While Huntington’s disease is traditionally thought of as a disease of the brain, its effects are much more widespread: many people with HD lose a dangerous amount of weight, complicating a disease that is already complicated enough. Although weight loss is one of the most serious non-neurological problems of HD, scientists don’t fully understand why it occurs. This medical mystery has driven scientists deep into the biology underlying weight loss in HD. Researchers have recently turned up a few potential explanations, and our increased understanding of this symptom is leading scientists to look at possible new ways of treating the disease.
Weight Loss in HD^
People with HD tend to weigh less than those without the disease. A group of researchers from the Huntington Study Group followed 927 people with early-stage HD. For a description of the stages of HD, please click here. The investigators found that people with early-stage HD weighed an average of 10 kilograms (22 pounds) less than age-matched controls, which are people of the same age who don’t have the disease. Another study found that people with HD lose an average of 0.9 pounds per year, which stands in stark contrast to the average American, who gains 0.4-2 pounds yearly.
Unfortunately, while 0.9 pounds doesn’t seem like much, that’s just an average; some people with HD lose so much weight that their health is impacted. Weight loss worsens other aspects of the disease as underweight patients become malnourished and weak. Underweight patients are more susceptible to infection, and take longer to recover from illness, operations, and wounds. Weight loss also increases the likelihood of developing pressure ulcers, commonly known as bedsores, as bedridden patients have less fat tissue to cushion them from pressure. Patients who lose the most weight report a lower quality of life, and are more likely to feel apathetic and depressed. In the late stages of the disease, some patients lose so much weight that they need a feeding tube to stay healthy, as described here. On the other hand, people who start out heavier fare better; people who have a high body-mass index (BMI) when symptoms begin progress more slowly through the disease. Visit this website for an explanation of BMI and a for BMI calculator.
A Medical Mystery^
While weight loss is one of the most serious non-neurological problems associated with HD, doctors don’t understand why it happens. Many suggestions have been put forth, but most of them have been disproved, forcing researchers to dig deeper to understand this phenomenon.
Doctors once believed that weight loss was due to chorea, the uncontrolled movements characteristic of HD. Doctors thought that people with HD lost weight because they burned extra energy as a result of the involuntary movements of chorea. However, three experiments indicate that chorea can’t be fully responsible for weight loss.
The first piece of evidence comes from looking at the early stages of the disease. People who have just been diagnosed with HD – and therefore have very mild symptoms – already weigh less than people without the disease. As mentioned earlier, people in early-stage HD weigh an average of 10 kg less than those who are not affected by the disease. Another group of researchers arrived at similar results; a study of 361 people with early-stage HD found that they have BMIs an average of 2 points lower than those without the disease, even if the patients had just been diagnosed with HD within that year and hadn’t yet begun to experience choreic movements. Researchers concluded that chorea alone could not explain why people with HD have lower BMIs, and that other factors are at play.
Other studies suggest that chorea may not have as much of an impact as doctors once thought. Pratley et al. measured how much movement chorea caused, in an attempt to quantify how much weight patients lose due to choreic movement. After measuring the movements of 17 people with mild to moderate HD for a week, they found that chorea caused people with HD to move more than people without the disease when sedentary: people with HD moved 14% more than people without HD while sitting or lying down. However, people with HD do less voluntary activity. Study participants with HD walked around and exercised less than people without the disease. In the end, Pratley et al. were surprised to discover that sedentary over-activity balanced out voluntary under-activity: people in the early and middle stages of HD don’t actually move more than people without the disease.
A similar study by the European Huntington’s Disease Initiative Study Group (EHDI) measured weight loss in 517 people with HD, and found no correlation between the amount of weight people lost and the severity of their motor symptoms; people with good scores on tests measuring motor symptoms (such as the UHDRS) were just as likely to lose weight as those with bad motor scores. For more information on diagnostic tests like the UHDRS, click here.
The final strike against the chorea theory comes from observations of people with late-stage HD. Weight loss is most drastic in the final stages of HD, despite the fact that chorea has usually ceased and patients are largely bedridden. So while chorea contributes to weight loss in HD, it cannot stand as the sole explanation.
Reduced Food Intake^
Others suggest that people with HD lose weight because they have trouble eating; as the disease progresses, it becomes increasingly difficult to perform the complicated series of movements needed to eat, chew, and swallow.
However, this theory is also not enough to fully explain the weight loss. Studies have shown that people with HD actually tend to eat more than people without the disease; a study of 25 people with HD found that they ate an average of almost 400 calories more each day than people without the disease. Others report that they’ve had patients who eat up to 5000 calories a day – over twice the average daily caloric intake – just to maintain their weight.
So two popular explanations for weight loss in HD – chorea and insufficient diet – cannot entirely explain why people with HD lose so much weight.
Possible Biological Causes^
Though the reasons for the mysterious weight loss are unclear, scientists are currently testing a few ideas.
Abnormalities in Energy Metabolism^
One leading idea has to do with metabolism, the way the body burns calories to produce energy. HD researchers have long suspected that the disease-causing form of huntingtin (hereafter described as mutant huntingtin) interferes with energy metabolism, as described here. Results from a recent study suggest that this interference might contribute to weight loss.
After discovering that weight loss is not correlated with motor symptoms, scientists from the EHDI Study Group looked for other factors that might be to blame. They found that weight loss could be partially predicted by the number of CAG repeats on a patient’s copy of the mutant huntingtin gene; for every additional CAG repeat a patient had, they lost on average an extra 0.136 BMI points (0.8 pounds) over the course of the three year period that the study was conducted. For an explanation of CAG repeats, please click here.
The same holds true in mouse models of HD. The EHDI Study Group found that the more CAG repeats an HD mouse had, the more it tended to eat. Yet paradoxically, the mice with the most CAG repeats lost the most weight. So people and mice with more CAG repeats lose more weight.
The EHDI investigators suspect that this is due to the long tail of the mutant huntingtin protein. People with more CAG repeats produce mutant huntingtin with a longer tail, as described here. The EHDI investigators suggest that the mutant huntingtin protein interferes with the way cells make energy, and that longer-tailed proteins cause more problems. Mutant huntingtin has been shown to disrupt proteins that are needed to make energy and can damage mitochondria, the “energy factory” of our cells, as described here. In support of the theory that proteins with longer tails are more problematic, scientists at the MacDonald lab in Boston studied cells engineered to express mutant huntingtin. They found that cells with more CAG repeats made less ATP, the energy currency of the cell. So it seems possible that the more CAG repeats individuals have, the less efficient their cells are at converting calories to energy.
A second school of thought suggests that weight loss is due to hormonal disturbances in people with HD. Hormones are the body’s chemical messengers, and are important for regulating physiological processes, like hunger. The hypothalamus secretes many hormones, so when HD causes cells in the hypothalamus to malfunction and die, hormone production is disturbed.
Some of the hormonal signals that the hypothalamus sends out go to the gut and fat tissue, and direct processes like eating and burning energy – processes that are very important in maintaining a healthy weight. Therefore, some scientists think that cell death in the hypothalamus causes hormonal changes that might contribute to weight loss and other problems such as sleep disturbances, as described here.
Further insights have come from studying the way mutant huntingtin interacts with the digestive system. Certain symptoms of HD have hinted that the disease might affect the gut; apart from weight loss, people with HD often experience nutritional deficiencies, cramps, and wasting of skeletal muscles. People with HD are also prone to gastritis, a disease where the stomach lining becomes irritated or swollen.
Despite these symptoms, many HD researchers have traditionally thought that mutant huntingtin only affected the brain – a belief that struck some as strange because the protein is made and found throughout the body. However, results from a recent study suggest that mutant huntingtin in the gut might interfere with important digestive processes, thus contributing to weight loss.
In the study, van der Burg and colleagues looked at R6/2 mice, which are mouse models of HD described in greater detail here. They noticed several physiological changes that could all impact digestion. First, they noticed that the small intestines of HD mice were 10-15% shorter than those of normal mice, and that they had smaller villi, the tiny finger-like projections in the gut that take up nutrients. On top of that, scientists noticed that the mucus lining of the gut of the HD mice was 20-30% thinner. Since all of these structures are needed for nutrient absorption, these findings suggest that HD mice can’t take up nutrients as efficiently as normal mice.
Furthermore, the group found that the HD mice were missing a few key hormones that control the speed at which food passes through the body. This caused an increase in ‘transit time’: the food passed more slowly through the gut. Longer transit time might foster bacterial growth; if food takes longer to pass through the gut, harmful bacterial have more time and a better opportunity to flourish. This could make the small intestine irritated and inflamed, which could cause malabsorption of nutrients, chronic diarrhea, nausea, bloating, flatus, and weight loss. Those bacteria might also use up nutrients that the body would have otherwise taken up.
To see whether these physiological differences actually have an impact on digestion, researchers then compared the feces of HD mice to those of normal mice. They found that HD mice excreted more of what they ate, suggesting that they absorbed fewer calories and nutrients from their food. Notably, the mice that were the worst at absorbing nutrients from their food lost the most weight.
Van der Burg et al. had a few ideas as to what mutant huntingtin might be doing to interfere with digestion. Since the protein is present in gut cells, it could interfere with cell function and nutrient absorption. They also thought that mutant huntingtin might affect transcription, the process by which DNA is converted into protein as described here. If mutant huntingtin affects transcription in gut cells, it could cause a decrease in levels of important proteins needed for cells to survive and function properly.
While findings in HD mice don’t always translate to humans, these results indicate that scientists might benefit from studying the way HD affects digestion in people. Van der Burg et al. suggest that such research might help doctors improve their understanding of nutritional supplements for HD, and might even change the way we think about how people with HD metabolize and react to medicine.
Weight loss in HD has long puzzled doctors, patients, and caretakers alike. Two popular explanations of the phenomenon – chorea and reduced food intake – have been debunked as major contributors to weight loss. However, scientists have made new in-roads in recent years. By discovering that mutant huntingtin might disrupt energy metabolism, digestion, and hormones in HD mice, scientists have enhanced our understanding of HD, which may pave the way to new treatments and therapies. For example, the hypothesis that weight loss is linked to abnormalities in energy metabolism suggests that energy-boosting drugs – namely creatine and Coenzyme Q10 – are strong candidates to fight HD, as described in these articles here. Each further discovery about HD leads to a greater understanding of the disease, and brings hope for patients and families.
1. Aziz NA, van der Burg JM, Landwehrmeyer GB, Brundin P, Stijnen T; EHDI Study Group, Roos RA. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology. 2008 Nov 4;71(19):1506-13.
This medium-difficulty study describes how people with more CAG repeats lose more weight – and provides some theories as to why that might be the case.
2. Djoussé L, Knowlton B, Cupples LA, Marder K, Shoulson I, Myers RH. Weight loss in early stage of Huntington’s disease. Neurology. 2002 Nov 12;59(9):1325-30.
This medium-difficulty article describes weight loss in people with early-stage HD
3. Hamilton JM, Wolfson T, Peavy GM, Jacobson MW, Corey-Bloom J; Huntington Study Group. Rate and correlates of weight change in Huntington’s disease. J Neurol Neurosurg Psychiatry. 2004 Feb;75(2):209-12.
