Recent studies have revealed that changes occur in the brain’s white matter in pre-symptomatic people with Huntington’s disease. Specifically, the volume of white matter tends to be reduced in the brains of HD patients and pre-HD individuals. This article describes some recent research conducted on HD and white matter degeneration, as well as hypotheses of the mechanism by which this degeneration occurs.
What is white matter?^
The brain is made up of gray matter and white matter. While gray matter consists of neurons, white matter consists of glial cells and myelinated axons, and is responsible for transmitting messages from one part of the central nervous system to another. White matter is white in color because of myelin, a layer of fat coating the axons of neurons that helps action potentials move faster, like the insulation around an electric wire. White matter is located in the deep parts of the brain while gray matter makes up the outer surface of the brain. In the spinal cord, the other component of the nervous system, the location of white matter and gray matter is reversed; white matter surrounds the gray matter in the center. Approximately 60% of the brain is made up of white matter; the rest is gray matter.
What happens to the white matter in brains of those with HD or presymptomatic HD?^
Previously, it was known that gray matter in the basal ganglia deteriorates in the brains of HD patients. Recent studies suggest that white matter atrophy is also a neurological symptom of HD and may actually precede gray matter atrophy. Furthermore, there is white matter deterioration in the brains of presymptomatic HD individuals who do not yet display any symptoms of HD.
Paola et al. (2012) studied the corpus callosum in brains of subjects with HD, subjects with pre-HD, and healthy controls. Damage of the corpus callosum was a measure of disease progression. The researchers discovered that white matter degeneration in the corpus callosum seems to occur in a posterior (back of the brain) to anterior (front of the brain) direction. The brains of pre-HD subjects showed corpus callosum damage in the posterior parts of the corpus callosum, while the brains of HD subjects were damaged across the entire corpus callosum.
Ciarmiello et al. (2006) also found evidence of decreased brain white matter volume many years before symptoms of HD first appear. The study participants were individuals who tested positive for HD with a range of disease progression, from presymptomatic through stage V. The subjects, including those that were presymptomatic, had significantly smaller white matter volumes than those of control subjects. Furthermore, the researchers discovered an inverse relationship between the degree of white matter degeneration in individuals with presymptomatic HD and estimated time to onset of disease, suggesting that white matter degeneration may be a marker for onset of HD.
To study white matter degeneration, scientists used a variety of neuroimaging techniques, including magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) in order to detect change in volume. (For more on neuroimaging, click here: http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/neuroimaging/)
Why does white matter break down, and what is its relationship with HD pathology?^
One hypothesis for the mechanism behind white matter degeneration in HD is demyelination. The myelin of particularly heavily myelinated axons breaks down prematurely in HD patients. One explanation for this is that axons with thicker myelin sheaths depend more heavily on myelin basic protein – an important protein in myelin that helps to maintain the structure of myelin – than axons with thinner myelin sheaths do. Production of myelin basic protein is normally supported by brain-derived neurotrophic factor (BDNF), whose production is supported by the normal huntingtin protein. Production of BDNF decreases drastically as a result of mutant huntingtin (For more information on BDNF, click here: http://web.stanford.edu/group/hopes/cgi-bin/hopes_test/brain-derived-neurotrophic-factor-bdnf/), which results in decreased production of myelin basic protein, which in turn decreases the stability of myelin such that it breaks down more readily. This is one potential mechanism that needs to be tested in the lab.
Further research is needed to explore and understand the effects of white matter degeneration on HD. Since white matter begins to deteriorate years before HD symptoms first appear, targeting this process could be one potential mechanism to delay progression and/or treat symptoms, although the exact relationship between white matter degeneration and HD symptoms remains unclear.
For further reading^
1. Bartzokis, G., Lu, P. H., Tishler, T. A., Fong, S. M., Oluwadara, B., Finn, J. P., … & Perlman, S. (2007). Myelin breakdown and iron changes in Huntington’s disease: Pathogenesis and treatment implications. Neurochemical Research, 32(10), 1655-1664.
This article describes the process of myelin breakdown/demyelination.
2. Di Paola, M., Luders, E., Cherubini, A., Sanchez-Castaneda, C., Thompson, P. M., Toga, A. W., … & Sabatini, U. (2012). Multimodal MRI analysis of the corpus callosum reveals white matter differences in presymptomatic and early Huntington’s disease. Cerebral Cortex.
This article describes white matter degeneration in the corpus callosum of individuals with HD, individuals with pre-HD, and healthy individuals. This article is fairly technical.
