Journal of Huntington's Disease - Volume 1, issue 2

Authors: Wexler, A.

Article Type: Other

DOI: 10.3233/JHD-129007

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 139-141, 2012

Authors: Waldvogel, Henry J. | Kim, Eric H. | Thu, Doris C.V. | Tippett, Lynette J. | Faull, Richard L.M.

Article Type: Review Article

Abstract: We review recent investigations regarding the relationship between selective neurodegeneration in the human brain and the variability in symptom profiles in Huntington's disease. Huntington's disease is a genetic neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of the Huntingtin gene on chromosome 4, encoding a protein called huntingtin. The huntingtin protein is expressed ubiquitously in somatic tissue, however, the major pathology affects the brain with profound degeneration in the striatum and the cerebral cortex. Despite the disease being caused by a single gene, there is a major variability in the neuropathology, as well as major heterogeneity in …the symptom profiles observed in Huntington's disease patients. The symptoms may vary throughout the disease course and present as varying degrees of movement disorder, cognitive decline, and mood and behavioral changes. To determine whether there is an anatomical basis underlying symptom variation, recent studies on the post-mortem human brain have shown a relationship between the variable degeneration in the forebrain and the variable symptom profile. In this review, we will summarize the progress relating cell loss in the striatum and cerebral cortex to symptom profile in Huntington's disease. Show more

Keywords: Huntington's disease, human brain, pathology, symptoms, cortex, basal ganglia

DOI: 10.3233/JHD-2012-120018

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 143-153, 2012

Authors: Giralt, Albert | Saavedra, Ana | Alberch, Jordi | Pérez-Navarro, Esther

Article Type: Review Article

Abstract: Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder due to an expanded CAG/polyglutamine repeat in the coding region of the huntingtin (htt) gene that causes the preferential degeneration of striatal neurons. Although HD is classically considered a motor disorder, cognitive decline manifests even before the appearance of motor symptoms, and reflects the impairment of additional neuronal populations, such as cortical and hippocampal neurons, in the presence of mutant htt (mhtt). Studies on cognitive dysfunction in HD patients have focused on the cortico-striatal pathway. Here we will describe that HD patients and mouse models share many cognitive defects. Alterations …in hippocampal synaptic plasticity and function found in HD mouse models highlight that changes in the functioning of the hippocampal formation contribute to cognitive dysfunction in humans. The similarity between the cognitive dysfunction in HD patients and mouse models has helped to understand better how cognitive dysfunction takes place. Moreover, it validates the use of HD mice to study the molecular mechanisms involved in HD cognitive decline. Several studies in HD mouse models indicate that altered synaptic composition/function, deficient neurotrophic support, kinase/phosphatase imbalance, and transcription dysregulation play an important role in cognitive impairment. This knowledge opens the possibility of identifying relevant therapeutic targets to fight cognitive decline in HD. The finding that in HD many mechanisms are similarly altered in hippocampal and striatal neurons suggests the possibility of a common therapeutic strategy to ameliorate both cognitive and motor dysfunction. Show more

Keywords: BDNF, CBP, hippocampus, LTD, LTP, PKA, striatum

DOI: 10.3233/JHD-120023

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 155-173, 2012

Authors: Busse, Monica | Khalil, Hanan | Brooks, Simon | Quinn, Lori | Rosser, Anne

Article Type: Review Article

Abstract: Physical therapies and exercise may have potential as a disease modifying agent in Huntington's disease (HD) and in recent years, there have been several small scale feasibility studies that have shown benefit as a result of physical interventions. When evaluating complex physical interventions, a phased approach using mixed methodology designs that report specific intervention components, adherence, acceptability, adverse events and defined intervention protocols is important for replication and planning of future trials and to ensure potential for implementation in clinical practice. A narrative review of the available literature related to physical activity, physical therapy and exercise in people with HD …was performed using a population, intervention, comparison and outcome (PICO) approach. Eight studies met specific inclusion criteria and were reviewed in terms of their systematic conduct and reporting standards. All of the studies (n = 8) provided details of intervention including location and duration. The majority of interventions included balance training activities in combination with other complex activities of daily living that required therapist supervision. Two of the interventions were home based, the remainder were facility or hospital based. None of the studies reported adverse events whilst only 3/8 reported adherence rates which were ranging from 60–80%. In general, limited detail was provided on the specific individual components of the interventions. This review of primary publications and conference proceedings, suggests that researchers working in the field need to focus on clearer reporting of intervention protocols so as to generate a clearer understanding of the impact of exercise and physical therapies on the symptoms of HD, as well as any potential synergistic role alongside the impending disease-modifying interventions. Show more