This medium-difficulty article describes weight loss in people with early-stage HD
4. Kremer HP, Roos RA. Weight loss in Huntington’s disease. Arch Neurol. 1992 Apr;49(4):349.
This short, medium-difficulty column suggests that cell death in the hypothalamus could contribute to weight loss
5. Petersén A, Björkqvist M. Hypothalamic-endocrine aspects in Huntington’s disease. Eur J Neurosci. 2006 Aug;24(4):961-7. Epub 2006 Aug 21. Review
This technical article describes how hormonal changes in people with HD might lead to weight loss
6. Pollard J, Best R, Imbrigilo S, Klasner E, Rublin A, Sanders G, Simpson W. A Caregiver’s Guide for Advanced-Stage Huntington’s Disease. Huntington’s Disease Society of America, 1999.
This easy-to-read handbook is a very helpful resource for caregivers taking care of people in late-stage HD
7. Pratley RE, Salbe AD, Ravussin E, Caviness JN. Higher sedentary energy expenditure in patients with Huntington’s disease. Ann Neurol. 2000 Jan;47(1):64-70
This study measured movements of people with HD, and found that their total energy expenditure was the same as that of people without the disease, and is somewhat technical
8. Seong IS, Ivanova E, Lee JM, Choo YS, Fossale E, Anderson M, Gusella JF, Laramie JM, Myers RH, Lesort M, MacDonald ME. HD CAG repeat implicates a dominant property of huntingtin in mitochondrial energy metabolism. Hum Mol Genet. 2005 Oct 1;14(19):2871-80. Epub 2005 Aug 22.
This technical article describes how huntingtin interferes with energy metabolism in a CAG-dependent fashion
9. Trejo A, Tarrats RM, Alonso ME, Boll MC, Ochoa A, Velásquez L. Assessment of the nutrition status of patients with Huntington’s disease. Nutrition. 2004 Feb;20(2):192-6.
This medium-difficulty paper discusses the result of the study on 25 HD patients that ate an average of 400 calories more than controls each day.
10. van der Burg JM, Winqvist A, Aziz NA, Maat-Schieman ML, Roos RA, Bates GP, Brundin P, Björkqvist M, Wierup N. Gastrointestinal dysfunction contributes to weight loss in Huntington’s disease mice. Neurobiol Dis. 2011 Oct;44(1):1-8. Epub 2011 May 23.
This technical article describes the impact of huntingtin on digestion in HD mice
M. Hedlin 11.16.11
In the last stages of Huntington’s disease (HD), patients have difficulty thinking and communicating clearly, so decisions about their end-of-life medical care often fall to doctors and relatives. However, many people with HD have strong opinions as to how they would like their last years to unfold. Advance directives are instructions written by mentally and physically competent patients to convey their preferences about end-of-life medical care ahead of time. They are powerful expressions of a person’s wishes about their future health care. Anyone over the age of 18 is legally qualified to make these decisions for himself or herself. Health care professionals who are caring for a patient will refer to advance directives if the patient is unable to make or communicate their decisions later in life.
Advance Directives and HD
Why are advance directives important for patients with HD? Because the age of onset and severity of HD symptoms are relatively unpredictable, sudden changes can quickly change the course of patients’ lives. During the end stages of HD, many patients are nonverbal and unable to communicate their wishes. Advance directives allow patients to decide their end-of-life care ahead of time so that their treatment fits their unique mental and emotional needs.
While it may seem like a simple task to address advance directives before late-stage symptoms occur, there are numerous obstacles that make it difficult for patients to make such decisions earlier in their life. These obstacles mostly fall into three categories: the doctor, the patient, and the patient’s family. Regarding doctors, there are currently no guidelines requiring doctors to discuss advance directives with patients early in the course of the disease. Thus, many doctors do not discuss end-of-life care with their patients when they are in earlier stages of chronic diseases. This greatly contributes to the difficulty of the decision process for the patient.
Patients themselves may exhibit cognitive dysfunction, denial, poor judgment, or psychiatric symptoms and thus may not be able to make an informed decision even at early stages of the disease. In early stages of the disease, patients may want to avoid the topic of advance directives, as they have difficulty confronting their declining ability to function as parents, employees, and other roles they fill in their lives. In late stage HD, communication becomes the predominant issue, as patients cannot make their wishes clearly known.
Advance directive decision-making may also be delayed by the dynamics of the family. First of all, once a patient becomes mentally incompetent or is unable to communicate his or her wishes, deciding on who should make these decisions becomes a source of controversy. Furthermore, the family not only has to deal with the shock of a newly diagnosed relative, but also may become increasingly worried about other at-risk individuals. In order to cope, families may be experiencing what medical professionals have deemed denial —a common, short-term protective mechanism for dealing with the shock of diagnosis. If end-of-life care is not discussed early enough, family members may not agree with the patient’s decisions.Addressing advance directives at an early stage of disease is one means of ensuring autonomy for HD patients.
Elements of Advance Directives
Advance directives have several important elements: a health care proxy, a living will, do-not-hospitalize and do-not-resuscitate orders; decisions about tube feeding; and decisions about brain donation for diagnosis and research purposes.
A healthcare proxy is a person who makes decisions for the patient once the patient is deemed unable to make those decisions for himself or herself, and is usually a family member of the patient. The healthcare proxy should be an adult over 18 who is mentally, physically and emotionally equipped to make decisions. The healthcare proxy form is approved by law in all states and is a written document.
A living will is a set of instructions to a doctor about treatment and life-sustaining procedures. It is helpful for the patient to discuss living wills with a medical professional to stay informed about the advantages and disadvantages of all types of treatments and procedures. These instructions do not become effective until two doctors certify in writing that the patient is unable to make a healthcare decision. Lastly, the patient can change or revoke advance directive instructions anytime, as long as s/he has the mental capacity/communication abilities to do so.
The wishes of the patient in regards to use of a feeding tube can be stipulated in the advance directive. Feeding tubes are usually used when the patient has no other way to swallow food. They may also be used to provide supplements when the patient can eat but needs to receive more nutrition through the tube. Tube feeding is common in late-stage HD treatment. The tube is made of soft plastic and is usually inserted into the stomach. It can be used to avoid problems such as aspiration, which is when food goes into the lungs instead of the stomach. Aspiration can increase the likelihood of pneumonia, which can cause serious medical complications in HD patients. The advantages of the feeding tube include: 1) ensuring that the body receives essential nutrients, 2) allowing patients to eat foods that they enjoy, 3) ameliorate weight loss, which is a serious health risk for late-stage HD. Disadvantages include: 1) medical risks associated with feeding tube insertion, such as infection or bleeding, 2) not all patients gain weight and feel full while on the feeding tube, 3) vomiting and aspiration can still occur occasionally, 4) potential re-hospitalization if the feeding tube is dislodged.In the end, it is the patient’s decision whether or not he/she would like a feeding tube if he/she is deemed capable of making healthcare decisions—but the advanced directive accommodates for the chance that the patient may not continue to be able to choose for him/herself.
Do Not Hospitalize Order
A “Do Not Hospitalize Order” (DNO) is one way for patients and families to influence the type of care patients and their families receive, and where the care takes place. During late-stage HD, people may prefer the warmth and comfort of a home, or they may wish to be hospitalized. There are numerous advantages and disadvantages to each choice. Hospitalization allows patients to have more advanced medical care. Physicians can more quickly diagnose and treat patients and have access to specialized equipment that might be needed to treat certain conditions. However, hospitalization is undesirable for some patients because hospital staff is less familiar with the patient and their individual needs. Patients sometimes become anxious in the unfamiliar surroundings, and may dislike the repeated diagnostic tests, such as blood pressure measurements.
Do Not Resuscitate Order
A “Do Not Resuscitate” (DNR) order is written by the patient’s doctor in consultation with the health care proxy and other family members. This order states that cardio-pulmonary resuscitation (CPR) will be withheld when a person’s breathing or heart stops. When anyone is admitted to a hospital or nursing home, the staff is required by law to perform CPR if and when breathing or the heart stops unless there is a DNR order in effect (3). Like the “do not hospitalize” order, the DNR can be changed at anytime provided that the patient is mentally capable.
Brain donation involves donating brain tissue after death so researchers can use it to study HD and other neurodegenerative diseases. Researchers can use brain tissue to directly analyze nerve cells and brain changes due to HD in humans, which is an important step on the path towards better understanding HD and finding treatments that work.
There are several challenges that make brain donation challenging for some individuals.
First, the patient or his/her relatives must agree to donate the brain before the time of death. Second, not all institutions have the resources to pay for brain donation, as it costs between 10,000-30,000 US dollars to collect each brain.
Thinking Towards the Future
There is a lot of information available regarding each of these decisions, and speaking about each of them early on can potentially reduce stress during late-stage HD when family members and health care workers need to be aware of a patient’s desires. Finally, it is important to remember that the advance directive is a “living” legal document and any instructions specified in the document can be changed or revoked at the patient’s discretion at any time, as long as s/he has the mental capacity/communication abilities to do so.
Further Reading (GREAT LINKS!):
Klager J., Duckett A., et al. Huntington’s Disease, A Caring Approach to the End of Life, Care Management Journals. 9.2 (2008).
This medium-difficulty article describes challenges in end-of-life care, identified in a long-term care facility specializing in Huntington’s disease
Kretzschmar H. Brain banking: opportunities, challenges and meaning for the future. Nat Rev Neurosci. 2009 Jan;10(1):70-8. Epub 2008 Dec 3.
This easy-to-read article describes how brain banking is important for science, and the challenges that stand in the way
Sheila A. Simpson, Late Stage Care in Huntington’s disease, Brain Research Bulletin. 72.2-72.3 (2007): 179-181.
This easy-to-read article describes issues that should be addressed in late stage care for HD.
P. Bakhai, 9.19.11
Introduction to Antidepressants
Antidepressants are medications that are used to treat depression by improving symptoms such as mood, sleep, appetite and concentration. There are many different types of antidepressants, and they are classified based on how they affect the brain. Broadly, antidepressants work by increasing the amount of a certain neurotransmitter (a chemical messenger) in the brain. Most relevant to Huntington’s Disease (HD) is a class of antidepressant called SSRIs, or selective serotonin reuptake inhibitors. SSRIs increase the effect of the neurotransmitter called serotonin. Normally, serotonin transmits chemical messages to a postsynaptic cell when it is released from a presynaptic neuron into a synapse, which is the space between two nerve cells. To stop serotonin’s action, the presynaptic neuron re-absorbs the serotonin it just released. SSRIs block this re-uptake which increases the amount of serotonin present in the synapse and magnifies its effects. For more information about SSRIs, click here.
Serotonin is mostly present in intestinal membranes and the central nervous system (CNS). For more information on serotonin, click here. It has a wide range of functions in the CNS including the regulation of mood, appetite, sleep, behavior, learning, memory and muscle contraction. In the brain, there are more receptors for serotonin than any other neurotransmitter, which emphasizes the widespread effects of serotonin. Recently, researchers have been attracted to the idea of using SSRIs as a potential treatment for HD. The mutant HD gene has been found to reduce the number and activity of serotonin receptors, and SSRIs may be a way to overcome the reduction in serotonin signaling. SSRIs are also an attractive drug because they are known to have fewer side effects than other classes of antidepressants. The most common side effects of SSRIs include upset GI tract, diarrhea, restlessness, weight loss or insomnia.