3. Rosas, H. D., Lee, S. Y., Bender, A. C., Zaleta, A. K., Vangel, M., Yu, P., … & Hersch, S. M. (2010). Altered white matter microstructure in the corpus callosum in Huntington’s disease: implications for cortical “disconnection”. NeuroImage, 49(4), 2995-3004.
This article describes corpus callosum changes in HD in detail and is a fairly technical article.
4. Ciarmiello, A., Cannella, M., Lastoria, S., Simonelli, M., Frati, L., Rubinsztein, D. C., & Squitieri, F. (2006). Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. Journal of Nuclear Medicine, 47(2), 215-222.
This is another article on white matter changes in presymptomatic HD.
Lithium is a soft, light metal that is used in various industries, including in the production of ceramics, glass, and batteries. It is found in trace amounts in all living organisms. While it is not necessary for survival, lithium does play some role in the human body since the lithium ion (Li+ ) has neurological effects. In medicine, Li+ is used to treat psychiatric disorders, specifically to stabilize mood and treat mania symptoms of bipolar disorder, a mood disorder characterized by alternating episodes of depression and mania.
The method by which lithium affects the brain to influence mood remains unclear but several mechanisms have been suggested. Scientists believe that lithium could stabilize mood by regulating levels of glutamate, the main excitatory neurotransmitter in the brain (For more on glutamate, click here.), or by interacting with nitric oxide, a gaseous signaling molecule. It could also work by altering the body’s circadian rhythm (biological clock).
HD and Lithium
In recent years, researchers have investigated lithium as a potential treatment for HD because of its ability to regulate glutamate levels. Several studies have evaluated the effects of lithium on rat models of HD.
In the Wei et al. (2001) study, rats were injected with a lithium solution or with a control saline solution daily. After 16 days, the researchers infused the rats’ brains with quinolinic acid (QA), a chemical that has neurotoxic effects and is an agonist that activates the glutamate NMDA receptors. QA injections produce rats with lesions that lead to HD-like symptoms because one potential cause of HD pathology is over-activation of NMDA receptors due to high concentrations of glutamate. This over-activation can cause neuron death. Results showed that the brains of rats that received pre-treatment with lithium contained significantly smaller lesions (40-50%) than those treated with the control solution. Since lithium inhibits excessive NMDA receptor function, it could potentially counteract over-activation of NMDA receptors that occurs in the HD brain (For more on NMDA receptors and its role in HD, click here.). Nevertheless, it remains unclear how long the rats must be treated with lithium in order to sustain these positive effects. Future studies need to be conducted to answer this question.
Another study by Senatorov et al. (2004) used a similar QA-infused rat model of HD but instead injected rats with either lithium or saline control twice, once 24 hours prior to, and 1 hour after, QA infusion. Seven days later, lithium treatment again decreased lesions by 40% as compared to the control. In addition to its role in preventing neuronal death, the researchers believe lithium also has ability to produce new neurons in the hippocampus, a brain area involved in learning and memory.
Lithium has numerous side effects and can be toxic at high doses. The most common side effects are nausea, headaches, and hand tremor. Because lithium is a salt, it can also cause electrolyte imbalance and dehydration.
Research on lithium and HD is still in its early stages, as studies with HD patients have yet to be conducted. However, research on lithium in rat models of HD has yielded promising results so far.
For further reading:
1. Wei et al. “Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington’s disease.” Neuroscience, Volume 106, Issue 3, 27 September 2001, Pages 603-612.
2. Senatorov et al. “Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington’s disease.” Molecular Psychiatry (2004) 9, 371–385.
– A. Zhang, 08-21-12
What are clinical trials?
In order for any drug or treatment to be approved for human use by the FDA, it must first successfully pass clinical trials. A clinical trial is a medical or health-related research study in humans that follows a strict protocol in a carefully monitored, scientifically controlled setting. Clinical trials are generally conducted after a drug or treatment has shown promise in research studies using animal models.
What are the different types of clinical trials?
There are four main types of clinical trials: treatment trials, prevention trials, diagnostic trials, and screening trials.
- Treatment trials test the effects of new drugs, new combinations of drugs, or new procedures used to treat an illness or condition. Participants in this type of trial would already experience symptoms of HD and could be in any stage of HD.
- Prevention trials aim to prevent or delay onset of a disease in people who are at risk and test the effects of treatments that do so. Participants in this type of trial would be pre-symptomatic HD patients, usually people who have tested positive for the HD gene but have not yet exhibited any symptoms.
- Diagnostic trials are conducted to discover better procedures to diagnose an illness or disease.
- Screening trials are conducted to discover better ways to detect an illness or disease.
