Journal of Huntington's Disease - Volume 3, issue 2

Authors: Bowles, Kathryn R. | Jones, Lesley

Article Type: Review Article

Abstract: Alterations in numerous signal transduction pathways and aberrant activity of specific kinases have been identified in multiple cell and mouse models of Huntington's disease (HD), as well as in human HD brain. The balance and integration of a network of kinase signalling pathways is paramount for the regulation of a wide range of cellular and physiological processes, such as proliferation, differentiation, inflammation, neuronal plasticity and apoptosis. Unbalanced activity within these pathways provides a potential mechanism for many of the pathological phenotypes associated with HD, such as transcriptional dysregulation, inflammation and ultimately neurodegeneration. The characterisation of aberrant kinase signalling regulation in …HD has been inconsistent and may be a result of failure to consider integration between multiple signalling pathways, as well as alterations that may occur over time with both age and disease progression. Collating the information about the effect of mHTT on signalling pathways demonstrates that it has wide ranging effects on multiple pro- and anti-apoptotic kinases, resulting in the dysregulation of numerous complex interactions within a dynamic network. Show more

Keywords: Huntington's disease, kinase signalling, inflammation, pro-survival, pro-apoptotic, AKT, MEK/ERK, CDK5/P35, MAPKs, P53, IKK

DOI: 10.3233/JHD-140106

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 89-123, 2014

Authors: Sitek, Emilia J. | Thompson, Jennifer C. | Craufurd, David | Snowden, Julie S.

Article Type: Review Article

Abstract: People with Huntington's disease (HD) may show reduced awareness of physical and mental changes in themselves. This article reviews the evidence for loss of awareness (anosognosia) in an attempt to elucidate its characteristics and possible underlying mechanisms. It is shown that defective awareness occurs across domains. People with HD may under-report the presence or severity of involuntary movements, under-estimate cognitive impairment and deny behavioural change. Nevertheless, awareness is not all or none. Moreover, it may be affected differentially for different symptom domains and emerge at different stages of disease, raising the possibility of distinct contributory mechanisms. Findings of an inverse …relationship between insight and severity of disease suggest that cognitive impairment, in particular executive dysfunction, may be an important contributory factor. Evidence has accrued to support this argument. However, cognitive impairment cannot fully account for patients' lack of awareness of involuntary movements. Findings that patients accurately report consequences but not the experience of involuntary movements, and better acknowledge their presence when watching videotapes of themselves suggests that physiological factors play an important role. The putative role of denial as a coping mechanism is discussed. Recognition by clinicians of deficient self-awareness is crucial because of its implications for diagnosis and optimal clinical management of HD. Show more

Keywords: Huntington disease, anosognosia, chorea, awareness

DOI: 10.3233/JHD-140109

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 125-135, 2014

Authors: Margolis, Russell L.

Article Type: Research Article

DOI: 10.3233/JHD-140107

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 137-138, 2014

Authors: Beglinger, Leigh J. | Adams, William H. | Langbehn, Douglas | Fiedorowicz, Jess G. | Caviness, John | Biglan, Kevin | Olson, Blair | Paulsen, Jane S.

Article Type: Research Article

Abstract: Background: “Practice effects” (PE), or performance improvements due to prior exposure to testing, are known to confound cognitive test results, particularly when short intervals occur between two test sessions. Objective: We examined two subsamples with short or long re-test intervals from a recent clinical trial. Methods: Thirty-four non-depressed adults with mild Huntington Disease (HD) participated. Three cognitive tests were administered at screening and again at baseline, before active treatment randomization. Half the sample had a 24-hour retest interval while the other half was >6-days. Results: The two groups differed on demographic/clinical factors (age, Total Motor Score and Total Functional Capacity). …After controlling for age and motor score, PE differences were found on three of the five UHDRS cognitive tests: the longer interval group showed larger PE on Symbol-Digit Modalities and Stroop color, while the rapid interval group had larger PE on Stroop interference. Controlling for screening cognitive performance yielded similar results. Conclusions: Length of interval between screening and baseline visits and level of disease severity may influence stability of UHDRS cognitive test results in clinical trials in HD. Show more

