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. Author manuscript; available in PMC: 2010 Jan 29.
Published in final edited form as: Ann N Y Acad Sci. 2008 Dec;1147:196–205. doi: 10.1196/annals.1427.034

COMPLEXITY AND HETEROGENEITY: WHAT DRIVES THE EVER-CHANGING BRAIN IN HUNTINGTONS DISEASE?

H Diana Rosas 1,2,3, David H Salat 2,3, Stephanie Y Lee 1,2,3, Alexandra K Zaleta 1,2,3, Nathanael Hevelone 4, Steven M Hersch 1
PMCID: PMC2813569  NIHMSID: NIHMS58197  PMID: 19076442

Abstract

Significant advances are being made in our understanding of basic pathophyiological and biochemical mechanisms that cause HuntingtonÕs disease (HD). There is increasing reason to believe that pathologic alterations occur in the brain for years before symptoms manifest. The “classic” hallmark of neuropathology in HD is selective neurodegeneration in which vulnerable populations of neurons degenerate while less vulnerable populations are spared. While, the earliest and most striking neuropathologic changes have been found in the neostriatum, neuronal loss has been identified in many other regions of the brain. We report topologically selective, early, and progressive changes in the cortex, striatum, extra-striatal brain structures and white matter throughout the spectrum of disease. Our growing understanding of HD underscores the reality that points to the complexity of HD. A single, well-defined genetic mutation causes a cascade of events whose final result is an aggregate insult of the homeostatic process. We explore possible explanations for the selective vulnerability of the brain in HD.

The ultimate goal in HD is to develop disease-modifying therapies that will prevent the onset of clinical symptoms in those individuals who are at risk and slow the progression of symptoms in those individuals already affected with symptoms. Understanding changes in brain morphometry and their relationship to clinical symptoms may provide important new and important insights into basic pathophysiological mechanisms at play in the disease.

Keywords: Huntington’s disease, cortex, neurodegeneration, pre-manifest HD, sub-cortical atrophy, white matter degeneration, oxidative stress, circuitry

Background

Huntington’s disease (HD) is a fully penetrant autosomal dominant inherited neurodegenerative disorder that is characterized by progressive motor dysfunction, emotional and psychiatric disturbances, cognitive dysfunction, and weight loss. HD occurs worldwide in all races and ethnic groups 1. Its prevalence is 5–10 cases per 100,000, and there is a new mutation rate as high as 1–3% 2. There are about 30,000 affected individuals in North America while another 150,000 have a genetic risk for developing the disease. The average age of clinical onset is about 37 years of age, however the range is from infancy into the 80’s. Affected individuals are rapidly disabled by early functional decline and require multidisciplinary care and supervision for another 15–25 years before succumbing to the effects of severe physical, psychiatric and mental deterioration. There is no therapy proven to delay onset or slow progression, and current medical care focuses on symptom management and maximizing function 35. Progressive functional, cognitive, and physical decline leads to increasingly intense levels of care, creating a disproportionate strain on family and healthcare resources

The HD gene, first cloned in 1993 6 codes for a large, highly conserved, protein of unknown function (“huntingtin”) containing 3144 amino acids. In individuals with HD, a polymorphic trinucleotide repeat sequence (CAGn), near the 5′ end of the gene, is expanded beyond the normal repeat range 6, leading to translation of an expanded polyglutamine sequence in the protein. In the normal population the number of CAG repeats varies from 17 to 29. In individuals with HD there are more than 38 repeats; there is reduced penetrance for CAG repeats between 36 and 397. The CAG repeat also exhibits dramatic instability when transmitted to subsequent generations 8; repeats between 27 and 35 are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents 9. Once expanded into the pathogenic ranges, there is an inverse relationship between the CAG repeat number and the age of onset 10, while a correlation with progression has not been demonstrated. Even for a specific CAG repeat, there is considerable heterogeneity in the actual “time to onset”; the CAG repeat accounts for only 50–65% of the variance in age of onset 11. Other genetic modifiers are currently being sought.