Keywords: Huntington's disease, chorea, exercise, physical activity, physiotherapy, physical therapy, rehabilitation

DOI: 10.3233/JHD-120025

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 175-185, 2012

Authors: Fisher, Fiona | Andrews, Sophie | Churchyard, Andrew | Mathers, Susan

Article Type: Research Article

Abstract: Background: The progressive nature of Huntington's disease (HD) means that families often struggle to cope with increasing care needs of their affected family member. As a result, individuals with HD are likely to be at risk of hospitalization and subsequent early placement into residential care facilities. Objective: To explore which factors were associated with early residential care placement in a group of hospitalized patients with HD. Methods: A retrospective, systematic medical file audit of a neurological inpatient unit was conducted. Fifty-nine patients with HD were admitted from the community between January 2008 and December 2011; of these, 31 patients were …discharged home while 28 patients required discharge to a residential care facility. These two groups were compared on a range of demographic, clinical and psychosocial variables identified as precipitating the hospital admission. Group comparisons were performed using t-tests and chi-square tests with Bonferroni correction for multiple comparisons. Results: A higher proportion of men were placed in residential care than were able to return home (p = 0.045); and the group placed in residential care had longer inpatient hospital stays (p < 0.001). Groups did not differ in age, medications or disease duration. We found that psychosocial difficulties (p < 0.001) and behavioral problems (p = 0.001), but not physical, cognitive, or psychiatric factors, significantly differentiated the groups. Conclusions: Patients with HD discharged to residential care were more likely to have psychosocial and behavioral problems, and lengthy hospital stays. These findings indicate the need for community-based psychosocial and behavior management interventions aimed at preventing residential care admissions for persons with HD. Show more

Keywords: Huntington's disease, social support, behavior, residential facilities, institutionalization, hospitalization

DOI: 10.3233/JHD-120022

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 187-193, 2012

Authors: Sarantos, Melissa R. | Papanikolaou, Theodora | Ellerby, Lisa M. | Hughes, Robert E.

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD. Objective: To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD. Methods: A chemical screen was performed in a mouse HdhQ111/Q111 striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HD …mouse model. Results: We found that in striatal HdhQ111/Q111 cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HD mouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance. Conclusions: These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD. Show more

Keywords: Huntington's disease, Drug screening, Pizotifen, ERK Pathway, R6/2 HD mouse model

DOI: 10.3233/JHD-120033

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 195-210, 2012

Authors: Cherny, Robert A. | Ayton, Scott | Finkelstein, David I. | Bush, Ashley I. | McColl, Gawain | Massa, Stephen M.

Article Type: Research Article

Abstract: Background: There is evidence that interaction with biologically important metals, particularly copper and iron, contributes to the pathological aggregation and toxicity of the mutant huntingtin protein in HD. PBT2 is a novel 8-hydroxyquinoline drug in clinical trials for AD and HD which restores metal homeostasis and has demonstrated neuroprotective and cognitive benefits in animal models of AD and in a Phase IIa clinical trial in AD patients. Objectives: We assessed efficacy of PBT2 to improve function in nematode and mouse models of HD. Methods: We assessed the effects of PBT2 on motility in a strain of C. elegans engineered to …overexpress an extended polyglutamine tract. We then assessed the effects of daily oral administration of PBT2 on the R6/2 mouse a vertebrate model of HD. Behavioural measures (Rotarod performance, clasping latency and duration) and measures of overall health (body weight, lifespan) were assessed throughout the study. At conclusion brains were evaluated for weight and lateral ventricle area. Results: PBT2 significantly decreased paralysis caused by overexpression of an extended polyglutamine tract in a C. elegans. R6/2 mice treated with PBT2 showed significantly better performance in the Rotarod task and significantly decreased duration of clasping than control animals. Mean body weight and brain weight in the PBT2 treatment group were significantly higher than the control cohort and median lifespan was prolonged by 26%. Mean lateral ventricle area in the PBT2-treated group was 46% smaller than in the control group. Conclusions: Treatment with PBT2 may be beneficial as a disease modifying therapy for HD. Show more