Keywords: Huntington disease, neuropsychological assessment, cognitive disorders/dementia, practice effects

DOI: 10.3233/JHD-140100

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 139-144, 2014

Authors: Farrar, Andrew M. | Murphy, Carol A. | Paterson, Neil E. | Oakeshott, Stephen | He, Dansha | Alosio, William | McConnell, Kristi | Menalled, Liliana B. | Ramboz, Sylvie | Park, Larry C. | Howland, David | Brunner, Dani

Article Type: Research Article

Abstract: Background: Huntington's disease (HD) is characterized not only by severe motor deficits but also by early cognitive dysfunction that significantly increases the burden of the disease for patients and caregivers. Considerable efforts have concentrated, therefore, on the assessment of cognitive deficits in some HD mouse models. However, many of these models that exhibit cognitive deficits also have contemporaneous serious motor deficits, confounding interpretation of cognitive decline. Objective: The BACHD and zQ175 mouse models present a more slowly progressing disease phenotype in both motor and cognitive domains, and might therefore offer a better opportunity to measure cognitive decline over a longer …timeframe; such models could be useful in screening therapeutic compounds. In order to better define the cognitive impairments evident in BACHD and zQ175 HD mice, both were tested in an instrumental touchscreen visual discrimination assay designed to assess discrimination learning and cognitive flexibility. Methods: BACHD and zQ175 mice, as well as their WT controls were tested for their ability to discriminate two complex visual stimuli. Following this discrimination phase, the reinforcement contingencies were reversed and the previously incorrect stimulus became the correct stimulus. In a final, third phase of testing, two novel stimuli were introduced and mice were required to undergo a second round of discrimination testing with these stimuli. Results: Our results show that learning during the discrimination phase was similar between the WT and BACHD mice. In contrast, the zQ175 at 26 weeks of age showed decreased accuracy over the last 10 days of discrimination, compared to WT controls. During subsequent reversal and novel stimuli phases, both BACHD and zQ175 mice exhibited significant deficits compared to WT controls. CONCLUSIONS: Our results suggest that the BACHD, and for the first time, zQ175 HD models exhibit cognitive inflexibility and psychomotor slowing, a phenotype that is consistent with cognitive symptoms described in HD patients. Show more

Keywords: BACHD, zQ175, mouse, touchscreen, visual discrimination, reversal learning

DOI: 10.3233/JHD-130061

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 145-158, 2014

Authors: Vodicka, Petr | Lim, Junghyun | Williams, Dana T. | Kegel, Kimberly B. | Chase, Kathryn | Park, Hyunsun | Marchionini, Deanna | Wilkinson, Stephen | Mead, Tania | Birch, Helen | Yates, Dawn | Lyons, Kathy | Dominguez, Celia | Beconi, Maria | Yue, Zhenyu | Aronin, Neil | DiFiglia, Marian

Article Type: Research Article

Abstract: Background: Increasing mutant huntingtin (mHTT) clearance through the autophagy pathway may be a way to treat Huntington's disease (HD). Tools to manipulate and measure autophagy flux in brain in vivo are not well established. Objective: To examine the in vivo pharmacokinetics and pharmacodynamics of the lysosomal inhibitor chloroquine (CQ) and the levels of selected autophagy markers to determine usefulness of CQ as a tool to study autophagy flux in brain. Methods: Intraperitoneal injections of CQ were administered to WT and HDQ175/Q175 mice. CQ levels were measured by LC-MS/MS in WT brain, muscle and blood at 4 to 24 hours …after the last dose. Two methods of tissue preparation were used to detect by Western blot levels of the macroautophagy markers LC3II and p62, the chaperone mediated autophagy receptor LAMP-2A and the late endosome/lysosomal marker RAB7. Results: Following peripheral administration, CQ levels were highest in muscle and declined rapidly between 4 and 24 hours. In the brain, CQ levels were greater in the cortex than striatum, and levels persisted up to 24 hours post-injection. CQ treatment induced changes in LC3II and p62 that were variable across regions and tissue preparations. HDQ175/Q175 mice exposed to CQ had variable but diminished levels of LC3II, p62 and LAMP-2A, and increased levels of RAB7. Higher levels of mHTT were found in the membrane compartment of CQ treated HD mice. Conclusion: Our findings suggest that the response of brain to CQ treatment, a blocker of autophagy flux, is variable and not as robust as it has been demonstrated in vitro, suggesting that CQ treatment has limitations for modulating autophagy flux in vivo. Alternative methods, compounds, and technologies need to be developed to further investigate autophagy flux in vivo, especially in the brain. Show more