Using SSRIs to treat HD may address both the psychiatric and neurological abnormalities in HD patients. HD patients have commonly exhibited psychiatric symptoms both before and after diagnosis, such as depression, hostility, obsessive–compulsiveness, anxiety, interpersonal sensitivity, phobic anxiety, and psychoticism. As stated above, SSRIs are normally used to treat depression and severe anxiety disorders. However, current research suggests that SSRIs not only can help treat depression, but also may have therapeutic potential as neuroprotective agents.
SSRIs and HD: From Animals Models to Clinical Trials
In 2005, researchers studied the effects of a SSRI for the first time in huntingtin mutant mice. These scientists found that the administration of paroxetine, a widely prescribed antidepressant drug (and SSRI) increased serotonin levels, delayed onset of neuronal degeneration and motor dysfunction, improved energy metabolism, and increased mouse lifetime. The researchers did not investigate how paroxetine could have exerted these effects on the mice. For more information on paroxetine, click here. The researchers also observed that there were few or no side effects of the drug in mice. Most importantly, this study was the first to demonstrate the positive effects of SSRIs on neurological aspects of HD, calling for further investigation of these effects in both mice models and HD patients.
Another study conducted in 2005 investigated the relationship between SSRIs and neurogenesis, the birth of new neurons, in HD mice. In this study, researchers used another SSRI, fluoxetine (also known by the tradename Prozac), to determine whether it would promote neurogenesis and mitigate HD symptoms in a mouse model of the disease. Through extensive behavioral testing of the mice, the researchers demonstrated that flouxetine did not affect motor activity or body weight, but did improve cognitive function and “reversed” a depressive phenotype of HD mice. Furthermore, the flouxetine-treated mice displayed a considerable increase in neurogenesis and volume of the dentate gyrus. The dentate gyrus is a part of the hippocampus, which is a region of the brain thought to contribute to memory formation. The growth in the volume of the denate gyrus of the hippocampus in mice treated with flouxetine was so significant that it was comparable to the size of the denate gyrus in mice without HD.
Many recent studies have emphasized the role of the hippocampus in depression. The finding that SSRIs are able to target both neurological symptoms and those of depression implies a link between the two. In the fluoxetine study, the researchers propose a possible mechanism relating neurogenesis with the action of antidepressants in the body. They suggest that antidepressant stimulation of neurogenesis may act through the increased expression of neurotrophic factors such as BDNF, or brain-derived neurotrophic factor. BDNF is required for neurons to survive and regenerate. The loss of BDNF in the brains of HD patients and mouse models has been shown to play a crucial role in the development of the disease. For more information about BDNF click here.
Interestingly, serotonin stimulates the expression of BDNF, and BDNF enhances the growth and survival of neurons that release serotonin. Because Huntington’s patients have decreased levels of both BDNF and serotonin, this interaction could play an important role in the pathogenesis of HD. Peng and Masuda, researchers at Johns Hopkins, decided to further investigate the impact of SSRIs on BDNF levels and neurogenesis in mice. These scientists used yet another SSRI, sertraline, which has also been widely used in the treatment of depression. Their study concluded that sertraline prolongs survival, improves motor performance, and decreases brain atrophy in HD mice. Furthermore, it showed that sertraline significantly increased BDNF protein levels in HD mice, and that the effective levels of sertraline in mice are comparable in humans—providing a case for the testing of sertraline in HD patients.
Due to the evidence in HD mouse models supporting the use of SSRIs to treat HD, the University of Iowa facilitated a randomized, double-blind placebo controlled clinical trial to test the efficacy of citalopram, also an SSRI, in HD patients. This clinical trial is currently in phase II, and researchers are now recruiting more participants. For more information about clinical trials, click here.
In conclusion, many different SSRIs have consistently been shown to increase neurogenesis, motor control, cognitive ability, and brain metabolism in mouse models of HD. It is likely that SSRIs such as sertraline influence neurogenesis via increasing BDNF, a neurotrophic factor essential to neuron growth and survival that has been found in abnormally low levels in HD patients. Thus far, the data investigating the relationship between SSRIs and HD are very promising. It is also encouraging that SSRIs have been tolerated for long-term treatment in humans without significant side effects for depression—suggesting (but not proving) the safety of SSRI treatment for HD patients. Clinical trials such as the one being conducted on citalopram are necessary in order to confirm the safety and efficacy of SSRIs for HD patients. If the findings in mouse models translate to human medicine, this promising avenue of research may allow for SSRIs to be co-opted for Huntington’s Disease.
1) Visit HD drug works for specific information about different categories of antidepressants
2) This article gives an in depth discussion (not too complex) about various psychiatric symptoms of HD and drugs commonly used to treat them.
Duan W, Peng Q, Zhao M, Ladenheim B, Masuda N, Cadet JL, Ross CA. Sertraline Retards Progression and Improves Survival in a Mouse Model of Huntington’s Disease. Society for Neuroscience.s 2005.
Duan W, Guo Z, Jiang H, Ladenheim B, Xu X, Cadet JL, Mattson MP. Paroxetine retards disease onset and progression in Huntingtin mutant mice. Ann Neurol 2004 Apr;55(4):590-4.
Duff K., Paulsen J.S., Beglinger L.J., et al. Psychiatric Symptoms in Huntington’s Disease before Diagnosis: The Predict-HD Study. Biological Psychiatry, 62(12): 1341-1346
Lazic SE, Grote HE, Blakemore C, Hannan AJ, van Dellen A, Phillips W, Barker RA. Neurogenesis in the R6/1 transgenic mouse model of Huntington’s disease: effects of environmental enrichment. Eur J Neurosci 2006 Apr;23(7):1829-38. PubMed abstract
Grote HE, Bull ND, Howard ML, van Dellen A, Blakemore C, Bartlett PF, Hannan AJ. Cognitive disorders and neurogenesis deficits in Huntington’s disease mice are rescued by fluoxetine. Eur J Neurosci 2005 Oct;22(8):2081-8.
P. Bakhai 9.13.11
This article will seek to provide an overview of current understandings of what huntingtin protein does and why it is important.
HOPES summary of the talks from scientists and clinicians
Note: This article includes references to Dimebon, which is no longer being considered as a potential treatment for HD after the HORIZON clinical trial showed that Dimebon was not better than a placebo. For more information, click here
Lisa Ellerby, PhD, Buck Institute for Age Research
Target Validation in Huntington’s Disease
Dr. Ellerby’s talk focused on the question: “What are possible biological targets for drugs designed to treat HD?” Therapeutic drugs work by targeting specific processes in the human body that have gone awry in disease. For example, the common symptom chorea in HD is thought to be a result of the increased activity of the neurotransmitter dopamine. Tetrabenazine is used to treat chorea because the drug reduces the amount of dopamine in the brain.
At present, the pharmaceutical industry is focused on developing therapeutics for approximately 200 to 300 different targets in the human body that may be related to HD. However, those few hundred targets represent a very small subset of all possible biological targets and it is possible that drugs that have been created for other diseases could have therapeutic benefits for individuals with HD. One example of this is Dimebon, a drug that was originally used as an anti-histamine and is now being studied in clinical trials for HD because of its neuroprotective effects.
Dr. Ellerby is interested in identifying targets that play specific roles in the death of neurons in HD. While it is well known that the mutated Huntingtin protein (Htt) results in the neurodegeneration characteristic of HD, Dr. Ellerby’s research is important because it can provide insight into how this neuronal death occurs. Her lab used small interfering RNA (siRNA) to block the production of different proteins and then assessed the effects of these knockdowns on neuronal death. If shutting off a particular target results in decreased neuronal death, it is possible that this target plays a role in neurodegeneration due to mutant Htt. These experiments found that blocking the activity of proteases, enzymes that break down other proteins, reduces the death of neurons in a cellular model of HD. Specifically, Dr. Ellerby mentioned that decreasing the level of a family of proteases known as matrix metalloproteases (MMP) reduces the toxicity of mutant Htt. By using siRNA to identify targets that play a role in HD, Dr. Ellerby’s research is laying a foundation for the discovery and development of drugs that can prevent, treat, and reverse the devastating effects of HD.
Jill Larimore, BSc, 4th year graduate student in neurobiology at UCSF
Immune System Dysfunction in Huntington’s Disease
Ms. Larimore, as a member of Dr. Muchowski’s lab, researches the effect of HD on immune system function. Using yeast and animal models, her lab explores the HD on the molecular level in order to find new therapeutic targets. Ms. Larimore began her talk by explaining the immune system of the brain and the role of microglia cells. These specialized cells differ from those found in the peripheral immune system (i.e. the immune system which operates in all parts of the body besides the brain and spinal cord). Although the blood-brain barrier normally keeps these immune systems apart, Larimore’s research interestingly showed that there was peripheral immune system activation in HD patients. This indicates that the neurological symptoms of HD are either paralleled in the peripheral immune system or communication between cells traverses the blood-brain barrier to connect the two immune systems.
The Muchowski lab’s research also showed that HD increased inflammatory response in both the neural and peripheral immune system, even before manifestations of HD symptoms. Inflammation is an acute immune response that counters tissue injury by releasing chemical signals in the area of injury. Physical inflammation acts as a barrier against the spread of infection while immune cells repair the damaged tissue. Although normally beneficial, inflammation can be harmful when it becomes chronic and remains after healing. In HD patients, a key immune protein, interleukin-6 (IL-6) was found at higher concentrations both in the brain and body. IL-6 helps activate and regulate inflammatory response in the immune system, and indicates immune activity when found in heightened concentrations. In the brain, microglia activation increased as well, indicating microglia were responding to tissue damage in the brain. While immune activation could potentially be a natural healing response, Muchowski’s lab hypothesized that it was chronic inflammation that contributes to HD progression.
Similar inflammatory symptoms found in other neurodegenerative diseases have been extensively researched. Treatments have been found to regulate the heightened inflammatory response that occurs when certain immune proteins are activated. In mouse models of Alzheimer’s disease, the cannabinoid type 2 receptor (CB2) in the brain was found to decrease IL-6 and other proteins involved in the immune response in both the peripheral and neural immune systems. Inhibition of the CB2 receptor in a mouse model of HD worsened symptoms, as shown in behavioral assays (testing the mouse for motor functions and balance). Activating the CB2 receptor resulted in improved coordination and motor function, and slowed the onset of HD symptoms. Because CB2 therapeutics are already in clinical trials for autoimmune diseases, if CB2 is found to be beneficial in HD models by decreasing inflammation in the brain and the peripheral immune system these drugs could potentially be clinically tested as a therapy for HD.
Jan Nolta, PhD, Stem Cell Program, UC Davis
Working toward mesenchymal stem cell-based therapies for HD
Dr. Jan Nolta, director of stem cell research at UC Davis, presented on recent developments in her work on therapies for HD using mesenchymal stem cells (MSCs). MSCs have been found to deliver protein products throughout tissue for 18 months at a time. MSCs can potentially be engineered to deliver proteins that help prevent neurodegeneration to the brain. MSCs themselves exhibit neuroprotective activities. They restore synaptic connections, decrease inflammation, decrease neuron death and increase vascularization. Using vessels in the brain as train tracks, they are able to travel throughout the brain to assist other cells. Videos taken under a microscope show that MSCs are “social cells,” meaning they are constantly communicating with other cells around them. By interacting with another cell, an MSC can sense the needs of that particular cell and initiate a flow of appropriate nutrients directly into the other cell. In this way, MSCs act as cellular “paramedics” of the body.