“The basics”: What is known

The hallmark of neuropathology in HD is selective neurodegeneration in which vulnerable populations of neurons degenerate while less vulnerable populations are spared 12. The earliest and most striking neuropathologic changes are found in the neostriatum 13 but neuronal loss has been identified in may other regions of the brain 14. Proliferative and degenerative changes in vulnerable neurons 14, 15 suggest that the presence of mutant huntingtin leads to both compensatory and degenerative genetic programs in a prolonged process leading to neuronal dysfunction and death 14, 16(20).

Altered synaptic plasticity in the R6/2 mouse model of HD occurs prior to the more overt disease phenotypes 17, indicating early synaptic pathology in the disease. Morphological changes occur in medium spiny neurons of the striatum and in cortical pyramidal cells prior to degeneration, including dendritic remodeling and altered size and number of dendritic spines 14, 18. This suggests that these neurons undergo a period of stress and injury prior to perishing. It is important to consider that cortical degeneration and cell death follows cortical dysfunction 19.

Although many leads have been uncovered, a direct pathway from the genetic mutation to neuronal dysfunction and death has not yet been established. Huntingtin is a widely expressed, predominantly cytoplasmic, protein of unknown function found heterogeneously in neurons throughout the brain 12, 20, 21. In HD, both normal and mutant alleles are expressed and both gain of function alterations in which mutant huntingtin is toxic and loss of function alterations 22, 23 in which suppression of normal huntingtin functions might also be toxic have been identified. Proteolysis of mutant huntingtin, whereby an abnormal and ultimately toxic N-terminus fragment of huntingtin is released, may play a role in causing disease 2426. This fragment has been shown in humans and in animal and cellular models to form protein aggregates in the nucleus, cytoplasm, and processes of neurons 12, 27. These aggregates induce chaperone expression and become ubiquitinated yet persist, indicating protein misfolding and failed proteolysis 28.

Huntingtin aggregates also sequester a variety of other proteins including chaperones 29 proteasomal proteins 30, normal huntingtin 31, and transcription factors 3234 35, another means of disturbing protein homeostasis. These aggregates can be readily detected in the brains of individuals at risk for HD who died prior to exhibiting any symptoms and in brains from individuals who died throughout the course of the disease 12 36. While the role of huntingtin aggregates continues to be debated 37, most evidence continues to point to a proximal toxicity residing in mutant huntingtin or its proteolytic fragments and their interactions with other proteins, including huntingtin itself or the dozens of other proteins that have been demonstrated to associate with huntingtin or huntingtin aggregates, including a number of transcription factors which have been implicated in widespread transcriptional alterations that appear to occur in HD. Several recent studies have also suggested that the transcriptional alterations that occur in human brain are variable across cortical regions, providing one more clue to selective vulnerability that requires further investigation 38, 39.

The connection with mitochondrial dysfunction

In postmortem studies, severe deficiencies in mitochondrial complex II and III and sometimes complex IV have been reported in the striatum 40, 41. Inhibition of complex II may impart dysfunction by reducing the levels of complex II/succinate dehydrogenase subunits and result in diminished activity. A decrease in succinate oxidation has also been shown to occur in the striatum 42, 43. Dysfunction of complex I has been reported in human blood in HD 44 and expression of sub-units of mitochondrial complex-I have been found to be reduced in HD brain 45. Elevated lactate levels have also been shown to correlate with CAG repeat length in HD occipital cortex and in striatum 46, 47.

