Correction There is an error in the second author’s name. The correct name is Elizabeth A. Wang. The correct citation is Chen JY, Wang EA, Galvan L, Huynh M, Joshi P, Cepeda C, Levine MS. Effects of the Pimelic Diphenylamide Histone Deacetylase Inhibitor HDACi 4b on the R6/2 and N171-82Q Mouse Models of Huntington’s Disease. […]
Correction There is an error in the second author’s name. The correct name is Elizabeth A. Wang. The correct citation is Botelho EP, Wang EA, Chen JY, Holley S, Andre V, Cepeda C, Levine MS. Differential Synaptic and Extrasynaptic Glutamate-Receptor Alterations in Striatal Medium-Sized Spiny Neurons of Aged YAC128 Huntington’s Disease Mice. PLOS Currents Huntington […]
Objective: Huntington’s disease (HD) is characterized by motor symptoms, psychiatric symptoms and cognitive impairment in, inter alia, executive functions and social cognition. The aim of this study was to investigate the relationship between subjective feeling of psychological distress using a self-report questionnaire and performances on tests of executive functions and social cognition in a large consecutive cohort of HD patients.
Method: 50 manifest HD patients were tested in social cognition and executive functions and each answered a self-report questionnaire about current status of perceived psychological distress (the Symptom Checklist-90-Revised (SCL-90-R)). Correlation analyses of test performance and SCL-90-R scores were made as well as stepwise linear regression analyses with the SCL-90-R GSI score and test performances as dependent variables.
Results: We found that less psychological distress was significantly associated with worse performances on social cognitive tests (mean absolute correlation .34) and that there were no significant correlations between perceived psychological distress and performance on tests of executive functions. The correlations between perceived psychological distress and performance on social cognitive tests remained significant after controlling for age, Unified Huntington’s Disease Rating Scale-99 total motor score and performance on tests of executive functions.
Conclusions: Based on previous findings that insight and apathy are closely connected and may be mediated by overlapping neuroanatomical networks involving the prefrontal cortex and frontostriatal circuits, we speculate that apathy/and or impaired insight may offer an explanation for the correlation between self-report of psychological distress and performance on social cognitive tests in this study.
Introduction: Huntington’s disease (HD) has profound motor, behavioural and cognitive symptoms. Despite the enormous burden of this disease on the quality of life (QoL) of patients and their families, there is very limited evidence on this topic. Considering the severity of HD patients, and the high prevalence in Cyprus more studies are needed to assess QoL among Cypriot patients, in order to improve our knowledge about their living conditions and to assist the management of this condition.
Project Aim: The aim of this cross-sectional study is to assess QoL among Cypriot patients with HD, using a standardized health-related QoL questionnaire.
Materials and Methods: A generic QoL questionnaire was used, namely EQ-5D, which is a standardised instrument for use as a measure of health outcomes and is applicable to a wide range of health conditions. The study was conducted with 34 patients, which represented 46% of the Cypriot HD patient population.
Results: Ability of patients to care for themselves and to carry out usual activities were reported to be most severely affected (37.5% and 40.6% replying “Severe Problems” respectively). Mobility and psychosocial well-being were also affected to a lesser extent (25.0% and 15.6% replying “Severe Problems”). Interestingly, in the anxiety/depression scale, 77.8% of asymptomatic patients reported “Some Problems”. Half of the patients did not experience pain or discomfort but 40.6% reported “Some Problems” and 6.3% reported “Severe Problems”. The Health Status as perceived by the patients was found to be moderately to severely affected. In multivariate ordinal regression analyses, age at onset and disease duration significantly impacted on self-care. In addition, disease duration was significantly associated with mobility, self-care and usual activities scales. No significant determinants were evidenced for Pain/Discomfort and Anxiety/Depression. Lastly, age of onset was found to be the only significant determinant of the cumulative QoL score (Range=5-15).
Conclusions: Age at onset and disease duration were found to severely affect the QoL of Cypriot HD patients, and more specifically their mobility, ability to self-care and perform usual activities. The percentage of patients reporting “Some Problems” in the Pain/Discomfort category can be explained by the direct translation of the word as presented in the questionnaire, indicating the need for language specific instruments. Perhaps more noteworthy is the phychosocial burden on even asymptomatic patients, which needs to be acknowledged and managed to improve their quality of life.
Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by CAG repeat expansions in the HTT gene. Somatic repeat expansion in the R6/1 mouse model of HD depends on mismatch repair and is worsened by base excision repair initiated by the 7,8-dihydroxy-8-oxoguanine-DNA glycosylase (Ogg1) or Nei-like 1 (Neil1). Ogg1 and Neil1 repairs common oxidative lesions.
Methods: We investigated whether anthocyanin antioxidants added daily to the drinking water could affect CAG repeat instability in several organs and behaviour in R6/1 HD mice. In addition, anthocyanin-treated and untreated R6/1 HD mice at 22 weeks of age were tested in the open field test and on the rotarod.
Results: Anthocyanin-treated R6/1 HD mice showed reduced instability index in the ears and in the cortex compared to untreated R6/1 mice, and no difference in liver and kidney. There were no significant differences in any of the parameters tested in the behavioural tests among anthocyanin-treated and untreated R6/1 HD mice.
Conclusions: Our results indicate that continuous anthocyanin-treatment may have modest effects on CAG repeat instability in the ears and the cortex of R6/1 mice. More studies are required to investigate if anthocyanin-treatment could affect behaviour earlier in the disease course.
Background: Huntington disease (HD) is a genetic neurodegenerative disease leading to progressive motor, cognitive, and behavioral decline. Subtle changes in these domains are detectable up to 15 years before a definitive motor diagnosis is made. This period, called prodromal HD, provides an opportunity to examine lifestyle behaviors that may impact disease progression. Theoretical Framework: Physical activity relates to decreased rates of brain atrophy and improved cognitive and day-to-day functioning in Alzheimer disease and healthy aging populations. Previous research has yielded mixed results regarding the impact of physical activity on disease progression in HD and paid little attention to the prodromal phase.
Methods: We conducted analyses of associations among current physical activity level, current and retrospective rate of change for hippocampus and striatum volume, and cognitive, motor, and day-to-day functioning variables. Participants were 48 gene-expanded cases with prodromal and early-diagnosed HD and 27 nongene-expanded control participants. Participants wore Fitbit Ultra activity monitors for three days and completed the self-reported International Physical Activity Questionnaire (IPAQ). Hippocampal and striatal white matter volumes were measured using magnetic resonance imaging. Cognitive tests included the Stroop Color and Word Test, and the Symbol Digit Modalities Test (SDMT). Motor function was assessed using the Unified Huntington’s Disease Rating Scale total motor score (TMS). Day-to-day functioning was measured using the World Health Organization Disability Assessment Schedule (WHODAS) version 2.0.
Results: Higher Fitbit activity scores were significantly related to better scores on the SDMT and WHODAS in case participants but not in controls. Fitbit activity scores tracked better with TMS scores in the group as a whole, though the association did not reach statistical significance in the case participants. Higher Fitbit activity scores related to less day-to-day functioning decline in retrospective slope analyses. Fitbit activity scores did not differ significantly between cases and controls.
Conclusions: This is the first known study examining the associations between activity level and imaging, motor, cognitive, and day-to-day functioning outcomes in prodromal and early HD. Preliminary results suggest physical activity positively correlates with improved cognitive and day-to-day functioning and possibly motor function in individuals in the prodromal and early phase of the condition.
Insufficient evidence exists to guide the long-term pharmacological management of Huntington’s disease (HD) although most current interventions rely on symptomatic management. The effect of many frontline treatments on potential endpoints for HD clinical trials remains unknown. Our objective was to investigate how therapies widely used to manage HD affect the symptom for which they are prescribed and other endpoints using data from TRACK-HD. We used longitudinal models to estimate effects of medication use on performance on tests of motor, cognitive and neuropsychiatric function using data from 123 TRACK-HD stage 1/2 participants across four study visits. Adjustment for confounding by prior medication use, prior clinical performance, concomitant use of other medications, and baseline variables (sex, disease group, age, CAG, study site, education) enabled a closer-to-causal interpretation of the associations. Adjusting for baseline variables only, medication use was typically associated with worse clinical performance, reflecting greater medication use in more advanced patients. After additional adjustment for longitudinal confounders such “inverse” associations were generally eliminated and in the expected directions: participants taking neuroleptics tended to have better motor performance, improved affect and poorer cognitive performance, and those taking SSRI/SNRIs had less apathy, less affect and better total behaviour scores. However, we uncovered few statistically significant associations. Limitations include sample size and unmeasured confounding. In conclusion, adjustment for confounding by prior measurements largely eliminated associations between medication use and poorer clinical performance from simple analyses. However, there was little convincing evidence of causal effects of medication on clinical performance and larger cohorts or trials are needed.