Diagnostic and screening trials are not needed to diagnose HD since current genetic tests can reliably and accurately identify HD. However, these types of trial design may be useful to research presymptomatic measures of HD disease progression and/or develop ways to better assess disease risk in the intermediate range where definitive genetic diagnosis is not currently possible. For more on genetic testing of HD, click here.
Clinical trials are conducted in phases.
- In Phase I trials, researchers first test a new treatment on a small group of individuals, typically 20-80 people, to evaluate its safety, determine a safe dosage range, and to identify side effects.
- Once the treatment passes Phase I trials, Phase II trials are conducted on more people, around 100-300 people, to see if it is effective and to further evaluate its safety and side effects.
- Once Phase II trials are completed successfully, the drug moves onto Phase III trials, in which researchers confirm the drug’s effectiveness, monitor any side effects, compare it to standard treatments, and collect information that will allow the experimental drug or treatment to be used safely long-term.
- Only after the drug or treatment has passed all phases will it be approved by the government.
For more information on the different phases of clinical trials, click here.
All clinical trials have criteria specifying who can or cannot participate. There are many risks and benefits to participating in a clinical trial. For example, participants contribute to medical research, have access to medical care, and if assigned to the treatment group, are given new potential treatments throughout the trial. However, participants may also experience negative side effects as a result of participating, or they may receive a placebo. Clinical trials must follow strict ethical codes and are highly regulated to ensure the safety of participants as much as possible.
What is the Huntington Study Group?
The Huntington Study Group (HSG) is an international non-profit group whose aim is to support clinical research of Huntington’s disease (HD). It was formed in 1993 and has members and research sites in the US, Canada, Europe, Australia, New Zealand and South America. The HSG often partners with pharmaceutical companies, private foundations, and government agencies to fund research investigating the effects and safety of HD interventions. (For more information on the HSG, click here).
Ongoing Studies that are Currently Enrolling Participants
2CARE is a phase III trial that aims to study coenzyme-Q10 as a potential treatment for HD. For more on coenzyme-q10, click here. The study aims to measure the effectiveness of coenzyme q-10 in slowing the symptoms of HD and to study the long-term safety of administering the compound to people with HD. Previous studies have shown that coenzyme q-10 slightly slowed the progression of HD, but not enough to yield significant results. Compared to these previous studies, 2CARE uses a much higher dosage for a longer time period. To date, it will be the largest therapeutic clinical trial of HD, with expected enrollment of over 600 in the United States, Canada, and Australia. The study began in March of 2008 and is expected to be completed by April 2014. 2CARE is a double blind placebo study, in which participants are randomly assigned to one of two groups. The experimental treatment group will receive oral administration of coenzyme q10 in chewable form twice a day, for a total of 2400 mg/day. In a preliminary study called Pre2CARE, dosages ranging from 1200 to 3600 mg/day were tested; 2400 mg/day appeared to be the most effective dosage, as smaller dosages were not as effective, and larger dosages resulted in the mildly unpleasant side effect of upset stomach. Researchers will compare total function capacity (TFC) scores, tolerability, adverse events, vital signs, and laboratory test results between the two groups.
The Huntington Study Group (HSG), Massachusetts General Hospital, and the University of Rochester are currently conducting a phase III clinical trial to assess the effects of creatine supplements on slowing the progression of symptoms in HD patients. Creatine is a molecule naturally produced in the body and consumed in the diet, found mostly in meat. Previous studies conducted on transgenic mouse models have shown that mice supplemented with creatine displayed improved motor performance, diminished loss of brain mass, reduced huntingtin aggregates, and delayed neuronal death. The study is called the Creatine, Safety, Tolerability, & Efficacy in Huntington’s disease (CREST-E). Participants are randomly selected to receive either 40g per day of powdered creatine monohydrate or 40g per day of a placebo. The study is a fairly large clinical trial. It will involve 44 research centers from around the world and enroll up to 650 participants. The study will last 37 months and is estimated to be completed in December of 2014. (For the most updated information on this study, click here).
Earlier in 2009, the HSG received funding from the NIH to test the safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not yet show any motor symptoms. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials) and is a phase II trial. The study will be conducted at 10 clinical sites throughout the nation and is the first therapeutic research study in pre-manifest HD patients. Participants will be randomly assigned to experimental groups receiving 600, 1200, and 2400 mg/day of coenzyme q10. The principal investigators hope that this initial trial will lead to later trials that study the delay of HD.
