Which factors influence age at onset and rate of progression in Huntington's disease?

Buruma, O. J. S.; Kamp, Wim van der; Barendswaard, E.C.; Roos, Raymund A.C.; Kromhout, D; Velde, E. A. van der

doi:10.1016/0022-510x(87)90164-x

Cited by 26 publications

(14 citation statements)

References 16 publications

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“…Preclinical studies of HD transgenic mouse models (Hockly et al, 2002;van Dellen et al, 2000) have corroborated with clinical evidence that the age of onset of HD symptoms is not solely predicted by the CAG repeat mutation but is subject to modulation by various lifestyle factors (Buruma et al, 1987;López-Sendón et al, 2011;Marder et al, 2009;Simonin et al, 2013;Trembath et al, 2010;Wexler et al, 2004). Here we report for the first time that treatment with corticosterone (CORT) accelerated the onset of short-term memory impairment in male R6/1 HD mice.…”

Section: Discussionmentioning

confidence: 88%

“…A handful of environmental modulators have been correlated with age of onset in HD patients based on retrospective questionnaire studies (Buruma et al, 1987;López-Sendón et al, 2011;Marder et al, 2013;Marder et al, 2009;Simonin et al, 2013;Trembath et al, 2010). For example, Trembath et al found that a premorbid lifestyle of activities lacking in physical or intellectual challenge (a passive lifestyle) was correlated with an earlier age of onset in HD, independent of CAG repeat length.…”

Section: Accepted Manuscript Introductionmentioning

confidence: 99%

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High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Mo¹,

Pang²,

Ransome³

et al. 2014

Neurobiology of Disease

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Huntington's disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation in the huntingtin gene. Lifestyle factors, such as lack of activity may contribute to the variability in the age of disease onset. Therefore, better understanding of environmental modifiers may uncover potential therapeutic approaches to delay disease onset and progression. Recent data suggest that HD patients and transgenic mouse models show a dysregulated stress response. In this present study, we elevated stress hormone levels through oral corticosterone (CORT) treatment and assessed its impact on the development of motor impairment and cognitive deficits using the R6/1 transgenic mouse model of HD. We found that CORT consumption did not alter rotarod performance of R6/1 HD or wild-type (WT) littermates. However, the onset of hippocampal-dependent Y-maze deficits was accelerated in male R6/1 mice by 5days of CORT treatment, whereas short term memory of WT and female R6/1 mice was unaffected. We then further investigated the male HD susceptibility to CORT by measuring TrkB activation, BDNF and glucocorticoid receptor expression as well as the level of cell proliferation in the hippocampus. CORT treatment increased the levels of phosphorylated TrkB in male R6/1 mice only. There were no effects of CORT on hippocampal BDNF protein or mRNA levels; nor on expression of the glucocorticoid receptors in any group. Hippocampal cell proliferation was decreased in male R6/1 mice and this was further reduced in CORT-drinking male R6/1 mice. Female mice (WT and R6/1) appeared to be protected from the impacts of CORT treatment in all our hippocampal measures. Overall, our data demonstrate that treatment with corticosterone is able to modulate the onset of HD symptomatology. We present the first evidence of a male-specific vulnerability to stress impacting on the development of short-term memory deficits in HD. More generally, we found that female mice were protected from the detrimental effects of CORT treatment on a variety of hippocampus-based measures. Hippocampal plasticity and memory in HD may be more susceptible to the impacts of stress in a sex-dependent manner. We propose clinical investigations of stress as a key environmental modifier of HD symptom onset.

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Section: Discussionmentioning

confidence: 88%

Section: Accepted Manuscript Introductionmentioning

confidence: 99%

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Mo¹,

Pang²,

Ransome³

et al. 2014

Neurobiology of Disease

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“…Further studies on the role of on the role of the adaptive immune system and in particular effects of anti-AT1R antibodies on T cell function in HD and also other neurodegenerative diseases are warranted. Indeed, immune factors like anti-AT1R antibodies may add to the determinants influencing age of onset and rate of progression in HD which were previously discussed [ 24 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

Lee

Heidecke²,

Schröder

et al. 2014

Mol Neurodegeneration

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BackgroundIn the recent years, a role of the immune system in Huntington’s disease (HD) is increasingly recognized. Here we investigate the presence of T cell activating auto-antibodies against angiotensin II type 1 receptors (AT1R) in all stages of the disease as compared to healthy controls and patients suffering from multiple sclerosis (MS) as a prototype neurologic autoimmune disease.ResultsAs compared to controls, MS patients show higher titers of anti-AT1R antibodies, especially in individuals with active disease. In HD, anti-AT1R antibodies are more frequent than in healthy controls or even MS and occur in 37.9% of patients with relevant titers ≥ 20 U/ml. In a correlation analysis with clinical parameters, the presence of AT1R antibodies in the sera of HD individuals inversely correlated with the age of onset and positively with the disease burden score as well as with smoking and infection.ConclusionsThese data suggest a dysfunction of the adaptive immune system in HD which may be triggered by different stimuli including autoimmune responses, infection and possibly also smoking.

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“…29 Numerous studies have shown an inverse relationship between consumption of dairy products and plasma uric acid, such that lower dairy consumption is associated with higher acute and long-term urate levels. 30 Higher urate levels have been associated with slower HD progression as measured by the total functional capacity scale over a 30 month period.…”

Section: Discussionmentioning

confidence: 99%

Relationship of Mediterranean Diet and Caloric Intake to Phenoconversion in Huntington Disease

Marder

Eberly

et al. 2013

JAMA Neurol

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Which factors influence age at onset and rate of progression in Huntington's disease?

Cited by 26 publications

References 16 publications

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

High stress hormone levels accelerate the onset of memory deficits in male Huntington's disease mice

Increase of angiotensin II type 1 receptor auto-antibodies in Huntington’s disease

Relationship of Mediterranean Diet and Caloric Intake to Phenoconversion in Huntington Disease

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