One possibility for an HD therapy involves injecting MSCs into the brain where the cells could help reduce neurodegeneration by saving damaged neurons. Scientists at UC Davis conducted tests on non-human primates to ensure that injecting MSCs into the brain is safe for humans. Safety testing was recently completed with MSCs being injected through the skull into the brains of fetal non-human primates. Fortunately, results showed that after 5 months, the MSCs were still present. This means MSCs will be able to stay in the brain for a good length of time, theoretically assisting neurons and preventing additional cell death. Also, no tumors or tissue abnormalities were detected, indicating that MSC injection is largely safe. More studies about the intracranial transplantation and long-term MSC safety are needed.
Research on MSCs in Dr. Nolta’s lab currently involves three main goals: test bone marrow-derived MSCs to see if they restore neurons in non-human primates, test MSCs for the ability to secrete factors like brain-derived neurotrophic factor (BDNF) that help brain cell function, and to investigate MSC production of siRNA. Dr. Nolta was happy to announce that the FDA recently approved injection of MSCs into the central nervous system of individuals with another disease called amyotrophic lateral sclerosis. This sets an important precedent that will increase the likelihood that Dr. Nolta’s eventual therapy will work in other diseases.
Michael Geschwind, MD PhD, UC San Francisco Memory and Aging Center
Update on Clinical Studies and Trials in Huntington’s Disease
Dr. Michael Geschwind, a neurologist at the UCSF Memory and Aging Center, provided updates about clinical trials in HD. First, he reviewed the two types of clinical research: observational and clinical trials. An observational study is a type of study in which individuals are observed and certain outcomes are measured (such as motor control or mental function) but no attempt is made to affect the outcome in the form of treatment or therapy. In contrast, a randomized double-blind clinical trial is a study in which each individual is assigned randomly to a treatment group (experimental therapy) or a control group (placebo or standard therapy) and the outcomes are compared. Currently, there is important and promising HD-related clinical research being conducted both within and outside of the United States. The following paragraphs summarize the significant points regarding recent or ongoing studies in the HD field.
The PREDICT-HD study is an observational study that began in 2001, was expanded in 2008, and is still underway. The ultimate goal of the PREDICT-HD study is to define the earliest biological and clinical features of HD before at-risk individuals have diagnosable symptoms of the disease. While the current approach is to treat HD at the beginning of the onset of symptoms, this study aims to help design future studies of experimental drugs aimed at slowing or postponing the onset of HD in the at-risk population prior to observable symptoms. The PREDICT-HD study has identified markers that were shown to appear long before an individual would expect to be diagnosed. One marker is CAG repeat length: CAG stands for the nucleotides (DNA building blocks), cytosine, adenine, and guanine. The HD mutation consists of multiple repeats of CAG in the DNA. This study validated the CAG repeat length-age formula, in which the CAG repeat length for an individual could estimate the average age of HD onset. In general, fewer than 30 repeats is considered normal, whereas more than 39 repeats means the person will likely develop HD in a normal lifespan. To read more about CAG repeat lengths click here. Other markers such as the size of ventricles in the brain and the volume of other specific brain areas (i.e. striatum) were also found. In short, the PREDICT study has validated models for predicting motor onset of HD, which will ultimately increase the likelihood of treating HD before patients become symptomatic.
The DIMOND-HD study was a phase II clinical trial investigating the efficacy of the drug Dimebon, which is a small molecule that inhibits nerve cell death. This drug has been shown to decrease cognitive impairment in Alzheimer’s patients, and has been shown to improve cognition and memory in rats. Dimebon is often referred to as latrepirdine. The DIMOND-HD study evaluated the safety of administering Dimebon for 3 months and the efficacy of Dimebon in improving cognitive, motor, and overall function in subjects with Huntington’s Disease. The study was completed in the summer of 2008, and showed that Dimebon is a well-tolerated drug that generally improves cognition in HD. The researchers concluded that the drug should be tested in phase III clinical trials, which has resulted in the HORIZON trial described below. To read more about Dimebon click here.
The HORIZON study is a randomized, double-blind, placebo-controlled study that is ongoing at 37 sites, spanning 7 countries. The study is in phase III of clinical trials, and also aims to expand upon the results of the DIMOND-HD study and determine if Dimebon (latrepiridine) safely improves cognition in patients with Huntington’s disease.
The HART study is also a randomized, double-blind, placebo controlled study that is ongoing in both Europe and North America. The purpose of the study is to determine if ACR-16, also known as pridopidine and Huntexil, is effective and safe in the symptomatic treatment of HD. ACR-16 is a dopamine stabilizer, which means that it works to help regulate the many functions of dopamine in the striatum and other areas of the brain. ACR-16 has passed phase II of the clinical trials in Europe, and has been allowed to be tested in stage III in North America (US and Canada). Initial results of the clinical trials are promising, and have shown that ACR-16 can improve motor control and may translate to 0.5-1.5 years of disease improvement in voluntary and involuntary movements. To read more about ACR-16, click
The following table outlines the types of characteristics researchers are looking for in each of the ongoing HD Clinical Trials described above. For more information, click on the links provided.
Inclusion Criteria for HD Clinical Trials
|PREDICT-HD StudyFor more information on the PREDICT-HD study click here
||• Gene negative and gene positive individuals: specifically, men and women at risk for HD, who have been tested for the HD gene mutation, and who have not been diagnosed with symptoms of HD (CAG > or equal to 36 for CAG-expanded group or CAG < 36 for CAG-norm group).
• 18 years of age or older
• Able to commit to a minimum of 5 yearly evaluations
• Commitment of a companion to attend visits or complete surveys via mail
• Able to undergo a MRI
|HORIZON StudyFor more information on the HORIZON study click here
||• Have clinical features of HD and a CAG polyglutamine repeat expansion ≥ 36• Have cognitive impairment as noted by the following:
1. A screening MMSE and a baseline (pre-dose) MMSE score between 10 and 26 (inclusive); and
2. A subjective assessment of cognitive impairment with decline from pre-HD levels by the Investigator after interviewing the subject and caregiver;
• Are willing and able to give informed consent
• Aged 30 years or older
• Have a caregiver who assists/spends time with the subject at least five days per week for at least three hours per day and has intimate knowledge of the subject’s cognitive, functional, and emotional states, and of the subject’s personal care.
|HART StudyFor more information on the HART study click here
||• Able to provide written Informed Consent prior to any study related procedure, including consent to genotyping of the CYP2D6 gene.• Clinical features of HD, and a positive family history and/or the presence of ≥ 36 CAG repeats in the Huntington gene.
• Male or female age ≥ 30 years.
• Willing and able to take oral medication and to comply with the study specific procedures.
• Ambulatory, being able to travel to the assessment center, and judged by the Investigator as likely to be able to continue to travel for the duration of the study.
• Availability of a caregiver or family member to accompany the subject to two visits.
• A sum of ≥ 10 points on the mMS at the screening visit.
• For subjects taking allowed antidepressants or other psychotropic medication, the dosing of medication must have been kept constant for at least 6 weeks before enrollment.
F. Clum, C. Garnett, T. Wang and A, Lanctot, 2010
Explaining the variable onset, manifestation, and progression of HD
Mesenchymal stem cells (MSCs) are a type of multipotent stem cell, meaning that they can give rise to many but not all types of cells in the body. MSCs secrete substances, including cytokines and growth factors, that are essential to cell growth and help repair damaged tissue. Researchers are still exploring the functions of human MSCs in the body, but current knowledge about the stem cells suggests that they play an important role in cell repair, acting as a sort of “cellular paramedic.”
Mesenchymal Stem Cells: The Cellular Paramedic
MSCs can be thought of as “cellular paramedics,” helping to restore damaged cells and tissue. As mentioned before, MSCs are able to secrete substances like cytokines and growth factors that can promote tissue repair. MSCs have even been shown to transfer products as large as mitochondria to damaged cells that need help. Specifically, MSCs stimulate angiogenesis, the process of new blood vessel formation, which has been linked to neurogenesis, the process by which new nerve cells are produced. The factors secreted by MSCs also reduce the harmful effects of oxidative damage and apoptosis.
When researchers discovered the “paramedic” quality of MSCs, they conducted several experiments to see how MSCs could potentially be used to help treat human diseases. In one experiment, MSCs obtained from humans were injected into mice that had some type of tissue damage and did not have a functional immune system. The MSCs were labeled so that scientists could track where they migrated after being injected into the mice. The researchers observed that the cells migrated throughout the damaged tissues apparently evenly and continued to be present in the tissue for a substantial period of time. The continued presence of MSCs is important to therapeutic development because it indicates that potential positive long-term effects of a treatment might be capable of persisting.
In additional experiments, scientists found that MSCs function differently in chronic disease models than in more temporary conditions like injury and trauma. In mouse models of acute injury, injected MSCs responded by helping to repair the tissue but were not present in the tissue for a substantial period of time, as they were in mouse models of chronic disease. For more information on mouse models, click here. When the experiment was repeated in injured mice without functional immune systems, the MSCs were again only temporarily present in the tissue. This suggests that temporary presence of MSCs is not a result of the host immune system. It is important to establish what types of environment foster the sustained presence of MSCs in the tissue so that clinicians can increase the effectiveness of future treatments using MSCs.
Research Using Mesenchymal Stem Cells
The unique ability of MSCs to secrete their own growth factors enables scientists to culture them in a laboratory with relatively little maintenance. Furthermore, MSCs multiply rapidly in cell cultures. As a result, compared to other cells, it is easier to grow many MSCs after obtaining a limited number of the cells from a patient. Cells that are grown in vitro often develop different characteristics or stop multiplying after a period of time. However, MSCs have been found to maintain their characteristics and the ability to multiply even after many cycles of replication. Most other cells require expensive cytokines and growth factors to grow in vitro, so the low maintenance of MSCs increases their appeal as a source of stem cells to investigate potential treatments.
In the body, MSCs are found in the bone marrow, umbilical cord tissue, and fat pads. MSCs are relatively rare in the bone marrow, comprising only 1 out of every 10,000 cells. On the other hand, umbilical cord blood and fat are rich sources of MSCs. Human MSCs can be harvested with minimal patient discomfort by tapping into an individual’s marrow space or fat pads.
Unlike most other cells, MSCs can be transferred between organisms with little immune rejection, in which the immune system of the organism receiving the transplant attacks the foreign tissue being transplanted. Scientists have found that MSCs suppress the immune system and reduce inflammation, making them good candidates for transplantation or injection into a host because they can avoid rejection by the host’s immune system.
The ease with which MSCs can be obtained, cultured, and transferred into a host without immune rejection is one reason why researchers are hopeful that MSCs may offer a promising way for scientists to develop treatments for neurodegeneration.
MSCs and the Brain
In the brain, MSCs can help repair neurodegeneration by providing neurotrophic factors, proteins in the nervous system that promote the growth of nerve cells. For example, detailed experiments have shown that human MSCs express the neurotrophic factor BDNF (brain-derived neurotrophic factor) but do not express certain types of neurotrophins. You can read more about BDNF by visiting the HOPES article here. Interestingly, MSCs still exhibited their “cellular paramedic” effects when BDNF activity is blocked by an antibody, suggesting that MSCs secrete factors other than BDNF that help with cellular growth in the brain. The effects of these factors allow nerve cells to carry out several processes that support survival: axon extension, growth, and cell attachment. In essence, MSCs change the tissue environment to enhance cell growth and regeneration in the brain.