Correction The author order is incorrect. The correct order of the authors is: Lu Z, Barrows L, Fox J. Reference Fox J, Lu Z, Barrows L. Thiol-disulfide Oxidoreductases TRX1 and TMX3 Decrease Neuronal Atrophy in a Lentiviral Mouse Model of Huntington’s Disease. PLOS Currents Huntington Disease. 2015 Nov 6 . Edition 1. doi: 10.1371/currents.hd.b966ec2eca8e2d89d2bb4d020be4351e.
Huntington disease (HD) is caused by the CAG (Q) expansion in exon 1 of the IT15 gene encoding a polyglutamine (poly-Q) stretch of the Huntingtin protein (Htt). In the wild type protein, the repeats specify a stretch of up 34 Q in the N-terminal portion of Htt. In the pathological protein (mHtt) the poly-Q tract is longer. Proteolytic cleavage of the protein liberates an N-terminal fragment containing the expanded poly-Q tract becomes harmful to cells, in particular to striatal neurons. The fragments cause the transcriptional dysfunction of genes that are essential for neuronal survival. Htt, however, could also have non-transcriptional effects, e.g. it could directly alter Ca2+ homeostasis and/or mitochondrial morphology and function. Ca2+ dyshomeostasis and mitochondrial dysfunction are considered important in the molecular aetiology of the disease. Here we have analyzed the effect of the overexpression of Htt fragments (18Q, wild type form, wtHtt and 150Q mutated form, mHtt) on Ca2+ homeostasis in striatal neuronal precursor cells (Q7/7). We have found that the transient overexpression of the Htt fragments increases Ca2+ transients in the mitochondria of cells stimulated with Ca2+-mobilizing agonists. The bulk Ca2+ transients in the cytosol were unaffected, but the Ca2+ content of the endoplasmic reticulum was significantly decreased in the case of mHtt expression. To rule out possible transcriptional effects due to the presence of mHtt, we have measured the mRNA level of a subunit of the respiratory chain complex II, whose expression is commonly altered in many HD models. No effects on the mRNA level was found suggesting that, in our experimental condition, transcriptional action of Htt is not occurring and that the effects on Ca2+ homeostasis were dependent to non-transcriptional mechanisms.
Huntington’s disease (HD) is caused by a trinucleotide CAG repeat in the huntingtin gene (HTT) that results in expression of a polyglutamine-expanded mutant huntingtin protein (mHTT). N-terminal fragments of mHTT accumulate in brain neurons and glia as soluble monomeric and oligomeric species as well as insoluble protein aggregates and drive the disease process. Decreasing mHTT levels in brain provides protection and reversal of disease signs in HD mice making mHTT a prime target for disease modification. There is evidence for aberrant thiol oxidation within mHTT and other proteins in HD models. Based on this, we hypothesized that a specific thiol-disulfide oxidoreductase exists that decreases mHTT levels in cells and provides protection in HD mice. We undertook an in-vitro genetic screen of key thiol-disulfide oxidoreductases then completed secondary screens to identify those with mHTT decreasing properties. Our in-vitro experiments identified thioredoxin 1 and thioredoxin-related transmembrane protein 3 as proteins that decrease soluble mHTT levels in cultured cells. Using a lentiviral mouse model of HD we tested the effect of these proteins in striatum. Both proteins decreased mHTT-induced striatal neuronal atrophy. Findings provide evidence for a role of dysregulated protein-thiol homeostasis in the pathogenesis of HD.