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

Authors: Hart, Ellen P. | Dumas, Eve M. | Giltay, Erik J. | Middelkoop, Huub A.M. | Roos, Raymund A.C.

Article Type: Review Article

Abstract: Background: Cognitive decline in Huntington's disease (HD) remains an area of inconsistencies, especially far from disease onset. Objective: To clarify the course of cognition in premanifest HD. Methods: Twenty-six premanifest HD, 19 manifest HD, and 87 control subjects were followed for ten years, using an extensive cognitive battery. Differences in baseline levels and change over time, on four factors (motor speed, global cognition, executive functioning (EF), and memory) were examined, using multilevel regression analyses. Converters were additionally analysed as a separate group. Also, the influence of motor speed and predicted years to disease onset on the cognitive factors was studied. …Results: Manifest HD subjects showed lower baseline scores compared to controls on the motor speed (p = 0.002), memory (p < 0.001) and EF (p < 0.001). They additionally deteriorated over the ten-year follow-up on memory (p = 0.01). Converters deteriorated on EF (p = 0.04). Further analyses of premanifest subjects ‘far from and close to predicted onset’ revealed lower baseline scores for the ‘close’ group on EF, as compared to controls (p = 0.001). They also deteriorated on memory (p = 0.01). Motor speed substantially mediated the results of the three cognitive factors; when added as covariate to the model several baseline and slope differences for the cognitive factors ceased to be significant. Conclusions: Memory and EF are highly sensitive for ascertaining deterioration in premanifest HD gene carriers, especially in subjects close to onset. Lack of deterioration for the subjects further away from onset suggests that both domains are largely unaffected in those far from onset. Also, motor influence on cognition is substantial and should be taken into account in cognitive HD research. Show more

Keywords: Huntington's disease, executive functioning, longitudinal, converters, premanifest

DOI: 10.3233/JHD-130059

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 137-147, 2013

Authors: Lin, Fang | Qin, Zheng-Hong

Article Type: Review Article

Abstract: Autophagy is a degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. The accumulation and aggregation of misfolded proteins are hallmarks of several neurodegenerative diseases. Many researchers have reported that autophagy degrades disease-causing misfolded and aggregated proteins, including mutant huntingtin (Htt) in Huntington's disease, mutant synuclein in familial Parkingson's disease, mutant Cu, Zn− Superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis. In this review, we will bring up new evidence to elucidate the involvement of autophagy in degradation of mutant Htt, discuss the mechanisms regulating the degradation of mutant Htt by autophagy and the therapeutic effects of drugs …that enhance autophagy to improve clearance of mutant Htt. We propose that enhancement of autophagy by drugs may be a strategy to treat or retard progression of Huntington's disease. Show more

Keywords: Huntington's disease, huntingtin, polyglutamine expansion, autophagy

DOI: 10.3233/JHD-130052

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 149-157, 2013

Authors: Read, Joy | Jones, Rebecca | Owen, Gail | Leavitt, Blair R. | Coleman, Allison | Roos, Raymund A. C. | Dumas, Eve M. | Durr, Alexandra | Justo, Damian | Say, Miranda | Stout, Julie C. | Tabrizi, Sarah J. | Craufurd, David | the TRACK-HD investigators

Article Type: Research Article

Abstract: Background: Given the multifaceted nature of this inherited neurodegenerative condition, typically affecting adults in mid-life, it is perhaps not surprising that studies indicate poorer Health Related Quality of Life (HrQoL) in those with the gene-expansion and, by association, in their families. Objective: This study aimed to extend the current literature by exploring specific life domains, including at an earlier disease stage than usually reported in the HRQoL literature, and in a subgroup of gene-negative partners. Methods: 355 participants from the TRACK-HD cohort (120 Controls, 118 Pre-HD and 117 early-HD) completed standardised self-report measures of HrQoL (SF36 and QoLI), underwent clinical …assessments of capacity and motor function (UHDRS), semi structured interviews assessing neuropsychiatric symptoms (PBA-s), completed paper and computerized cognitive tasks and assessment of behaviours associated with damage to frontal brain circuits (FrSBe). Results: Each gene-expanded group scored statistically significantly lower than gene-negative sibling controls on the SF36 General Health subscale; neuropsychiatric symptoms and executive dysfunction were associated with reduced HrQoL. Those with Stage II disease reported statistically significantly lower HrQoL than gene-negative controls across physical, emotional and social life domains. Those partnered with manifest participants reported lower HrQoL in the social domain compared to those partnered with at-risk participants furthest from disease onset; and perseverative symptoms in manifest partners were found to be related to lower HrQoL in their gene-negative partners. HrQoL in gene-negative partners of pre-manifest individuals was associated with pre-manifest individuals' neuropsychiatric and cognitive function. Conclusions: Understanding the nature and timing of disruption to the HrQoL in people who are pre-manifest and diagnosed with HD, and their gene-negative partners, can inform the development of appropriate strategies and interventions. Show more

Keywords: Huntington's disease, quality of life, TRACK-HD, life domains, cognitive function, neuropsychiatric function

DOI: 10.3233/JHD-130051

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 159-175, 2013

Authors: Medina, Luis D. | Pirogovsky, Eva | Salomonczyk, Danielle | Goldstein, Jody | Panzera, Robert | Gluhm, Shea | Simmons, Roger | Corey-Bloom, Jody | Gilbert, Paul E.

