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White Matter and HD

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.

brain

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.

Conclusion^

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 diseaseCerebral 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”. NeuroImage49(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 Medicine47(2), 215-222.

This is another article on white matter changes in presymptomatic HD.

-A. Zhang, 5-26-13

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Lithium

Background

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).

circadian_rhythm

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.

Side Effects

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.

Conclusion

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

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