Ongoing Studies that are No Longer Enrolling Participants
ACR16 is a dopamine stabilizer and can enhance or inhibit dopamine controlled functions. For more information on the role dopamine plays in HD, click here. The HSG is conducting a phase II clinical trial testing different doses of ACR16 on HD patients age 30 and older. HART is sponsored by NeuroSearch Sweden AB, a biopharmaceutical company, and is being conducted in 35 research sites across North America. Previous studies showed that ACR16 is safe and tolerable in patients with HD and Parkinson’s disease. Additionally, it has been shown to significantly improve patients’ voluntary and involuntary movements. Participants are randomly assigned to one of four groups-three experimental groups given different doses of ACR16 and a placebo group. The study occurs over a course of 12 weeks. As of October 2010, results have been promising, as patients in the highest dosage group (90 mg/day) displayed significant improvement in motor function as measured by the modified Motor Score (mMS).
Recently Completed Clinical Trials
HORIZON was a phase III clinical trial conducted by the HSG and the European Huntington’s Disease Network that investigated whether dimebon is safe and effective in improving cognitive abilities in patients with HD. Dimebon is an experimental drug that has been shown to prevent the death of brain cells in animal models and is currently being tested to treat HD and Alzheimer’s Disease. It is thought to work by stabilizing and improving function of the mitochondria. For more information on dimebon, click here. The study was conducted in various centers in the United States, Canada, Europe, and Australia. It was a double-blind, placebo study in which participants were either given 60 mg of Dimebon daily or a placebo. Results showed that dimebon is not effective in treating HD. There was no statistically significant difference in symptoms between the experimental and placebo groups. According to the president and chief executive officer of Medivation, development of dimebon in HD will be discontinued.
Minocycline is an antibiotic that is primarily used to treat acne and other skin disorders. For more on minocycline, click here. The goal of DOMINO was to assess whether minocycline was safe and effective in slowing HD progression and whether further studies should be conducted. The study is a phase II clinical trial that was started in 2006 and completed in November 2008 by the HSG with funding by the FDA Office of Orphan Products Development. It was a double-blind, placebo experiment in which participants were randomly assigned to a treatment group that received 100mg of minocycline twice daily or a placebo. The TFC scores of the two groups were then compared. Results showed that while minocycline was safely tolerated, it did not produce a significant effect in terms of delaying HD symptoms, and thus, further study of minocycline in treating HD is not warranted.
TREND-HD was a large phase III trial that began in September 2005 and was completed in August 2007. The goal of the study was to determine whether ethyl-EPA (Miraxion) slowed the progression of motor decline in HD patients. Ethyl-EPA is an omega-3 fatty acid commonly found in fish oil. Study participants had mild to moderate HD, meaning they displayed early signs of HD but were self-sufficient in daily living activities. For the first 6 months, the treatment group received ethyl-EPA while the placebo group received a placebo. For the next 6 months of the study, the placebo group was also given the active drug. Interestingly, there were no significant differences in Total Motor Scores between the two groups after the first 6 months of the placebo study. However, after the next 6 months in which all participants received the drug, the experimental group showed improvement as compared to the group that had initially received the placebo for the first 6 months. Further studies will need to be conducted to determine the efficacy of ethyl-EPA. There did not appear to be any safety concerns. After the study was completed, the investigators and sponsor of the study, Amarin Neuroscience Ltd., took the unprecedented step of telling the study participants about the results of the study by calling them and inviting them to a telephone conference regarding the study results. Study participants are typically not informed of the results of the clinical trials they participated in.
Huntington Study Group (HSG) and Prestwick Pharmaceuticals collaborated on a clinical trial. Called TETRA-HD involving tetrabenazine, a dopamine depletor. Led by Dr. Frederick J. Marshall from the University of Rochester Medical Center, TETRA-HD was a phase III clinical trial with the goal of determining the optimal dosage of tetrabenazine in treating chorea in people with HD. The trial was carried out at 16 different HSG sites in the United States, involving a total of 84 participants with HD. Fifty-four of the participants were randomly assigned to receive tetrabenazine for 12 weeks with increasing dosages over the first 7 weeks. The other 30 served as the comparison group and received a placebo. The results of the study indicated that tetrabenazine is effective in treating chorea with side effects that are less severe than those associated with other anti-choreic drugs. On the CGI Global Improvement Scale, 6.9% of the patients receiving placebo had more than minimal improvement compared to 45.1% of the patients receiving tetrabenazine. Clinical assessments showed that tetrabenazine was associated with drowsiness and insomnia in four patients, depressed mood in two, parkinsonism in two and akathisia in two. Most cases of adverse effects improved after adjusting dosage levels, but the risk of side effects should be considered. These results confirm the benefits of tetrabenazine usage in ameliorating the symptoms of chorea. In August 2008, the FDA approved tetrabenazine as the first drug for treatment of chorea, and it is used worldwide today.
For more information:
-A. Zhang, 7-5-11