Mutant huntingtin might also exert direct negative effects on mitochondria, through physical interaction with the huntingtin protein or its fragments. Mutant huntingtin has been localized to neuronal mitochondrial membranes and incubation of mutant mitochondria with normal mitochondria results in depolarization of the mitochondrial membrane at lower Ca2+ loads 48, 49. Neuronal dysfunction could subsequently occur secondary to disruption of the mitochondrial membrane potential, excitotoxic induced CA 2+ influx 50 and diminished ATP production. Mitochondrial dysfunction and secondary energy (ATP) depletion could subsequently lead further to unmitigated free radical production and cell death51, 52. There is broad evidence in human HD and in cellular and animal models that free radicals then cause cellular damage and up-regulated anti-oxidant responses in the brain and periphery53, 54.

Mitochondria are a major site of production of free radicals (reactive oxygen species) and primary targets of free radicals. Reactive oxygen species induce a variety of oxidative adducts of DNA and RNA. Hydroxy adducts of guanidine (DNA) or guanosine (RNA) are especially common, stable, and readily measured in tissues and tissue fluids. In DNA, hydroxy adducts induce repair (base excision or nucleotide excision) which is not always complete and is exhaustible because of oxidative injury to repair mechanisms. In situ, DNA adducts are mutagenic, causing substitutions, transcriptional blocks, and deletions which could contribute to transcriptional dysfunction in HD. 8OH2′dG (8-hydroxy 2-deoxyguanosine) is a hydroxy adduct of DNA that has been studied in HD55, 56. Levels of these hydroxy adducts in HD brain and blood are elevated dramatically; in particular, elevated levels of these adducts have been found in mitochondrial DNA isolated from human HD parietal cortex 57. Parenthetically, however, there was no evidence of oxidative damage to mitochondrial DNA from human cerebellum in the same study. This supports the notion that selective vulnerability of in HD, be it in neurons or astrocytes, for example, is directly tied into regionally specific pathophysiologic mechanisms and that further study of what drives this selectivity is extremely important.

Huntingtin is also appears involved in axonal trafficking 58, as shown in in vitro assays, and mutant huntingtin impairs trafficking of vesicles and mitochondria in transgenic mice 59 and in mammalian neurons 60. These changes are present prior to the onset of clinical symptoms, supporting a possible role of altered mitochondrial localization in axons in HD. Reactive oxygen species can also act as signaling molecules for transcription and therefore chronic exposure to free radicals in HD could activate cascades of genes. Peroxisome proliferators-activated receptor gamma co-activator (PGC-1 alpha) is a co-activator of several transcription factors and a potent stimulator of mitochondrial biogenesis and respiration whose altered expression has also been implicated in HD pathogenesis 45, 61.

A window into a complex biology

Modern neuro-imaging methods have been developed that provide a faster more reliable and sensitive method to study the entire brain 62, 63. They allow for a more comprehensive characterization of the progressive changes that occur in the brain in Huntington’s disease. A broader approach to understanding the selective vulnerability of distinct brain regions in HD is critical to understanding basic pathophysiological mechanisms. Much is not known, but it is becoming increasingly clear that the striatum, while severely affected in HD, is only a small piece of the puzzle and cannot fully, in isolation, explain the varied and progressive symptoms of HD.

Alterations in brain anatomy in HD are complex and begin very early. Striatal atrophy is known to begin more than a decade before motor symptoms develop 64; by the time of diagnosis, the striatum may be atrophied by as much as 50% 65. More recently, it has become clear that other brain regions also begin to atrophy during the pre-manifest period, more than a decade before a clinical diagnosis. This may reflect in part the capacity of the brain to compensate during periods of neuronal dysfunction 6668 by recruiting other brain 69. Neuronal death unfortunately is at present inevitable in HD. Elucidating the specific relationships between selective brain degeneration and clinical symptoms becomes all the more important as targeted therapies are developed.