Keywords: PBT2, C. elegans, R6/2, metals

DOI: 10.3233/JHD-120029

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 211-219, 2012

Authors: Strong, Melissa K. | Southwell, Amber L. | Yonan, Jennifer M. | Hayden, Michael R. | MacGregor, Grant R. | Thompson, Leslie M. | Steward, Oswald

Article Type: Research Article

Abstract: Mouse strain background can influence vulnerability to excitotoxic neuronal cell death and potentially modulate phenotypes in transgenic mouse models of human disease. Evidence supports a contribution of excitotoxicity to the selective death of medium spiny neurons in Huntington's disease (HD). Here, we assess whether strain differences in excitotoxic vulnerability influence striatal cell death in a knock-in mouse model of HD. Previous studies that evaluated resistance to excitotoxic lesions in several mouse models of HD had variable outcomes. In the present study, we directly compare one model on two different background strains to test the contribution of strain to excitotoxicity-mediated neurodegeneration. …Mice of the FVB/N strain, which are highly vulnerable to excitotoxicity, become extremely resistant to quinolinic acid-induced striatal neurodegeneration with age, when carrying a huntingtin (Htt) allele expressing a HD transgene (CAG140). The resistance is much greater than the age-dependent resistance that has been previously reported in YAC128 mice. By 12 months of age, both heterozygous and homozygous FVB.CAG140 mice displayed virtually complete resistance to quinolinic acid-induced striatal neurodegeneration. A similar resistance develops in CAG140 mice on a C57BL/6N background although the effect size is smaller because C57BL/6N mice are already resistant due to genetic background. In a direct comparison with the YAC128 mice, FVB.CAG140 mice have greater resistance. FVB.CAG140 mice are also resistant to neurodegeneration following kainic acid-induced status epilepticus suggesting the existence of a common cellular mechanism that provides protection against multiple types of excitotoxic insult. These findings establish FVB.CAG140 mice as a useful model to investigate the cellular and molecular mechanisms that confer neuroprotection against excitotoxicity. Show more

Keywords: Excitotoxin, Huntington's disease, inbred mouse strains, resistance, cell death, neurodegeneration, genetic background

DOI: 10.3233/JHD-129005

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 221-241, 2012

Authors: Graham, Rona K. | Deng, Yu | Pouladi, Mahmoud A. | Vaid, Kuljeet | Ehrnhoefer, Dagmar | Southwell, Amber L. | Bissada, Nagat | Franciosi, Sonia | Hayden, Michael R.

Article Type: Research Article

Abstract: Background: The amelioration of behavioral and neuropathological deficits in mice expressing caspase-6-resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine tract, highlights proteolysis of htt at the 586aa caspase-6 (casp6) site may be an important mechanism in the pathogenesis of Huntington disease (HD). One possible explanation of these effects is that C6R mhtt could act as a dominant negative on mhtt. Objective and Methods: To determine if the neuroprotective effect observed in the C6R mice is due to dominant negative effects, we crossed the C6R mice to the YAC128 HD mouse model to generate mice expressing both …caspase-cleavable and C6R mhtt (YAC/C6R) concurrently and assessed previously defined behavioral and neuropathological endpoints. Results: Our results demonstrate that YAC/C6R animals exhibit similar motor abnormalities and learning deficits as the YAC128 mice. Neuropathological analysis reveals a significant decrease in brain weight and striatal volume in the YAC/C6R mice comparable to the YAC128 mice. In contrast, and similar to previous findings, C6R mice demonstrate preserved brain weight and striatal volume. As expected, body weight is significantly increased in the YAC/C6R mice due to the increased levels of htt. Conclusions: The results of this study suggest that the lack of an HD phenotype in the C6R mice is most likely due to the absence of cleavage of htt and not due to suppression of expression of mhtt. Show more