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is associated with neuronal death in basal ganglia circuits important for postural control. Despite evidence of postural instability associated with HD, postural control at the limits of stability has not been investigated in this disease. Objective: To use computerized dynamic posturography to measure postural control at the limits of stability during the premanifest and manifest stages of HD. Methods: Patients with manifest HD, premanifest gene carriers, and matched controls stood on mechanically locked force plates while viewing a computer screen. The participant's estimated center of gravity was represented on the screen as a cursor along with …eight target icons arranged in a circular pattern at the theoretical edge of limits of stability. On each trial, one of the eight targets was highlighted and the participant was instructed to control the cursor by rapidly shifting his/her weight in the direction of the target. Measures included reaction time, movement velocity, endpoint excursion, maximum excursion, and directional control. Results: Analysis of variance revealed significant impairment on endpoint excursion, maximum excursion, and directional control (p ≤ 0.001) in the Huntington's disease group, but not in the premanifest gene carrier group as compared to controls. No differences were found on reaction time or movement velocity measures. Group signal to noise ratios also were examined for the measures. Conclusions: HD patients, but not premanifest gene carriers, showed impaired postural control at the limits of stability. Impaired performance in HD patients has potential functional consequences including increased risk of falling during weight-shifting activities. Show more

Keywords: Huntington's disease, posturography, limits of stability, posture, balance

DOI: 10.3233/JHD-130048

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 177-184, 2013

Authors: Diamanti, Daniela | Lahiri, Nayana | Tarditi, Alessia | Magnoni, Letizia | Fondelli, Costanza | Morena, Emilia | Malusa, Federico | Pollio, Giuseppe | Diodato, Enrica | Tripepi, Giovanna | Tabrizi, Sarah J. | Caricasole, Andrea | Mori, Elisa

Article Type: Research Article

Abstract: Background: Huntington's disease is a neurodegenerative disorder characterized by transcriptional alterations both in central and peripheral tissues. Therefore, the identification of a transcriptional signature in an accessible tissue can meaningfully complement current efforts in clinical biomarker development. Gene expression normalization represents an essential step in transcriptional signatures identification, and since many reference genes show altered expressions in several pathologies, the definition of stable genes in the desired tissue is required to allow correct result interpretations. Objective: The present work aimed at identifying a set of suitable reference genes for expression normalization in blood of HD patients and R6/2 mice. Methods: …By crossing literature investigation and analysis of microarrays performed on blood of HD patients and healthy subjects, a set of genes was selected and tested by RT-qPCR. Employment of statistical algorithms allowed the identification of the most stable genes in human samples that were than confirmed in R6/2. Results: PPIB, PGK1, ACTB and YWHAZ represent the best possible genes combination, useful to normalize blood transcriptional analysis. To link clinical and preclinical studies, the identified genes were investigated also in blood of R6/2 and wild type mice, confirming that Ppib, Actb and Ywhaz were appropriate for expression normalization. Selected references were subsequently applied to evaluate expression of genes known to be involved in Huntington's pathological progression. Conclusions: This work highlights the importance for correct data normalization to avoid misinterpretation of results, while providing a suitable method to support quantitative gene expression analysis in preclinical and clinical investigations. Show more

Keywords: Huntington's disease, blood, RT-qPCR, reference genes selection

DOI: 10.3233/JHD-120042

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 185-200, 2013

Authors: Zeng, Li | Tallaksen-Greene, Sara J. | Wang, Bo | Albin, Roger L. | Paulson, Henry L.

Article Type: Research Article

Abstract: Ataxin-3 is a deubiquitinating enzyme (DUB) that participates in ubiquitin-dependent protein quality control pathways and, based on studies in model systems, may be neuroprotective against toxic polyglutamine proteins such as the Huntington's disease (HD) protein, huntingtin (htt). HD is one of at least nine polyglutamine neurodegenerative diseases in which disease-causing proteins accumulate in ubiquitin-positive inclusions within neurons. In studies crossing mice null for ataxin-3 to an established HD knock-in mouse model (HdhQ200), we tested whether loss of ataxin-3 alters disease progression, perhaps by impairing the clearance of mutant htt or the ubiquitination of inclusions. While loss of ataxin-3 mildly exacerbated …age-dependent motor deficits, it did not alter inclusion formation, ubiquitination of inclusions or levels of mutant or normal htt. Ataxin-3, itself a polyglutamine-containing protein with multiple ubiquitin binding domains, was not observed to localize to htt inclusions. Changes in neurotransmitter receptor binding known to occur in HD knock-in mice also were not altered by the loss of ataxin-3, although we unexpectedly observed increased GABAA receptor binding in the striatum of HdhQ200 mice, which has not previously been noted. Finally, we confirmed that CNS levels of hsp70 are decreased in HD mice as has been reported in other HD mouse models, regardless of the presence or absence of ataxin-3. We conclude that while ataxin-3 may participate in protein quality control pathways, it does not critically regulate the handling of mutant htt or contribute to major features of disease pathogenesis in HD. Show more

Keywords: Ataxin-3, Huntington disease, ubiquitin-proteasome pathway, Neurodegenerative disease, polyglutamine

DOI: 10.3233/JHD-130058

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 201-215, 2013

Authors: Stanek, Lisa M. | Yang, Wendy | Angus, Stuart | Sardi, Pablo S. | Hayden, Michael R. | Hung, Gene H. | Bennett, C. Frank | Cheng, Seng H. | Shihabuddin, Lamya S.

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD. Objective: To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 …mouse model of HD. Methods: Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment. Results: Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts. Conclusions: The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD. Show more

Keywords: Antisense oligonucleotides, Huntington's disease, mutant huntingtin, transcriptional dysregulation, YAC128 mouse model

DOI: 10.3233/JHD-130057

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 217-228, 2013

Article Type: Other

DOI: 10.3233/JHD-139004

Citation: Journal of Huntington's Disease, vol. 2, no. 2, pp. 229-229, 2013