this section, we review their key findings to date.

What percentage of couples looks favorably upon predictive testing? And what motivations drive their decisions?

In a 1989 study in Belgium, where HD predictive testing has been available since 1987, Evers-Kiebooms found that a moderate majority of people at-risk for HD and their non-carrier partners looked positively on predictive testing. Out of 349 study subjects, 66% of the at-risk adults and 74% of their partners wanted testing for the at-risk individual. The difference between these percentages can partly be explained by the difference in motivations between the at-risk person and his/her partner in approving the predictive testing. When asked why they approved, at-risk adults tended to cite worries about their futures, while their partners tended to cite worries about current and/or future children. A reason that some couples decided not to undergo predictive testing was concern about the effects of the testing on their relationship; this concern was more often a major consideration for non-carrier partners than for the at-risk adults. (For specifics on the process of HD predictive testing, please click here.

Is there a theory on how predictive testing affects couple relationships?^

Yes, a perspective called family systems theory, developed over the past few decades, has proven particularly useful in genetic counseling. This theory is especially relevant to the genetic counseling of couple relationships because its central focus is on the family rather than the individual. The family systems theory describes human behavior as a consequence of family relationship patterns, rather than individual psychology. Consequently, family systems theory can help explain the effects of predictive testing on couple relationships by analyzing how family relationship patterns can influence post-test behavior.

In a 2004 study by Richards and Williams, 43 couples were divided into two groups: those that chose to undergo predictive testing and those that chose not to. Couples in both groups answered the same questionnaire before predictive testing, then 6 months later (3 months after those tested received their test results), and again 24 months after the first questionnaire. The questionnaire consisted of 32 Dyadic Adjustment Scale questions that measured couple relationship functioning, known as a “couple score.” Those couples that received higher couple scores frequently interacted and communicated with each other, rarely disagreed with each other on significant marital issues, and settled disagreements in a way that was satisfying to both partners.

The major finding of this study was that, over the 24 month period, there was no statistically significant difference in couple scores between couples who had decided to undergo predictive testing and couples who had decided not to. The key conclusion was that predictive testing has few negative effects on couple relationships. As the authors noted, this conclusion matches the findings of several other studies (Tibben et al., 1993a; Cordori and Brandt, 1994; Quaid and Wesson, 1995; Taylor and Myers, 1997. For a look at these studies, please see “For Further Reading” at the end of this chapter).

An additional finding from the 2004 study is interesting. The couples that underwent predictive testing were categorized into couples in which the at-risk partner was a carrier and couples in which the at-risk partner was a non-carrier. Unexpectedly, the carrier couples had higher couple scores (stronger couple relationships) of statistical significance than the non-carrier couples. This suggests that, for some couples, the knowledge that their at-risk partner did not have HD had a greater negative effect on their marital relationship than the knowledge that their partner did have HD. The authors give a possible explanation: “The threat of HD may have served as a factor in the continuance of the relationship. Once this threat is removed, partners may no longer feel a duty or need to remain in the marriage to care or to be cared for.”

Another possible explanation is provided by examining family patterns via family systems theory rather than individual behavior. Family systems theory suggests that the couple relationship can be negatively affected when one or both partners have different expectations for the predictive test’s results. When the results prove to be different from expectations, conflict can arise contributing to relationship deterioration and lower couple scores. Studies by Huggins et al. and Soldan et al. have found that professional genetic counseling can benefit the couple relationship by helping partners discuss their expectations of the predictive test’s results and their coping strategies (See “Further Reading” below for links to these two studies).

What does the medical literature say about the pros and cons of predictive testing for couple relationships, especially psychosocial aspects?^

Similar to the work of Richards and Williams reviewed above, a study by Decruyenaere in 2004 also used the Dyadic Adjustment Scale to measure changes in the couple relationship for 5 years following predictive testing. But the study also collected qualitative data from separate interviews with the at-risk persons and their partners. Qualitative data are useful because they can provide more thorough explanations for trends observed in couple relationship over time. The specific couple relationship examined in the Decruyenaere study was marriage.

In this study, all at-risk persons were undergoing predictive testing, with 26 carriers and 14 of their partners, and 33 of non-carriers and 17 of their partners participating in the study. The main finding was that the majority (70%) of the tested persons did not have a change in marital status over the 5 years of the study. As for the quality of the marital relationship, half of the couples reported no change in that interval compared to the quality before the predictive testing. Out of those that did report change, non-carrier couples cited less distress and more communication. Carrier couples that experienced increased relationship quality over the five years cited more mutual support.