Experiments done on mice with nerve cell injury have shown that MSCs injected into the brain promote recovery by secreting neurotrophic factors that facilitate nerve cell survival and regeneration. More relevant to HD are animal experiments showing that MSCs have the potential to repair striatal degeneration.
Bantubungi et al conducted experiments using rat MSCs to help treat rat models of HD with parts of their striatum removed. The research showed that MSCs proliferated more rapidly in the rat brains with striatal lesions than in healthy rat brains, suggesting that MSCs selectively respond to areas needing repair. Furthermore, the scientists identified a protein called stem cell factor that encouraged proliferation and directed migration of the MSCs to damaged tissue. Stem cell factor is a naturally occurring protein that plays an important role in communication between cells. The experiment by the scientists suggests that MSCs do in fact play an important role in the brain and have potential to become a cellular therapy for neural repair.
Amin et al. conducted an experiment in which rat models of Huntington’s disease with damage to one side of the brain responded positively to MSC implantation into the brain. Specifically, damage within the striatum, the region of the brain drastically affected in HD, was significantly reduced in rats that received MSC implantations.
It is important to note that although MSCs promote cell growth and repair in the brain, scientists have not yet confirmed that MSCs can become mature nerve cells with the ability to signal, or communicate with, other nerve cells. Other types of stem cells, such as neural stem cells have been found to generate mature nerve cells. MSCs may not be able to become mature nerve cells themselves.
Genetically Engineered MSCs
In addition to exploiting the natural ability of MSCs to help repair damaged nerve cells, scientists have found ways to genetically engineer MSCs to enhance their reparative properties in the brain. Scientists can introduce genes into MSCs that cause them to produce a greater quantity of factors such as cytokines and neurotrophins. Even after genetically engineered MSCs are allowed to multiply through several generations, they retain these genetic characteristics that boost production of helpful factors. Furthermore, MSCs have proven to be robust cells: genetic engineering does not hinder the cells’ ability to multiply or grow. It is important however to continue these types of studies to ensure there are no unintended side effects of enhanced neutrophin and cytokine productions in MSCs or other cells and tissues in the body.
An experiment conducted by Dey et al. showed that mouse models of HD responded positively to treatment by MSCs. When the MSCs were genetically engineered to produce greater quantities of BDNF, the delay in disease progression was even more drastic in the mice.
The potential to genetically engineer MSCs to deliver factors such as BDNF is important because directly injecting some of these factors is not effective. Transplanted MSCs, as indicated in the studies mentioned above, have been shown to disperse throughout damaged tissue for a sustained period of time. The characteristics of the compounds themselves often prevent them from having a sustained physiological effect on their own. Therefore, the genetically engineered MSCs serve as a vehicle to enable effective delivery of helpful factors into the brain.
Another exciting possibility is to have MSCs themselves become vehicles for delivering genetic material that can help with diseases like HD. Dr. Jan Nolta’s research group at University of California Davis, for example, hopes to have MSCs deliver molecules for RNA interference, a type of gene therapy, into the cells of HD patients. You can read more about RNAi in the HOPES article here. This area of research is still in its preliminary stages and may take several years to obtain approval from government agencies such as the Food and Drug Administration (FDA). Nevertheless, it holds promise as a potential future treatment for HD.
A Potential Treatment for HD Using MSCs
Future cellular therapies using MSCs would involve delivering MSCs into the brain, which has been approached in a number of different ways. Scientists have proposed delivering MSCs through an injection directly into the brain, an injection into the space surrounding the spinal cord, or a route through the nose (e.g. a nasal spray).
Although clinical trials using MSCs in humans have not yet been approved in the United States, one human cellular therapy trial has been conducted in France. In the trial, neural stem cells rather than MSCs were used. Five patients with HD received transplants from human fetal neural stem cells. After two years, three out of the five patients demonstrated motor and cognitive improvements. While this experiment provides hopeful evidence that stem cell therapies may provide a treatment for HD, the results should be interpreted with caution. First, two of the patients did not show significant improvements. Second, as noted before, neural stem cells and MSCs have different characteristics. Therefore, the results from this experiment do not indicate whether MSCs would provide an effective treatment. Finally, after four to six years, the patients showed clinical decline once again, suggesting that additional research is required before an effective long-term treatment is developed.
In addition to showing that stem cells are in fact an effective treatment for HD, researchers must also show that implanting MSCs into the brain is a safe procedure before treatments can continue to be developed. One of the main concerns with MSCs is that they could cause abnormal cell growth. Abnormal growth could result in extra bone or tumor formation. In particular, MSCs have been found to migrate to areas in the body that contain tumors. This could be dangerous if the MSCs excrete factors that encourage angiogenesis, cell growth, and cell proliferation within the tumor. For safety reasons, proposed clinical trials for cellular therapies exclude anyone who has had a brain tumor or other cancer within the past 5 years. Before treatment, an MRI will be administered to ensure the absence of any brain tumors.
Extensive biological safety trials have been conducted with MSCs by Dr. Gerhard Bauer and Dr. Jan Nolta at University of California at Davis. They have performed numerous experiments over the past decade on different animal models including mice, rats, and primates, to test if MSCs can be safely injected or grafted without tumorous growths. Additionally, a successful clinical trial in France with five HD patients suggests that transplantation of stem cells into the brain can be done without negative health consequences. However, more evidence for the biological safety of injecting MSCs into the brain is needed to meet the rigorous safety standards of the FDA in the United States
MSCs have potential to be a safe and effective therapy for HD. While there is promising evidence from animal research that MSCs can slow neurodegeneration, specifically in the striatum, there are still many aspects of the potential therapy that require additional experimentation.
1. Aggarwal, S. and M. F. Pittenger (2005). “Human mesenchymal stem cells modulate allogeneic immune cell responses.” Blood 105(4): 1815-1822.
A technical paper that discusses how MSCs interact with the immune system.
2. Aizman, I., C. C. Tate, et al. (2009). “Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth.” J Neurosci Res 87(14): 3198-3206.
A technical paper that talks about the various compounds secreted by MSCs
3. Amin, E. M., B. A. Reza, et al. (2008). “Microanatomical evidences for potential of mesenchymal stem cells in amelioration of striatal degeneration.” Neurol Res 30(10): 1086-1090.
This paper discusses how MSCs might help counter nerve cell damage in the striatum, and is difficult
4. Bachoud-Levi, A. C., V. Gaura, et al. (2006). “Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study.” Lancet Neurol 5(4): 303-309.
This is the study in which human fetal neural stem cells were transplanted into HD patients
5. Bantubungi, K., D. Blum, et al. (2008). “Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington’s disease.” Mol Cell Neurosci 37(3): 454-470.
A technical paper that discusses transplantation of MSCs in rats
6. Crigler, L., R. C. Robey, et al. (2006). “Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis.”
This paper discusses some of the compounds that MSCs secrete that play a role in nerve cell health, and is quite difficult
7. Danielyan, L., R. Schafer, et al. (2009). “Intranasal delivery of cells to the brain.” Eur J Cell Biol 88(6): 315-324.
This paper discusses one of the several ways MSCs might be delivered through the brain.
8. Dey, N. D., M. C. Bombard, et al. (2010). “Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease.” Behav Brain Res 214(2): 193-200.
This technical paper discusses how MSCs helped behavior problems in a mouse model of HD.
9. Joyce, N., G. Annett, et al. (2010). “Mesenchymal stem cells for the treatment of neurodegenerative disease.” Regen Med 5(6): 933-946.
This paper discusses potential applications of MSCs in medicine, and is of medium difficulty
10. Meyerrose, T. E., M. Roberts, et al. (2008). “Lentiviral-transduced human mesenchymal stem cells persistently express therapeutic levels of enzyme in a xenotransplantation model of human disease.” Stem Cells 26(7): 1713-1722.
This technical paper discusses how MSCs migrate through the nervous system when introduced into a mouse’s brain
11. Spees, J. L., S. D. Olson, et al. (2006). “Mitochondrial transfer between cells can rescue aerobic respiration.” Proc Natl Acad Sci U S A 103(5): 1283-1288.
This technical paper describes how transfer of mitochondria between cells can help the cell that receives the mitochonfrion
12. Wineman, J., K. Moore, et al. (1996). “Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells.” Blood 87(10): 4082-4090.
This technical paper discusses the conditions needed to grow MSCs
T. Wang, 7-25-11
The decision to have a family comes with a great deal of responsibility, and many important choices. For people with Huntington’s disease (HD), one of the most pressing considerations in their decision to have children relates to the disorder. People with HD have a 50% risk of passing the disease to their offspring each time they conceive, unless they attempt an alternative method that stops HD from being inherited through the generations. Those “at risk” of HD, who have parents or relatives with the disease but do not wish to be tested to see whether they are affected, also have the potential to pass HD on to their children as they might be HD-positive.
This article outlines a number of reproductive options available to couples that know their HD status, and to those who prefer not to know. There is no easy answer, and each couple may come to a different conclusion based on their personal preferences and system of beliefs. This article provides possibilities: the solutions, however, can only be reached by the individuals themselves.
Decide whether to get tested
The first decision a couple faces is whether or not the person at risk should get tested for HD; the test results might significantly shape the choices a couple makes in planning their family. For more information on genetic testing, click here, and to learn more about how getting tested might affect romantic relationships, click here. Getting tested is not necessary, as people who are at risk have several ways to avoid passing on HD without finding out their own status, but it might be helpful.
Not having children/Adoption
Upon learning of their HD-positive or at risk status, some people choose to not have children. Many people that make this choice do so to avoid the risk of passing HD on to their children, expressing guilt at the thought of transmitting the disease (Decruyanaere et al., 2007). Other couples worry they won’t be able to fully raise the child before the HD-affected parent’s symptoms set in, and they don’t want the disease to compromise their parenting (Klitzman et al., 2007). On one hand, couples who don’t have children can rest easy knowing that they will never pass HD on to future generations; on the other, some may regret not having children (Decruyanaere et al., 2007).
Couples that don’t want to remain childless sometimes decide to adopt instead. Adoption helps a needy child, and allows a couple to raise children without passing on HD. Prospective parents generally work with adoption agencies to help them through the adoption process, and to help them screen children to find the right match. The decision must be weighed carefully, as prospective parents need to consider whether HD will jeopardize their ability to raise children; some adoption agencies might refuse to let HD-positive people adopt on these grounds (Klitzman et al., 2007). For more information about adoption, click here.
Many couples choose to have children naturally. If one parent is HD-positive, then the child has a 50% chance of having HD. If one parent is at risk (and therefore has a 50% chance of having the disease), their child has a 25% of having HD – though that number increases to 50% if the at risk parent begins to show symptoms. If both parents have HD, then the child has a 75% chance of having the disease.
Parents who accept these risks and have children naturally often say that their desire to have children outweighs their fears about HD. They acknowledge that their child might inherit the disease, but express hope that a cure for HD may be found in their child’s lifetime; they also point out that even if no cure is found, their child will have many disease-free years, as HD rarely sets in before age 40 (Decruyenae et al., 2007).
