| 1. |
- Aziz, N. A., et al.
(author)
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Weight loss in Huntington disease increases with higher CAG repeat number
- 2008
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In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 71:19, s. 1506-1513
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Journal article (peer-reviewed)abstract
- Objective: Huntington disease (HD) is a hereditary neurodegenerative 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. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number. Methods: In 517 patients with early stage HD, we 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). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD. Results: 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. Conclusions: Weight loss in Huntington disease (HD) 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. Neurology (R) 2008;71:1506-1513
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| 2. |
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| 3. |
- van der Burg, Jorien m
(author)
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Beyond the basal ganglia
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Huntington’s disease (HD) is a fatal, hereditary disorder caused by a mutation in the gene encoding the protein huntingtin. Although mutant huntingtin is ubiquitously expressed throughout the body, HD research has mainly focused on the role of the basal ganglia. Dysfunction of these brain nuclei likely underlies motor disturbances in HD, including the conspicuous, uncontrollable, dance-like movements (chorea). However, HD is frequently complicated by other important signs and symptoms that cannot, or not solely, be attributed to basal ganglia dysfunction. Among these is unintended weight loss, which occurs in nearly all HD patients and can affect both quality of life and disease progression. Other symptoms that might occur irrespective of basal ganglia dysfunction are cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and atrophy of skeletal muscle. The past decade has seen an increasing interest in the role of mutant huntingtin in other areas of the brain and body. Although these effects are still poorly understood, their study could lead to a better understanding of the pathological mechanisms underlying HD, as well as to the identification of novel markers of disease progression and therapeutic options. The aim of this thesis was, therefore, to investigate the effects of mutant huntingtin outside the basal ganglia, especially those structures that might underlie weight loss in HD, including the hypothalamus, adipose tissue, and the gastro-intestinal tract. We found that weight loss in both HD patients and R6/2 mice (a transgenic model of HD) is not caused by changes in caloric intake or locomotor activity. Metabolism was, however, increased in R6/2 mice and this may be the cause of weight loss. Interestingly, weight loss increases with higher CAG repeat number in the mutant gene in both HD patients and R6/2 mice. This suggests that mutant huntingtin affects metabolic rate in a CAG repeat length dependant manner. The mechanism underlying this is unclear, but several regulators of metabolism, including the hypothalamus, were affected in R6/2 mice. In addition, the gastro-intestinal tract is affected in both HD patients and R6/2 mice and malabsorption of nutrients was observed in end-stage R6/2 mice. Although gastro-intestinal dysfunction is unlikely to be the cause of weight loss in HD, it may play an important role in the acceleration of weight loss in the final stages of the disease. The findings in this thesis demonstrate that mutant huntingtin does not only affect the areas that have traditionally received the most attention in HD research, i.e. the basal ganglia. Other areas in the brain and body, such as the hypothalamus and gastro-intestinal tract, are also affected. Dysfunction of these structures could account for weight loss as well as several other, yet poorly understood, signs and symptoms of HD. Elucidation of the role of mutant huntingtin throughout the body could provide a better understanding of HD pathogenesis, lead to the development of novel markers of disease progression, and open new avenues for treatment.
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| 4. |
- van der Burg, Jorien m, et al.
(author)
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Gastrointestinal dysfunction contributes to weight loss in Huntington's disease mice.
- 2011
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 44, s. 1-8
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Journal article (peer-reviewed)abstract
- Weight loss is the most important non-neurological complication of Huntington's disease (HD). It correlates with disease progression and affects the quality of life of HD patients, suggesting that it could be a valuable target for therapeutic intervention. The mechanism underlying weight loss in HD is unknown. Mutant huntingtin, the protein that causes the disease, is not only expressed in the brain, but also along the gastrointestinal (GI) tract. Here we demonstrate that the GI tract of HD mice is affected. At the anatomical level we observed loss of enteric neuropeptides, as well as decreased mucosal thickness and villus length. Exploring the functions of the GI system we found impaired gut motility, diarrhea, and malabsorption of food. The degree of malabsorption was inversely associated with body weight, suggesting that GI dysfunction plays an important role in weight loss in HD mice. In summary, these observations suggest that the GI tract is affected in HD mice and that GI dysfunction contributes to nutritional deficiencies and weight loss.
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| 5. |
- van der Burg, Jorien m, et al.
(author)
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Increased metabolism in the R6/2 mouse model of Huntington's disease.
- 2008
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In: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 29:1, s. 41-51
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Journal article (peer-reviewed)abstract
- 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. The aim of this study was to examine body weight changes and weight-regulating factors in HD using the R6/2 mouse model as a tool. We found 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. Indeed, 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.
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| 6. |
- Wood, Nigel I., et al.
(author)
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Increased thirst and drinking in Huntington's disease and the R6/2 mouse
- 2008
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In: Brain Research Bulletin. - : Elsevier BV. - 0361-9230. ; 76:1-2, s. 70-79
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Journal article (peer-reviewed)abstract
- While Huntington's disease (HD) is a condition that primarily involves the basal ganglia, there is evidence to suggest that the hypothalamus is also affected. Because the osmoreceptors regulating thirst are situated in the circumventricular region of the hypothalamus, we were interested in whether altered thirst is a part of the HD phenotype. We used the LABORAS behavioural monitoring system and water consumption to show that drinking behaviour was abnormal in R6/2 mice. By 10 weeks of age, R6/2 mice spent significantly more time drinking and drank a greater volume than their wild-type (WT) littermates. The numbers of immunoreactive vasopressin neurons in the paraventricular nucleus (PVN) of the hypothalamus in R6/2 mice were significantly decreased from 8 weeks of age, suggesting that the change in drinking behaviour may be the result of hypothalamic dysfunction. We gave a xerostomia (dry mouth) questionnaire to HD patients and control subjects, and also measured their urine osmolality and serum vasopressin. The mean total xerostomia score was significantly higher in HD patients than in controls, indicating greater thirst in HD patients. Urine osmolality was unaffected in HD patients up to clinical stage 111, and none of the patients had diabetes. However, serum vasopressin was increased, suggesting a dysregulation in the control of hypothalamic vasopressin release. A dry mouth can affect taste, mastication and swallowing, all of which may contribute to the significant weight loss seen in both HD patients and R6/2 mice, as can dehydration. We suggest that increased thirst may be an important and clinically relevant biomarker for the study of disease progression in HD.
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