The cortex has been little explored in HD but by end-stage, the entire brain is atrophic. We have found that the cortex begins to atrophy during the pre-manifest period, as shown in Figure 1. It is significant, as compared to age and gender matched controls subjects, occurs in some regions while others appear spared, and corresponds to loss of approximately the cortical thickness of approximately 5 to 10%. The areas that appear the most affected in these pre-manifest subjects correspond to sensori-motor (approximating BA areas 4, 6, and 8), superior parietal (approximating BA7), superior temporal (approximating BA areas 22, 41, 42), middle and inferior temporal, occipital (approximating BA 17, 18, 19) and precuneus (approximating BA 31), and occipital cortical areas 70. In contrast, there was no significant reduction in whole brain volumes in this group (p=0.46); this supports the importance of a fine-grained approach to the study of brain morphometric changes in HD. By looking too globally, we may miss important and clinically relevant changes. When this group of subjects was further stratified according to years from estimated onset (further > 12 years, closer < 12 years) 71, subjects further from onset show thinning in portions of motor, precuneus, superior temporal and occipital. Additional areas were thinned in the group closer to onset including parietal, other regions of occipital and more posterior regions of the superior frontal cortex. Interestingly, the anterior cingulate appeared thicker.

Figure 1.

Figure 1

Topologically selective thinning occurs in Pre-manifest Huntington’s disease. A. Surface maps of cortical thinning were generated by using a general linear model at each vertex across the entire mantle in 31 gene-carriers without symptoms of HD. Significant cortical thinning was present in sensor-motor, parietal, superior temporal, entorhinal, precuneus, occipital and portions of frontal cortex. B. Thickness maps of individuals greater than 12 years to expected onset; thinning is already present over the portions of superior temporal, motor, precuneus and entorhinal cortical regions. C. Thickness maps of individuals less than 12 years to expected onset; thinning is much more extensive, and begins to involve occipital, parietal, cuneus, posterior frontal cortical areas. Maps are presented on a semi-inflated cortical surface of an average brain. The color scale at the bottom represents the significance of the thickness change, transitioning from red (p<0.05) to yellow (p<0.001).

Early symptomatic HD subjects showed thinning of other cortical regions, to encompass more of posterior frontal areas as well as more of the occipital and parietal areas. This suggests a pattern of degeneration, starting with primary cortical regions, areas which subserve simpler functions, including motor, sensory and visual cortical regions, with progression to include uni-modal areas, regions that discriminate, categorize and integrate information within a single modality to form a precept of the same modality, and subsequently of hetero-modal multi-association cortical regions, regions whose central role is in the integration of precepts from various modalities to form complex multi-modal precepts 72. It is of note that more anterior frontal, middle and inferior temporal areas appeared relatively preserved in early HD. It is also interesting the anterior cingulate also appeared thicker in early symptomatic HD subjects; increases in microglial activation have been reported in this region in HD 68. Motor and occipital cortical regions were also more thinned, corresponding to a loss of the cortical mantle of approximately 30% in these regions.

These are very preliminary models that must be validated with longitudinal studies. There are several points on which to comment, however. First, even within gyral regions, specific regions of a gyrus appeared thinned while other regions of the gyrus appeared to remain unaffected. In the motor cortex, for example, in more superior regions thinning was more significant and extensive in the most superior regions, and less so in more inferior regions. Secondly, when we took into account cortical changes that might be related to striatal volume, we found regions of thinning that were independent, as shown in Figure 2. Because the cortex and striatum are so interconnected, it may be difficult to determine if cortical degeneration precedes or follows striatal atrophy, but our findings suggest that distinct mechanisms may also be present. Cortical thinning may reflect not only neuronal loss but also the dysmorphology and loss of dendrites and axons and associated connections that occur 73.

Figure 2.

Figure 2

Topologically selective thinning in Early symptomatic HD: extension of changes seen in Pre-manifest subjects. A. Surface maps of cortical thinning were generated by using a general linear model at each vertex across the entire cortical mantle. In Stage I and Stage II subjects, significant thinning was present in sensor-motor, parietal, posterior superior and middle frontal, enthorhinal, precuneus, cuneus and occipital cortical areas. Maps are presented on a semi-inflated cortical surface of an average brain. The color scale at the bottom represents the significance of the thickness change, transitioning from red (p<0.01) to yellow (p<0.00005). B. After adjusting for striatal volume, significant thinning of the cortex was still present over occipital, parietal, and precuneus, suggesting some degree of independence between striatal and cortical pathology.

