Huntington's Disease Correlation of Body Research Proposal

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Creatine treatment started at 6, 8, and 10 weeks of age, analogous to early, middle, and late stages of human HD, significantly extended survival at both the 6- and 8-week starting points. Significantly improved motor performance was present in both the 6- and 8-week treatment paradigms, while reduced body weight loss was only observed in creatine-supplemented R6/2 mice started at 6 weeks." (Dedeoglu, et al., 2003) Specifically it is stated that the "...Neuropathological sequelae of gross brain and neuronal atrophy and huntington aggregates were delayed in creatine-treated R6/2 mice started at 6 weeks. We show significantly reduced brain levels of both creatine and ATP in R6/2 mice, consistent with a bioenergetic defect. Oral creatine supplementation significantly increased brain concentrations of creatine and ATP to wild-type control levels, exerting a neuroprotective effect. These findings have important therapeutic implications, suggesting that creatine therapy initiated after diagnosis may provide significant clinical benefits to HD patients." (Dedeoglu, et al., 2003)

VII. Ferrante et al. (2002)

The work of Ferrante et al. (2002) entitled: 'Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington's Disease" states that there is "...substantial evidence that bioenergetic defects and excitotoxicity may play a role in the pathogenesis of Huntington's disease (HD). Potential therapeutic strategies for neurodegenerative diseases in which there is reduced energy metabolism and NMDA-mediated excitotoxicity are the administration of the mitochondrial cofactor coenzyme Q10 and the NMDA antagonist remacemide." (2003) Ferrante et al. states that they found "...that oral administration of either coenzyme Q10 or remacemide significantly extended survival and delayed the development of motor deficits, weight loss, cerebral atrophy, and neuronal intranuclear inclusions in the R6/2 transgenic mouse model of HD. The combined treatment, using coenzyme Q10 and remacemide together, was more efficacious than either compound alone, resulting in an approximately 32 and 17% increase in survival in the R6/2 and N171-82Q mice, respectively." (Ferrante et al., 2003) This study reports that magnetic resonance imaging "...showed that combined treatment significantly attenuated ventricular enlargement in vivo. These studies further implicate defective energy metabolism and excitotoxicity in the R6/2 and N171-82Q transgenic mouse models of HD and are of interest in comparison with the outcome of a recent clinical trial examining coenzyme Q10 and remacemide in HD patients." (Ferrante et al., 2003)

VIII. Aziz et al. (2008)

The work of Aziz, et al. (2008) entitled: "Weight Loss in Huntington Disease Increases with Higher CAG Repeat Number" states that Huntington Disease (HD) is a hereditary neurogenerative disorder "...caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown." Aziz et al. reports that in order to understand the mechanisms underlying weight loss in Huntington's Disease, they studied "its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number." (2008) the study involved 517 patients in the early stages of Huntington's Disease and "applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington's Disease Rating Scale (UHDRS)." (Aziz, et al., 2008) Additionally assessed was the "...relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD." (Aziz, et al., 2008) Results of the study report: "In patients with HD, mean body mass index decreased with -0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length." (Aziz, et al., 2008) Conclusions state that weight loss in Huntington's Disease "...
is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics." (Aziz, et al., 2008)

IX. Goodman et al. (2008)

The work of Goodman, et al. (2008) published by the Cambridge Center for Brain Repair entitled: "The Metabolic Profile of Early Huntington's Disease - a Combined Human and Transgenic Mouse Study" reports that Huntington's disease (HD) is a "...debilitating autosomal dominant, neurodegenerative disease with a fatal prognosis. Classical symptoms include motor disturbances, subcortical dementia and psychiatric symptoms but are not restricted to this triad. Patients often experience other problems such as weight loss, although why and when this occurs in the disease course is not known." This study focused on metabolism and its use in "whole body indirect calorimetry in both early stage HD patients and in the R6/2 transgenic mouse model of HD, at times before and after they displayed signs of disease." (Goodman, et al., 2008) Through use of the combined approach this study found "...that patients with early HD tended to be in negative energy balance for reasons not related to their movement disorder, which was paralleled in the transgenic R6/2 mice. These mice had significantly elevated total energy expenditure as they developed overt disease with weight loss due primarily to a loss of muscle bulk." (Goodman, et al., 2008) This study states findings that "in HD there is the development of early negative energy balance, which in turn may cause weight loss with loss of muscle bulk in particular. The reason for this is not known but may reflect a catabolic state secondary to hypothalamic pathology, as abnormalities have been reported in the hypothalamus early in the disease course." (Goodman, et al., 2008)

X. van der Burg et al. (2008)

The work of van der Burg, et al. (2008) entitled: "Increased Metabolism in the R6/2 Mouse Model of Huntington's Disease" relates that Huntington's disease (HD) is a hereditary disorder characterized by personality changes, chorea, dementia and weight loss. The cause of this weight loss is unknown." Van der Burg et al. (2008) reports a study with the aim being the examination of "...body weight changes and weight-regulating factors in HD using the R6/2 mouse model as a tool." This study states in its findings that "...R6/2 mice started losing weight at 9 weeks of age. Total locomotor activity was unaltered and caloric intake was not decreased until 11 weeks of age, which led us to hypothesize that increased metabolism might underlie the weight loss." (van der Burg, et al., 2008) This study found that oxygen consumption in R6/2 mice "...was elevated from 6 weeks of age, indicative of an increased metabolism. Several organ systems that regulate weight and metabolism, including the hypothalamus, the stomach and adipose tissue displayed abnormalities in R6/2 mice. Together, these data demonstrate that weight loss in R6/2 mice is associated with increased metabolism and changes in several weight-regulating factors." (van der Burg, et al., 2008)


NINDS Huntington's Disease Information Page (2009) National Institute of Neurological Disorders and Stroke. Online available at

Hamilton, J.M., et al. (2004) Rate and Correlates of Weight Change in Huntington's Disease. Journal of Neurology Neuroscience and Psychiatry 2004; 75:209-212. BMJ Publishing Group Ltd. Online available at

Gaba, Ann M. et al. (2005) Energy Balance in Early-Stage Huntington Disease. American Journal of Clinical Nutrition, Vol. 81, No. 6. June 2005.

Djousse, L. (2002) Weight Loss in Early Stage of Huntington's Disease. Journal of Neurology 2002. Nov. 12:59(9): 1325-30.

Sandoff, JA et al. (2003) Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model.....

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