DOI: 10.3233/JHD-130081

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 159-174, 2014

Authors: Busse, Monica | Quinn, Lori | Khalil, Hanan | McEwan, Kirsten | the Outcome Measures Subgroup of the European Huntington's Disease Network

Article Type: Research Article

Abstract: Background: Many of the performance-based mobility measures that are currently used in Huntington's disease (HD) were developed for assessment in other neurological conditions such as stroke. Objective: We aimed to assess the individual item-response of commonly used performance-based mobility measures, with a view to optimizing the scales for specific application in Huntington's Disease (HD). Method: Data from a larger multicentre, observational study were used. Seventy-five people with HD (11 pre-manifest & 64 manifest) were assessed on the Six-Minute Walk Test, 10-Meter Walk Test, Timed “Up & Go” Test (TUG), Berg Balance Scale (BBS), Physical Performance Test (PPT), Four Square Step …Test, and Tinetti Mobility Test (TMT). The Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, Functional Assessment Scale and Total Functional Capacity scores were recorded, alongside cognitive measures. Standard regression analysis was used to assess predictive validity. Individual item responses were investigated using a sequence of approaches to allow for gradual removal of items and the subsequent creation of shortened versions. Psychometric properties (reliability and discriminant ability) of the shortened scales were assessed. Results: TUG (β 0.46, CI 0.20-3.47), BBS (β −0.35, CI −2.10-0.14), and TMT (β −0.45, CI −3.14-0.64) were good disease-specific mobility measures. PPT was the best measure of functional performance (β 0.42, CI 0.00-0.43 for TFC & β 0.57 CI 0.15-0.81 for FAS). Shortened versions of BBS and TMT were developed based on item analysis. The resultant BBS and TMT shortened scales were reliable for use in manifest HD. ROC analysis showed that shortened scales were able to discriminate between manifest and pre-manifest disease states. Discussion: Our data suggests that the PPT is appropriate as a general measure of function in individuals with HD, and we have identified shortened versions of the BBS and TMT that measure the unique gait and balance impairments in HD. These scales, alongside the TUG, may therefore be important measures to consider in future clinical trials. Show more

Keywords: Huntington's Disease, mobility, outcome measures, function

DOI: 10.3233/JHD-140091

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 175-188, 2014

Authors: Bull, Michael T. | Darwin, Kristin | Venkataraman, Vinayak | Wagner, Joseph | Beck, Christopher A. | Dorsey, E. Ray | Biglan, Kevin M.

Article Type: Research Article

Abstract: Background: Virtual visits through web-based video conferencing can increase access to specialty care for individuals with Huntington disease (HD) and facilitate research participation. Objective: To determine the feasibility of conducting virtual visits directly into the homes of individuals with HD, to assess the reliability of conducting remote versus in-person motor assessments, and to determine the test-retest reliability of conducting motor assessments remotely. Methods: Individuals with mild to moderate HD underwent baseline in-person clinic assessments and completed a HD care survey. Participants were randomized to receive three virtual visits from one of two physicians over four months that included a modified …Unified Huntington's Disease Rating Scale motor examination (excluding rigidity and balance assessments) via web-based video conferencing. Intraclass coefficients (ICC) were calculated to determine the level of agreement between remote and in-person assessments. Participants also completed a survey on their interest in telemedicine. Results: Thirteen individuals underwent baseline assessments, eleven (85%) participants completed at least one virtual visit, and 27 (82%) of 33 total virtual visits were completed. Remote motor scores demonstrated good reliability (ICC = 0.78; n = 11) compared to in-person motor scores. Test-retest reliability of motor scores conducted remotely was excellent (ICC = 0.90; n = 11). Participants expressed moderate future interest in using virtual visits to participate in research and to receive care. Conclusion: In this pilot study, virtual visits into the home were feasible and reliable for conducting motor assessments in HD. Larger scale studies need to confirm and generalize these findings to a broader population of participants. Show more

