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://www.stanford.edu/group/hopes/cgi-bin/wordpress/2012/04/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://www.stanford.edu/group/hopes/cgi-bin/wordpress/2010/06/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.
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.
-A. Zhang, 5-26-13