Sperm or egg donation/Surrogate mother
Couples also have the option of sperm or egg donation, depending on which partner is affected by HD. If the prospective father is HD-positive, couples might consider sperm donation, in which a donor’s sperm is inserted into the prospective mother’s uterus or vaginal canal using a syringe. For more information on sperm donation, click here. If the prospective mother is HD-positive, couples can have children through egg donation, in which another woman donates her eggs and they are fertilized with the father’s sperm through in-vitro fertilization (IVF). Alternatively, a couple could consider having a child with a surrogate mother, where the father’s sperm is inserted into a surrogate mother. However, while sperm donation is relatively inexpensive at several hundred dollars, both egg donation and surrogacy cost thousands of dollars; couples in which the prospective mother has HD generally choose other reproductive options instead.
Test Tube Babies: Preimplantation Genetic Diagnosis (PGD)
Pre-implantation Genetic Diagnosis (PGD) screens embryos for genetic diseases, such as HD, before they are implanted in a woman’s body. This exciting new technology, developed in 1998, allows couples to prevent their children from inheriting genetic diseases that run in the family (Decruyenae et al., 2007).
To generate the embryos used in PGD, the couple must first undergo in-vitro fertilization (IVF). In IVF, a woman’s eggs and man’s sperm are combined in a laboratory. First, some of the woman’s eggs are collected. Since women usually only release one egg every month, doctors give the woman fertility medication to cause her to release many eggs at once, a process called “superovulation”. The eggs are monitored using ultrasound imaging. Once they are mature, the doctors perform a minor surgery. The woman is given local anesthetic, which numbs the area the doctor will be working on, and sedatives, which put her to sleep. Then, using ultrasound, the doctor guides a hollow needle to the ovary and removes the eggs.
The eggs are then fertilized using the man’s sperm. This is the step that earned this procedure the name “in vitro fertilization”: “in vitro” is Latin for “in glass”, referring to the fact that the fertilization is performed in test tubes or petri dishes, rather than in the body –which gave rise to the term “test tube babies”. The sperm and egg combine to form a single-celled embryo, which grows and divides. For more information on IVF, click here.
Once the embryo has reached the 8-cell stage, PGD is performed. One of the eight cells of the embryo is removed for testing. This procedure is harmless, as the embryo is still composed of stem cells, and can easily grow to replace the lost cell. Since every cell has a complete copy of the genetic code, any one cell will suffice for genetic testing. At this point, a “genetic diagnosis” is carried out on the cell. However, geneticists can’t use the same test that is used to check adults for the HD allele, as one cell isn’t enough to test for CAG repeats directly (a process described here). Instead, scientists take blood samples from both prospective parents, and from the parents of the at-risk individual. They then look at the genes right next to the HD allele, and choose a “marker” – a unique fingerprint of DNA that differs between the chromosome with the HD allele, and those without. Since genes that are close together are almost always inherited together, the embryos with the HD allele will also have this particular marker. Therefore, an embryo that tests positive for the marker is considered “affected”; it carries the HD allele, and is expected to have HD. Embryos that do not carry the marker are “unaffected”, and are considered for implantation (Sermon et al., 2002).
The doctor will then implant between 1-4 embryos. Usually, more than one embryo is implanted, to increase the chances of a successful pregnancy. If the first implantation process fails, and there are enough unaffected embryos remaining from the egg retrieval process, the doctor can simply perform a second implantation. However, if there aren’t enough unaffected embryos remaining, the woman will have to begin the entire process again, starting from egg retrieval.
To summarize, the woman undergoes egg retrieval in which several eggs are collected. Those eggs are fertilized with the man’s sperm through IVF, and allowed to divide to the 8 cell stage. PGD is performed on one cell of each embryo, and the embryos that are HD-free are selected for implantation. This process, while complicated and expensive, virtually ensures that the children of a PGD-tested couple will be HD-free – the only risk of the child having HD would come from human error, and is extremely small.
PGD comes with a handful of medical risks. As multiple embryos are implanted, some women end up having more than one child. Some may be happy with this result, but others might have a more difficult pregnancy. Another problem – ovarian hyperstimulation syndrome – is caused by an over-reaction to the fertility medication used. The problem, which causes symptoms such as diarrhea, nausea, and dizziness, can be solved by drinking more water. Other complications, such as infections acquired during surgery, are treated with antibiotics. For a full discussion of risks, click here.
An alternative form of PGD exists for those who don’t wish to be tested. As with disclosing PGD, IVF is performed to create embryos, and doctors perform PGD to determine which are affected, and which are HD-free. The difference between disclosing and non-disclosing PGD is that the doctor never reveals the at-risk parent’s status: the parents do not find out how many embryos were affected (if any), and do not know how many embryos were implanted.
Non-disclosing PGD brings up a number of weighty issues. First, the doctor knows the status of the at-risk parent, but must keep it a secret. Even if the news is good – if none of the embryos have HD, the parents are almost certain to be HD-free – the doctor can’t reveal the parent’s status, as this would compromise secrecy for other clients; clients who were not congratulated would know their HD-positive status by default (Braude et al., 1998).
Second, if the parent is a carrier, and all embryos are affected, then a “mock transfer” is carried out; the doctor performs an implantation in which no eggs are implanted. This ensures that the person doesn’t find out his or her HD-positive status. Some countries, such as Holland, consider this an unnecessary medical risk, and therefore require the at-risk individual to be tested before undergoing PGD (Asscher and Koops, 2010).
Third, half of the couples that choose non-disclosing PGD are perfectly healthy, and therefore undergo IVF-PGD when they could simply have a natural pregnancy. Again, this factored into Holland’s decision to force couples to get tested before resorting to PGD, as half of the couples will avoid the cost and medical risks of IVF-PGD. However, the US and most other countries have no such policy, and non-disclosing PGD is accepted and performed (Asscher and Koops 2010). For a discussion of the right not to know, click here.
In short, PGD allows couples to have children that will be HD-free. The procedure, admittedly, is physically and emotionally draining, particularly because the success rate is currently around 20%; a couple may have to undergo multiple rounds of IVF-PGD for a successful pregnancy (Sermon et al., 2002). Furthermore, with a price-tag of $9,000-$18,000, this procedure might be out of reach for some couples, particularly if their health insurance companies refuse to subsidize the cost. However, many HD-positive or at-risk couples have had successful pregnancies through IVF-PGD. For an account of an HD-positive mother who had twins through IVF-PGD, and successfully lobbied her health insurance company to cover most of the expenses, please click here.
Testing the Fetus: Prenatal Diagnosis
Another option exists for women who are already pregnant: Doctors can perform a prenatal diagnosis, in which the fetus is tested for HD. As with PGD, this procedure can take two forms: HD-positive people undergo a “disclosing” prenatal diagnosis, and people who are at-risk but do not wish to be tested can have “non-disclosing” prenatal diagnosis, in which their fetus is tested for the risk of HD and the parent’s status remains unknown.
Prenatal diagnosis can be performed through chorionic villus sampling (CVS) or amniocentesis. In both, a needle is guided by ultrasound imaging to collect a sample of cells for genetic testing. In CVS, the needle is inserted into the uterus through the vagina, and collects a few cells from the placenta, the organ that develops alongside the fetus and supplies it with oxygen and nutrients from the mother. CVS is usually performed 10-13 weeks after the mother’s last menstrual period. Amniocentesis is performed later, around 14-20 weeks into the pregnancy. In amniocentesis, a needle is inserted through the abdomen into the uterus and takes a sample of amniotic fluid – the fluid surrounding the fetus – for genetic testing. Both CVS and amniocentesis are very safe procedures, though there is a very small increase in risk of miscarriage. For more information on CVS, please click here, and to read more about amniocentesis, please click here.
Once those samples are taken, genetic tests are performed. For a disclosing prenatal diagnosis, doctors determine the number of CAG repeats the fetus has in its Huntington gene, as described here. If the fetus has 35 or fewer CAG repeats, it is considered HD-free; with 40 or more CAG repeats, it is considered HD-positive; with 36-39, the fetus has an uncertain prognosis, and may or may not develop HD in its lifetime.
If the parent is at-risk for HD, but does not wish to know their status, a non-disclosing prenatal diagnosis is performed through “exclusion testing”. In exclusion testing, the CAG repeats are not directly measured; instead, doctors look at “linked markers” to see which parent the fetus inherited its genetic material from, as previously described in the PGD section of this article. In this method, the couple must get in touch with their parents to collect small blood samples for testing. For the HD-positive parent of the “at-risk” person (the “grandparent” of the fetus), the doctors find markers for the Huntington gene. The doctors consider the fetus at risk of developing HD if either of the affected grandparent’s copies of the Huntington gene are present in the fetus; the grandparent’s HD allele, as well as the grandparent’s non-HD allele, both cause the fetus to be deemed “high-risk”. Therefore, there is a 50% chance that the fetus will have HD if it is marked as high-risk.
After a few weeks, the parents obtain their results. If the fetus is HD-free, the parents can rest easy; the child won’t suffer from the disease, and will never pass HD on. Unfortunately, some parents will receive upsetting results from the genetic test, and have a difficult choice to make.
Parents who are informed that their fetus has HD sometimes choose to keep the child, and do so for a number of reasons. Some say their desire for a child outweighs their fears about HD; others point out that the child will have many disease-free years before symptoms begin; still more express the hope that a cure for HD may be found in their child’s lifetime (Decruyenae et al., 2007). Views on abortion also play a large part in many people’s decisions; for some, their opposition to abortion outweighs their desire to prevent HD from being passed on to their children. A handful of parents don’t believe the results of a prenatal diagnosis should be grounds for abortion because they consider this the first step down a slippery slope towards a eugenic society, in which we begin choosing traits for our children (Klitzman et al., 2007).
All of these concerns are valid points, and deserve careful contemplation. However, most couples that learn that their fetus is HD-positive decide to terminate the pregnancy (Decruyenae et al., 2007). These parents often say they would feel unethical bringing an HD-positive fetus to term, as they don’t wish to subject a child to the difficulties they themselves have undergone (Klitzman et al., 2007).
The decision becomes even more difficult for parents who choose a non-disclosing prenatal diagnosis, and learn that their child is “high-risk”. While the fetus has a 50% chance of being HD-positive, there is still a 50% chance that the fetus is HD-free. For this reason, some countries, such as France, make it very difficult for a woman to have an abortion on the grounds of a non-disclosing prenatal diagnosis (Sermon et al., 2002).
This decision is difficult to make, and parents will have to weigh many personal, moral, and religious considerations; this article only scratches the surface of factors that might take a part in the choice. Some parents choose to avoid prenatal diagnosis entirely, as they don’t wish to risk the psychological and physical burden of abortion (Decruyenae et al., 2007). Ideally, a couple should discuss these issues with a genetic counselor; if possible, counseling should begin before the couple conceives, especially for non-disclosing prenatal diagnosis, as it may take longer than expected for doctors to find useful linked markers for the test.
Despite the difficulties of living with an inheritable disease, prospective parents should not feel limited by their HD-positive or at-risk status; those who wish to have children have many options, many of which prevent the passage of HD. This decision involves difficult choices, where a couple must weigh personal moral, ethical, and religious beliefs, while taking into account the opinions of family members and close friends. The end result, however, is well worth the work.