It is also very important to emphasize that it appears that no brain structure is spared in HD and that extensive changes in several other structures are present very early as well. In pre-manifest subjects greater than 12 years to estimated onset, we have found reductions in the volumes of not only the striatum (approximately 20%), but also of the amygdala, thalamus, hippocampus, and white matter. Parenthetically, we and others have shown that white matter changes are also regionally selective, significant and potentially important in HD7476. As shown in Figure 3, a complex, topologically selective pattern emerges if considers progressive changes that span a continuum from pre-manifest through to advanced HD.

Figure 3.

Figure 3

Bar-graphs demonstrating changes in the volumes of several other brain regions, spanning from pre-manifest individuals greater than 12 years to estimated onset through Stage III HD. A complex pattern of progressive changes emerges that also demonstrates the extensive involvement of brain structures in HD.

The precise relationship between topological alterations in brain structures and clinical symptoms of HD remains to be elucidated. Attempts to ascribe the symptoms of HD to striatal degeneration or to dysfunction of cortico-striatal circuity have been unsatisfying. Striatal degeneration alone, does not adequately explain the clinical symptoms of HD, that are highly variable, individual and neurologically complex. At the time of diagnosis, more than half of the striatum has degenerated, yet symptoms, which encompass multiple clinical domains, continue to progress. A growing body of evidence suggests that the natural history of gradually progressive motor and cognitive dysfunction in HD, which may begin years prior to a clinical diagnosis, based on unequivocal motor signs of HD77, is related to regionally specific changes of many diverse brain regions 65, 70, 78, 79 that include striatum and cortex.

The relationship between cortical atrophy and cognitive dysfunction has only recently and cursorily been investigated 80, 81. Others have focused on neuropsychiatric symptoms 82. We have found distinct relationships between regionally specific cortical degeneration and worsening performance on the cognitive and functional components of the UHDRS 72. Selective degeneration of specific cortical regions may explain some of the clinical heterogeneity. In some patients, psychiatric symptoms are early and debilitating, in others, cognitive dysfunction and in yet others chorea. Motor symptoms can also be quite variable, with some individuals showing the more typical chorea, while in others bradykinesia and dystonia are more prominent. In HD subjects with more prominent Parkinsonism, we have found more significant thinning in frontal cortical regions, specifically affecting portions of pre-motor and supplementary motor cortex 72. Of note, in patients with Parkinson’s disease, a disease characterized by akinesia, bradykinesia and hypokinesia, functional imaging studies have shown hypoactivity of the mesial premotor and prefrontal areas 83.

Summary

What emerges is a greater understanding that a single well-defined genetic expansion results in a complex cascade of biological events that ultimately leads to selective degeneration of the brain. Proximal events mediated by mutant huntingtin in turn trigger cascades of both damaging and compensatory molecular processes and genetic programs in which oxidative injury, and energy depletion appear to play major roles. Much remains to be elucidated. Refocusing attention on the human disease, the natural progression of the disease and how associated brain changes result in clinical symptoms may provide a critical window into basic mechanisms that are involved in Huntington’s disease.

Acknowledgments

We are very grateful to our patients and families, who so generously contributed their time and energy to this work, and without whom it would not have been possible. Thanks to Drs. Anne Young and Nancy Wexler for their continued support and encouragement. Funding for this work was provided by the National Institutes of Health, National Institute for Neurological Disorders and Stroke (NS042861, NS045242, P01NS058793), National Center for Complementary and Alternative Medicine (AT000613), the National Institute on Aging (NIAAG024898) and the High Q Foundation.

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