A conclusion that can be drawn from this study is that the test result does not by itself predict outcomes in the couple relationship; even couples with negative test results for HD may experience post-test psychosocial distress and couple relationship breakdown. The important factor for couples undergoing predictive testing is whether the test result causes role shifts that upset the balance of the pre-test couple relationship. For example, two couples that received positive test results reported frustration as the partners shifted toward caretaking roles even before the people with HD showed any symptoms. In another couple tested, a woman believed to be at risk for HD gained self-esteem from a negative result. With low self-esteem before the test, she had married someone who did not match her ideals in a spouse. After the testing showed she did not have HD, she regretted her decision to marry her husband, clearly leading to relationship deterioration.

Since undesired shifts in roles may contribute to couple relationship breakdown whether the test result is positive or negative, the researchers of this study strongly support post-test counseling. Post-test counseling can help couples find and maintain a new balance that is satisfying to both partners. This counseling should include open communication between the partners, with special attention paid to the desires and worries of each partner.

Conclusions^

It is clear from these studies that the psychosocial impact of predictive testing on the couple relationship is complex, with a number of factors that contribute to both positive and negative outcomes. First, the Richards and Williams study shows that pre-test discussion by the couple can be very helpful to their relationship. Such discussion can better prepare the couple for the test result by encouraging understanding of each other’s expectations of and reactions to the test result. In particular, this pre-test assessment can help identify particular challenges that the couple may face after the testing and may lead to re-consideration of testing in the first place. Complementing the Richards and Williams study, the Decruyenaere study shows the importance of post-test counseling. Post-test counseling can help protect against adverse effects of predictive testing by encouraging open discussion of each partner’s concerns as well as identification of any potential role-shifts that may disrupt the couple relationship.

Further Reading^

  • Decruyenaere M, Evers-Kiebooms G, Cloostermans T, Boogaerts A, Demyttenaere K, Dom R, Fryns JP. Predictive testing for Huntington’s disease: relationship with partners after testing. Clinical Genetics. 2004 Jan;65(1):24-31.
    This study is not only easy-to-read but also optimistic in its finding that most marital relationships remained the same five years after predictive testing, regardless of the test results.
  • Evers-Kiebooms G, Swerts A, Cassiman JJ, Van den Berghe H. The motivation of at-risk individuals and their partners in deciding for or against predictive testing for Huntington’s disease . Clinical Genetics. 1989 Jan;35(1):29-40.
    This early study found that the majority of at-risk persons and their partners looked favorably upon predictive testing, although the at-risk individual and his/her partner’s reasons for deciding to take the test varied. This study took place before predictive testing began in 1993; however, the couples’ explanations for deciding on predictive testing are still eye-opening and relevant.
  • Huggins et al. Predictive testing for Huntington disease in Canada : Adverse effects and unexpected results in those receiving a decreased risk . 1992 Am J Med Genet 42:508-515.
  • Richards F, and Williams K. Impact on couple relationships of predictive testing for Huntington disease: a longitudinal study. American Journal of Medical Genetics Part A. 2004 Apr 15;126(2):161-9.
    This is an easy-to-read article that is especially interesting because of its discussion on the benefits of pre- and post-test counseling.
  • Soldan et al. Psychological model for presymptomatic test interviews: Lessons learned from Huntington disease . 2000 J Genet Couns 9:15-31.

Studies, in addition to Richards and Williams 2004, that found few negative effects of predictive testing on couple relationships:

  • Codori AM, et al. Psychological costs and benefits of predictive testing for Huntington’s disease. 1994 Am J Med Genet 54:174-184.
  • Quaid KA, et al. Exploration of the effects of predictive testing for Huntington disease on intimate relationships. 1995 Am J Med Genet 57:46-51.
  • Taylor CA, et al. Long-term impact of Huntington disease linkage testing . 1997 Am J Med Genet 70:365-370.
  • Tibben A, et al. On attitudes and appreciation 6 months after predictive DNA testing for Huntington disease in the Dutch program . 1993 Am J Med Genet 48:103-111.

-C. A. Chen 5-7-07

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