Keywords: Telehealth, Huntington disease, feasibility, reliability, remote assessment

DOI: 10.3233/JHD-140102

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 189-195, 2014

Authors: Jones, Rebecca | Stout, Julie C. | Labuschagne, Izelle | Say, Miranda | Justo, Damian | Coleman, Allison | Dumas, Eve M. | Hart, Ellen | Owen, Gail | Durr, Alexandra | Leavitt, Blair R. | Roos, Raymund | O'Regan, Alison | Langbehn, Doug | Tabrizi, Sarah J. | Frost, Chris

Article Type: Research Article

Abstract: Background: Composite scores derived from joint statistical modelling of individual risk factors are widely used to identify individuals who are at increased risk of developing disease or of faster disease progression. Objective: We investigated the ability of composite measures developed using statistical models to differentiate progressive cognitive deterioration in Huntington's disease (HD) from natural decline in healthy controls. Methods: Using longitudinal data from TRACK-HD, the optimal combinations of quantitative cognitive measures to differentiate premanifest and early stage HD individuals respectively from controls was determined using logistic regression. Composite scores were calculated from the parameters of each statistical model. Linear regression …models were used to calculate effect sizes (ES) quantifying the difference in longitudinal change over 24 months between premanifest and early stage HD groups respectively and controls. ES for the composites were compared with ES for individual cognitive outcomes and other measures used in HD research. The 0.632 bootstrap was used to eliminate biases which result from developing and testing models in the same sample. Results: In early HD, the composite score from the HD change prediction model produced an ES for difference in rate of 24-month change relative to controls of 1.14 (95% CI: 0.90 to 1.39), larger than the ES for any individual cognitive outcome and UHDRS Total Motor Score and Total Functional Capacity. In addition, this composite gave a statistically significant difference in rate of change in premanifest HD compared to controls over 24-months (ES: 0.24; 95% CI: 0.04 to 0.44), even though none of the individual cognitive outcomes produced statistically significant ES over this period. Conclusions: Composite scores developed using appropriate statistical modelling techniques have the potential to materially reduce required sample sizes for randomised controlled trials. Show more

Keywords: Huntington disease, cognition, composite score, effect size, 0.632 bootstrap

DOI: 10.3233/JHD-140101

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 197-207, 2014

Authors: Davis, Marie Y. | Keene, C. Dirk | Jayadev, Suman | Bird, Thomas

Article Type: Research Article

Abstract: Background: Dementia is a common feature in both Huntington's disease (HD) and Alzheimer's disease (AD), as well as in the general elderly population. Few studies have examined elderly HD patients with dementia for neuropathologic evidence of both HD and AD. Objective: We present neuropathological findings in a retrospective case series of 15 elderly HD patients (ages 60–91 years), 11 of whom had prominent clinical dementia. Methods: Post-mortem brain tissue was examined and stained for evidence of both HD and AD including Vonsattel grading and Htt-repeat expansion, Bielskowsky, tau, β amyloid, and TDP43 immunostaining. Results: Mean age at death was 76.8 …years, mean disease duration was 18.6 years, and mean CAG repeat expansion was 42. Evidence of AD in addition to HD pathology was present in 9 of 11 (82%) patients with prominent dementia, suggesting that AD may be more commonly co-occurring with HD than previously appreciated. Two patients had only HD as the basis of dementia and four patients did not have prominent dementia. One patient with marked parkinsonian features was not L-dopa responsive and had no substantia nigra Lewy bodies at autopsy. Conclusions: Our study suggests that AD may frequently contribute to cognitive decline in elderly HD patients which complicates the assessment and management of such individuals. Further study is needed to determine if there is a higher incidence of AD in persons with HD compared to the general population. In addition, our series includes one HD patient whose clinical features masqueraded as Parkinson's disease but was not responsive to levodopa therapy. Show more

Keywords: Huntington's disease, Alzheimer's disease, dementia, parkinsonism

DOI: 10.3233/JHD-140111

Citation: Journal of Huntington's Disease, vol. 3, no. 2, pp. 209-217, 2014