1. “Amniocentesis : American Pregnancy Association.” Promoting Pregnancy Wellness : American Pregnancy Association. American Pregnancy Association, Apr. 2006. Web. 25 June 2011. <http://www.americanpregnancy.org/prenataltesting/amniocentesis.html>.
This is an easy-to-read website with an in-depth discussion of amniocentesis, going into how the procedure is done, and any risks that might be involved.
2. “Chorionic Villus Sampling: CVS.” Promoting Pregnancy Wellness : American Pregnancy Association. American Pregnancy Association, Apr. 2006. Web. 17 June 2011.
This is an easy-to-read website with an in-depth discussion of CVS, going into how the procedure is done, and any risks that might be involved.
3. Asscher E, Koops BJ. The right not to know and preimplantation genetic diagnosis for Huntington’s disease. J Med Ethics. 2010 Jan;36(1):30-3
This is an easy-to-read paper on the ethics of non-disclosing PGD and non-disclosing prenatal diagnosis
4. Braude PR, De Wert GM, Evers-Kiebooms G, Pettigrew RA, Geraedts JP. Non-disclosure preimplantation genetic diagnosis for Huntington’s disease: practical and ethical dilemmas. Prenat Diagn. 1998 Dec;18(13):1422-6. Review.
This article explores some of the ethical considerations that non-disclosing prenatal diagnosis and non-disclosing PGD bring up, and could be useful for at-risk individuals.
5. Decruyenaere M, Evers-Kiebooms G, Boogaerts A, Philippe K, Demyttenaere K, Dom R, Vandenberghe W, Fryns JP. The complexity of reproductive decision-making in asymptomatic carriers of the Huntington mutation. Eur J Hum Genet. 2007 Apr;15(4):453-62. Epub 2007 Jan 24.
This is an easy-to-read study looking into the reproductive decision-making process of couples who know their HD-positive status.
6. Klitzman R, Thorne D, Williamson J, Chung W, Marder K. Decision-making about reproductive choices among individuals at-risk for Huntington’s disease. J Genet Couns. 2007 Jun;16(3):347-62.
This is an easy-to-read study looking into the reproductive decision-making process of couples that are at-risk, but do now wish to be tested.
7. Sermon K, De Rijcke M, Lissens W, De Vos A, Platteau P, Bonduelle M, Devroey P, Van Steirteghem A, Liebaers I. Preimplantation genetic diagnosis for Huntington’s disease with exclusion testing. Eur J Hum Genet. 2002 Oct;10(10):591-8.
This technical paper describes how PGD is performed.
8. “What Are the Risks of PGD Treatment?” Guy’s and St Thomas’ Centre for Preimplantation Genetic Diagnosis. Centre for Preimplantation Genetic Diagnosis, 18 May 2009. Web. 29 June 2011. <http://www.pgd.org.uk/whatispgd/risks/pgdrisks.aspx>.
This easy-to-read website that discusses the medical risks of PGD.
M. Hedlin, 7.20.11; recorded by B. Tatum, 8/21/12
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Drug Summary: Pridopidine, also known as Huntexil or ACR-16, is a dopamine stabilizer intended to improve voluntary movements and reduce chorea. Initial clinical trials – the MermaiHD and HART studies – show promising results, but drug regulation agencies have requested another trial before pridopidine can be sold to the general public.
Dopamine in the HD Brain
The brain plays a delicate balancing act: it needs to maintain the right levels of many brain chemicals in order to orchestrate movements and execute thoughts. In people with Huntington’s disease (HD), that balance is threatened; the brain has trouble regulating neurotransmitters, chemicals in the brain that transfer messages between neurons. This causes miscommunication between different parts of the brain. As a result, people with HD have less control over behaviors and movements that are usually directed by the affected neurotransmitters, as described in greater detail here. Pridopidine, which is being investigated as a treatment for the motor symptoms of HD, is thought to restore the balance of neurotransmitters that the brain needs to function.
Specifically, pridopidine is believed to work by stabilizing levels of the neurotransmitter dopamine in the brain. Dopamine has a number of different roles depending on what part of the brain it acts on, but in the HD brain, the most relevant function is its effects on motion. Dopamine in the striatum, a part of the brain responsible for planning and controlling movements, helps coordinate voluntary motions (like walking or waving) and prevent involuntary motions (like the unwanted dance-like movements of chorea), as discussed in more detail here.
However, sometimes there’s too much of a good thing. When there’s too much dopamine in certain parts of the striatum, the brain has trouble stopping involuntary movements, which causes chorea. On the other hand, when there’s too little, the brain can’t start voluntary movements, and the symptoms – such as stiffness, staggering, and difficulties speaking – get in the way of everyday life. The brain walks a tightrope as it tries to maintain the right balance of neurotransmitters, and the slightest disturbance can cause movements to falter (Andre et al., 2011).
How Pridopidine Works
As a dopamine stabilizer, pridopidine is thought to reduce the effects of dopamine when there’s too much, and increase its effects when there’s too little. When dopamine levels are too high, pridopidine interacts with dopamine receptors, which act as the “ears” the neuron uses to “hear” dopamine. These receptors have a very specific shape that allows them to bind and recognize dopamine, and when levels of dopamine are high, the receptors change shape as they become more active. Pridopidine is particularly attracted to the “active” form of the receptor and lodges itself in the spot where dopamine usually binds, preventing dopamine from interacting with the receptor. In this way, pridopidine blocks the dopamine receptor from sensing and responding to dopamine when dopamine levels are too high (Pontel et al., 2010).
Conversely, when levels of dopamine are low, pridopidine has a round-about way of increasing dopamine production. HD affects more than just dopamine: low levels of the neurotransmitter glutamate in a region of the brain called the cortex are also associated with the disease (Pontel et al., 2010). The cortex is the part of our brain that helps us think and plan, and tells the striatum what voluntary movements to perform. Pridopidine raises glutamate levels in the cortex, allowing it to communicate better with the striatum. This increases dopamine levels in the parts of the striatum that had too little. By increasing glutamate signaling in the cortex, pridopidine increases dopamine levels in certain parts of the striatum, allowing voluntary movements to occur (Andre et al., 2011).
Pridopidine therefore plays two opposing roles in the brain, which stabilize dopamine levels. In this way, pridopidine is thought to help the brain reestablish a normal balance of neurotransmitters, and thus regain control over motion.
Research on HD
Neurosearch, a pharmaceutical company based in Sweden, has conducted two different clinical trials on pridopidine.
The MermaiHD study was a phase III clinical trial, conducted in 32 centers spread across eight countries in Europe. 437 HD patients were randomly assigned to one of three groups: one treatment group received 45 mg of pridopidine once per day; the second treatment group received 45 mg of pridopidine twice per day; the control group received a placebo. To prevent potential bias, MermaiHD was a double-blind study; neither doctors nor patients knew whether the patient was receiving pridopidine.
After 6 months, patients were given the opportunity to continue participating in the study for another 6 months. In this “open-label” phase, the 357 patients who opted to proceed took 45 mg of pridopidine twice daily – no patients were given placebo. The purpose of the open-label segment of the study was to test whether pridopidine is safe and effective for longer periods of time.
Preliminary results suggest that pridopidine might help HD patients control motor symptoms. Doctors measured patients’ progress using the modified Motor Score (mMS), which tests a patient’s ability to perform voluntary movements. Results suggest that patients taking pridopidine performed better on the mMS; patients taking 45 mg of pridopidine twice daily averaged a 1.0 point improvement on the test. However, the results of the mMS did not reach the goals that the scientists had set out to prove: these results reached a statistical significance level of p=0.042. This means that there is a 4.2% probability that pridopidine is no better than a placebo, and that these results occurred by chance; they had originally aimed for a p=0.025.
However, further data analysis indicates that pridopidine may still hold promise. The mMS is just a subsection of a more widely-used test called the Unified Huntington’s Disease Rating Scale (UHDRS), which is described in more detail here. When measured on the motor category of the UHDRS, a test called the UHDRS-TMS, the results were very significant: Patients taking 45 mg of pridopidine twice per day had a 3.0 point improvement, at a statistical significance level of p=0.004. To put that in perspective, HD patients generally experience a 3-point annual decline in their UHDRS-TMS score. This strongly indicates that pridopidine improves motor symptoms of HD.
Furthermore, pridopidine did not appear to have notable side effects, and didn’t make other symptoms of the disease worse. This was a concern because other treatments, such as tetrabenazine, sometimes cause depression and other side effects if they change neurotransmitters too much in the wrong parts of the brain, as described here.
In the HART study, Neurosearch and the Huntington Study Group teamed up to study pridopidine further. The HART study was a phase IIb clinical trial, which measures how well a drug works at the prescribed dose. The study was also conducted to see whether pridopidine is effective and safe, and to establish an optimal dose. HART enrolled 227 patients, and was run in 28 centers across America and Canada. Like the MermaiHD study, the HART study was randomized, double-blind, and placebo-controlled.
To determine the dose, there was one placebo group and three treatment groups; patients received 10 mg, 22.5 mg, or 45 mg of pridopidine twice per day.
After just 12 weeks, a significant effect was seen in the group taking the largest dose, 45 mg. Total motor function, as measured by the UHDRS-TMS, improved by 2.8 points, which was statistically significant with a p=0.039. Again, the original test – the mMS – did not show statistical significance, though it did show a strong trend with p=0.078.
The HART study backed up the findings of the MermaiHD study and also helped scientists determine which dose of pridopidine is most effective. This study will continue in an open-label phase, where patients who participated in HART are given the opportunity to continue taking pridopidine until the U.S. Food and Drug Administration (FDA) decides whether or not to approve pridopidine.
Pridopidine significantly improves motor function, and has a positive effect on both voluntary and involuntary motor actions. Furthermore, it is very well tolerated, even when patients are taking other drugs, such as antipsychotics. However, pridopidine isn’t a “miracle drug” – while the findings are very hopeful, the drug has only been shown to improve motor symptoms; there is no evidence that it can “cure” the disease. Also, pridopidine’s effects seem to be limited to motor symptoms; patients experienced no significant changes in cognition, mood, or general ability to function in day-to-day life.
Individually, neither MermaiHD nor HART lived up to the original standards the researchers had set out to meet. However, statistical significance was reached when the results of the two studies were combined, and when the UHDRS-TMS was used to evaluate patients. Based on these results, Neurosearch lobbied the FDA, which regulates American drugs, and the European Medicines Agency (EMA), which regulates European drugs, to accept pridopidine as a treatment for HD. However, both organizations have asked for another phase III clinical trial to validate that pridopidine lives up to these promises. Neurosearch has declared that it will carry out a further trial, but has not yet announced further details. If it successfully passes this trial, the FDA and EMA would be likely to allow pridopidine to start being marketed as a treatment for HD.
- André VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington’s disease: A balancing act. CNS Neurosci Ther. 2010 Jun;16(3):163-78. Epub 2010 Apr 8. Review. This article discusses dopamine and glutamate signaling in the brain, and is very technical.
- Miller, Marsha L. “The American ACR16 Trial Results.” HDAC.org. Huntington’s Disease Advocacy Center, 14 Oct. 2010. Web. 5 July 2011. This article discusses the MermaiHD and HART studies, and is moderately difficult.