Keywords: Huntington disease, mutant huntingtin, caspase-6, apoptosis, human, mouse models

DOI: 10.3233/JHD-120038

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 243-260, 2012

Authors: Renoir, Thibault | Argyropoulos, Andrew | Hannan, Anthony J.

Article Type: Research Article

Abstract: Background: The pre-motor stages of Huntington's disease (HD) are commonly associated with psychiatric manifestations including depression. Recent clinical data indicate that dopaminergic dysfunction is common in both symptomatic and pre-manifest HD gene carriers. There is also increasing evidence implicating catecholamine dysfunction in the pathophysiology of depression. Objective: In this study, we aimed to functionally investigate the dopaminergic system in the R6/1 mouse model of HD prior to onset of motor symptoms. Methods: We assessed the effects of acute administration of bupropion (a dopamine-norepinephrine reuptake inhibitor) on spontaneous locomotor activity and depression-like behaviour (using the forced-swim test). Results: Here we show …that the bupropion-induced increased locomotor activity found in wild-type animals was no longer observed in HD mice. We also found that acute administration with bupropion rescued depressive-like behaviours in HD animals, possibly through dopamine D2/D3 receptor mechanisms. Conclusion: Our present data are the first in vivo evidence of an impaired dopamine D1 receptor-dependent function in pre-motor symptomatic R6/1 HD mice. Moreover, our findings suggest clinical potential for bupropion to alleviate depressive symptoms in HD. Show more

Keywords: Huntington's disease, mouse model, depression, behaviours, dopamine, bupropion

DOI: 10.3233/JHD-120039

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 261-266, 2012

Authors: Bulley, Simon J. | Drew, Cheney J.G. | Morton, A. Jennifer

Article Type: Research Article

Abstract: Background: Spatial learning deficits are observed in R6/2 mice, a transgenic mouse model of Huntington's Disease (HD). Spatial learning is a hippocampal-dependent process, and impairment of memory is thought to be due, at least in part, to structural changes such as loss of dendritic spines. Objective: To analyse dendritic spines in the hippocampus of R6/2 mice to determine if there are changes that correlate with the hippocampal dysfunction observed in these mice. Methods: A double transgenic cross between R6/2 mice and a reporter line (YFP-H) of mice that express yellow fluorescent protein (YFP) in a subset of their neurons was …used. This allowed us to visualise dendritic spines in the brains of R6/2 mice directly. Results: Clear differences were seen in the distribution of YFP in the hippocampal formation of wild-type (WT)-YFP-H and R6/2-YFP-H mice, particularly in the CA1 region. We quantified dendritic spine density and dendritic spine length in the apical dendrites of the CA1 hippocampal neurons. A significant reduction in dendritic spine density, and a concomitant increase in dendritic spine length was observed in R6/2-YFP-H mice compared to WT-YFP-H mice. Conclusion: The R6/2-YFP-H mouse is a useful tool for directly visualising dendritic spines in the brain of a Huntington's disease mouse model. The changes we observed in dendritic spine density and length in the hippocampus might contribute to the synaptic plasticity deficits and behavioural alteration of impaired spatial learning seen in R6/2 mice. Show more

Keywords: Dendritic spines, learning, long-term potentiation, LTP, confocal microscopy, green fluorescent proteins, fragile X syndrome

DOI: 10.3233/JHD-120024

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 267-273, 2012

Article Type: Other

DOI: 10.3233/JHD-129006

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 275-275, 2012

Article Type: Other

Citation: Journal of Huntington's Disease, vol. 1, no. 2, pp. 277-279, 2012