- Ponten H, Kullingsjö J, Lagerkvist S, Martin P, Pettersson F, Sonesson C, Waters S, Waters N. In vivo pharmacology of the dopaminergic stabilizer pridopidine. Eur J Pharmacol. 2010 Oct 10;644(1-3):88-95. Epub 2010 Jul 24. This highly technical article discusses how Pridopidine is believed to work in the brain.
M. Hedlin, 7.16.11
Myth(edited)A novel track of research has unearthed new meaning to the old adage “you are what you eat”. Research suggests that our diet plays a role in neurogenesis, the process by which we produce new neurons. Therefore, a diet rich in “brain food” may promote neurogenesis and thereby might repair some of the damage brought on by Huntington’s disease (HD).
Neurogenesis and HD
Neurogenesis allows us to have flexible brains throughout life, which is critical for learning new skills (Greenwood and Parasuraman, 2010).This allows our brains to age gracefully, as these new neurons work to replace the neurons that inevitably die. For more information on neurogenesis, click here.
In particular, neurogenesis is important in the context of HD. Neurogenesis continues to occur in HD patients and, in fact, increases as the disease progresses. This increase is thought to be the brain’s attempt to repair itself in response to the widespread neuronal death caused by the disease. However, neurogenesis does not happen fast enough to counter the damage incurred (Taupin, 2008).
It is possible that a diet that promotes neurogenesis could help counter some of the deficits experienced by HD patients. Some scientists have explored how diet can impact neurogenesis, and have found a number of nutrients and dietary regimes that may play a role.
One major track of research on diet and neurogenesis focused on dietary restriction (DR). In rats and monkeys, DR helps protect against age-related diseases, like cancer, diabetes, and cardiovascular disease (Mattson et al., 2004)
Scientists think DR brings about these beneficial effects by conditioning cells to be better at protecting themselves. DR is a mild stress that puts cells on the defensive, and causes them to start expressing protective genes and stockpiling useful proteins. Therefore, cells stressed by DR are better able to cope with further stressors. For more information on DR, click here.
One stressor that occurs in many neurodegenerative conditions, like Alzheimer’s, Parkinson’s, and HD, and can be ameliorated by DR, is oxidative stress. In HD, oxidative damage occurs when injured neurons release free radicals, which go on to damage neurons around them (Mattson et al., 2004). For more information on oxidative damage, click here. Therefore, DR may help patients with neurodegenerative diseases by causing neurons to fortify themselves, which could prepare them for the stress caused by HD.
Scientists also believe that DR can help patients with neurodegenerative conditions by promoting neurogenesis. DR increases adult neurogenesis in young adult rats, and reduces age-related declines in neurogenesis in older mice (Levenson and Rich, 2007). Furthermore, DR stimulates neurogenesis in the hippocampus, a brain region important for memory. DR also causes an increase in levels of BDNF, a protein shown to help newly born neurons survive (Mattson et al., 2004). For more information on BDNF, click here. Researchers have found that DR can improve the symptoms of HD and several other neurodegenerative conditions in mice. When rats were injected with a chemical that causes brain damage, the rats kept on a restricted diet were more resistant to the chemical’s neurodegenerative effects, and showed fewer learning and memory problems (Mattson et al., 2004). When HD mice were kept on a restricted diet, they showed less striatal neuron death, it took longer for movement problems to arise, and the mice lived longer (Mattson et al, 2004). So DR may protect against neurodegenerative conditions by stimulating neurogenesis and causing neurons to fortify themselves.
DR, however, is a drastic strategy: it takes tremendous willpower to limit calories to 70% of the normal diet. Furthermore, DR is difficult to implement properly; there is a risk of starvation if the diet is unbalanced, which can have wide-ranging consequences. Luckily, similar effects to DR have been found in mice by simply increasing the amount of time between meals (Stangl and Thuret, 2009).
Some scientists have attempted to harness the beneficial effects of DR through resveratrol, a chemical found in red wine. Resveratrol mimics many of the effects of DR, and is thought to work through the same biological pathways (Greenwood and Parasuraman, 2010). For more information, click here.
So DR and resveratrol may promote neurogenesis, and in this way might protect against the brain damage found in HD.
Dangers of a High-Fat Diet
Conversely, researchers have also studied situations where cells have too many calories, and have found that neurogenesis is impaired. Mice on a high-fat diet have lower levels of BDNF in the hippocampus, and decreased neurogenesis in a particular area of the hippocampus called the dentate gyrus (Park et al., 2010). Furthermore, when injected with a chemical that injures the brain, mice fed a high-fat diet experienced much more damage than those fed a normal diet. Diets high in fat also decrease the learning and cognitive capabilities of rats (Greenwood and Prasuraman, 2010). Thus, experiments on rodents consistently show that a high-fat diet is unhealthy for the brain.
Vitamins, Nutrients, and Foods that promote Neurogenesis
Another line of research on diet and neurogenesis has investigated the effect of dietary nutrients on the birth of new neurons. Several antioxidants, such as flavonoids, vitamin E, and curcumin, increase neurogenesis in rodent brains.
Flavonoids, found in cocoa and blueberries, are chemicals that increase neurogenesis in the hippocampus of stressed rats, possibly by increasing levels of BDNF (Stangl and Thuret, 2009), and/or by improving blood flow to the brain, which can increase hippocampal neurogenesis (Spencer, 2009). Vitamin E, abundant in vegetable oils, nuts, and green leafy vegetables, aids neurological performance in aging mice (Gómez-Pinilla, 2008). Curcumin, found in yellow curry spice, may increase neurogenesis in the hippocampus of rodents by activating certain cell signaling pathways known to increase neurogenesis and decrease stress responses (Stangl and Thuret, 2009). For more information on curcumin, click here.
Another antioxidant, found in green tea, goes one step further than the others. The chemical (-)-epigallocatechin-3-gallate (called EGCG) promotes neurogenesis in the hippocampus (Yoo et al., 2010), and has been shown to reduce the damage from oxidative stress in other neurodegenerative diseases (Ehrnhoefer et al., 2006). When flies with a form of HD were treated with EGCG, their control over their movements improved (Ehrnhoefer et al., 2006). EGCG might also directly fight the damage of HD, as it has been shown to slow the rate at which the mutant form of the huntingtin protein forms the plaques that are thought to hurt the brain (Ehrnhoefer et al., 2006).
In addition to antioxidants, other nutrients have also been shown to play a role in neurogenesis. Omega-3 fatty acids, present in fish and flaxseed, might also promote neurogenesis, and have been shown to decrease cognitive decline seen with aging and neurodegenerative diseases such as Alzheimer’s (Yurko-Mauro et al, 2010). For more information, click here.
Deficits in zinc can also inhibit neurogenesis in the hippocampus of rodents. Zinc, a vitamin essential for normal brain development, promotes the survival and proliferation of neural stem cells, which are the main cell type capable of generating neurons (Adamo and Oteiza, 2010). Therefore, zinc deficiency inhibits neurogenesis in the hippocampus of rodents.
Altogether, research on diet and neurogenesis is not conclusive. It is difficult to study nutrients effectively: studying a nutrient in isolation ignores many of the complex interactions the nutrient may have in the body. However, there are a few relatively consistent messages that emerge. A vitamin-rich, low-fat diet aids neurogenesis in experiments with rodents, and a low-calorie diet mitigates the effects of neurogenerative disease in mice. As for humans, this diet has not been shown to directly help neurogenesis or ameliorate the problems of HD (Huntington Study group, 2008; Block et al., 2011), but healthy diets have a vast number of other physical and mental benefits: longer life, elevated mood, and higher energy levels, to name a few. In conclusion, eating healthy might promote neurogenesis – but even if it does not, a healthy diet certainly will not hurt.
For Further Reading
Adamo AM, Oteiza PI. Zinc deficiency and neurodevelopment: the case of neurons. Biofactors. 2010 Mar-Apr; 36 (2) :117-24
A technical paper that discusses the impact of zinc deficiency on the brain
Block RC, Dorsey ER, Beck CA, Brenna JT, Shoulson I. Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol. 2010 Jan-Feb;4(1):17-23. Review
A technical paper that discusses Omega-3 fatty acids and their effects on HD.
Curtis MA, Penney EB, Pearson AG, van Roon-Mom WM, Butterworth NJ, Dragunow M, Connor B, Faull RL. Increased cell proliferation and neurogenesis in the adult human Huntington’s disease brain. Proc Natl Acad Sci U S A. 2003 Jul 22; 100 (15) :9023-7.
A technical paper that discusses neurogenesis in an HD brain
Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. Epub 2006 Aug 7.
A technical paper that describes how EGCG, an antioxidant found in green tea, may change the way that the mutant huntingtin protein forms harmful plaques
Greenwood PM, Parasuraman R. Neuronal and cognitive plasticity: a neurocognitive framework for ameliorating cognitive aging. Front Aging Neurosci. 2010 Nov 29; 2:150.
A technical paper that discusses strategies to counter the neuron damage that accompanies aging, such as education, exercise, dietary restriction, and a low-fat diet, and goes into research that has been performed on rodents.
Gómez-Pinilla, F. Brain foods: the effects of nutrients on brain function. Nature Reviews Neuroscience. 2008 Jul. Review; 9:568-578.
A technical paper that discusses how various nutrients affect brain function.
Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 2008 Dec;65(12):1582-9.
Levenson CW, Rich NJ. Eat less, live longer? New insights into the role of caloric restriction in the brain. Nutr Rev. 2007 Sep; 65 (9) :412-5.
A paper that discusses the impact of caloric restriction on the brain in rodents
Park HR, Park M, Choi J, Park KY, Chung HY, Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 2010 Oct 4; 482 (3) :235-9.
A technical paper that discusses the impact of a high-fat diet on rodents
Mattson MP, Duan W, Wan R, Guo Z. Prophylactic activation of neuroprotective stress response pathways by dietary and behavioral manipulations. NeuroRx. 2004 Jan; 1 (1) :111-6.
A technical paper that discusses dietary restriction and its effect on the brain in rodents
Spencer JP. Beyond antioxidants: the cellular and molecular interactions of flavonoids and how these underpin their actions on the brain. Proc Nutr Soc. 2010 May; 69 (2) :244-60.
A technical paper that discusses the impact of flavonoids on the brain
Stangl D, Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr. 2009 Dec; 4 (4) :271-82.
A technical paper that discusses the science behind various dietary strategies and nutrients that have an impact on neurogenesis in the adult hippocampus
Taupin P. Adult neurogenesis, neuroinflammation and therapeutic potential of adult neural stem cells. Int J Med Sci. 2008 Jun 5; 5 (3) :127-32.
A technical paper that discusses neurogenesis and neural stem cells
Yurko-Mauro K, McCarthy D, Rom D, Nelson EB, Ryan AS, Blackwell A, Salem N Jr, Stedman M; MIDAS Investigators. Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010 Nov;6(6):456-64.
A technical paper that discusses how Omega-3 fatty acids may aid patients with neurodegenerative conditions
Yoo KY, Choi JH, Hwang IK, Lee CH, Lee SO, Han SM, Shin HC, Kang IJ, Won MH. (-)-Epigallocatechin-3-gallate increases cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus in adult mice. Phytother Res. 2010 Jul;24(7):1065-70.
A technical paper that discusses how EGCG enhances neurogenesis
M. Hedlin 6/17/2011