Browsing by Subject "Huntington Disease"

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    Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial
    (2016-07) Frank, Samuel; Testa, Claudia M.; Stamler, David; Kayson, Elise; Davis, Charles; Edmondson, Mary C.; Kinel, Shari; Leavitt, Blair; Oakes, David; O'Neill, Christine; Vaughan, Christina; Goldstein, Jody; Herzog, Margaret; Snively, Victoria; Whaley, Jacquelyn; Wong, Cynthia; Suter, Greg; Jankovic, Joseph; Jimenez-Shahed, Joohi; Hunter, Christine; Claassen, Daniel O.; Roman, Olivia C.; Sung, Victor; Smith, Jenna; Janicki, Sarah; Clouse, Ronda; Saint-Hilaire, Marie; Hohler, Anna; Turpin, Denyse; James, Raymond C.; Rodriguez, Ramon; Rizer, Kyle; Anderson, Karen E.; Heller, Hope; Carlson, Alexis; Criswell, Susan; Racette, Brad A.; Revilla, Fredy J.; Nucifora, Frederick, Jr.; Margolis, Russell L.; Ong, MaryJane; Mendis, Tilak; Mendis, Neila; Singer, Carlos; Quesada, Monica; Paulsen, Jane S.; Brashers-Krug, Thomas; Miller, Amanda; Kerr, Jane; Dubinsky, Richard M.; Gray, Carolyn; Factor, Stewart A.; Sperin, Elaine; Molho, Eric; Eglow, Mary; Evans, Sharon; Kumar, Rajeev; Reeves, Christina; Samii, Ali; Chouinard, Sylvain; Beland, Monica; Scott, Burton L.; Hickey, Patrick T.; Esmail, Sherali; Fung, Wai Lun Alan; Gibbons, Clare; Qi, Lina; Colcher, Amy; Hackmyer, Cory; McGarry, Andrew; Klos, Kevin; Gudesblatt, Mark; Fafard, Lori; Graffitti, Laura; Schneider, Daniel P.; Dhall, Rohit; Wojcieszek, Joanne M.; LaFaver, Kathrin; Duker, Andrew; Neefus, Erin; Wilson-Perez, Hilary; Shprecher, David; Wall, Paola; Blindauer, Karen A.; Wheeler, Lynn; Boyd, James T.; Houston, Emily; Farbman, Eric S.; Agarwal, Pinky; Eberly, Shirley W.; Watts, Arthur; Tariot, Pierre N.; Feigin, Andrew; Evans, Scott; Beck, Chris; Orme, Constance; Edicola, Jon; Christopher, Emily; Department of Neurology, IU School of Medicine
    Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.
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    Is There an Association of Physical Activity with Brain Volume, Behavior, and Day-to-day Functioning? A Cross Sectional Design in Prodromal and Early Huntington Disease
    (PLOS, 2016-03) Wallace, McKenzie; Downing, Nancy; Lourens, Spencer; Mills, James; Kim, Ji-in; Long, Jeffrey; Paulsen, Jane; Department of Biostatistics, School of Public Health
    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.
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    Longitudinal Beta-Binomial Modeling using GEE for Over-Dispersed Binomial Data
    (Wiley, 2017-03) Wu, Hongqian; Zhang, Ying; Long, Jeffrey D.; Department of Biostatistics, School of Public Health
    Longitudinal binomial data are frequently generated from multiple questionnaires and assessments in various scientific settings for which the binomial data are often overdispersed. The standard generalized linear mixed effects model may result in severe underestimation of standard errors of estimated regression parameters in such cases and hence potentially bias the statistical inference. In this paper, we propose a longitudinal beta-binomial model for overdispersed binomial data and estimate the regression parameters under a probit model using the generalized estimating equation method. A hybrid algorithm of the Fisher scoring and the method of moments is implemented for computing the method. Extensive simulation studies are conducted to justify the validity of the proposed method. Finally, the proposed method is applied to analyze functional impairment in subjects who are at risk of Huntington disease from a multisite observational study of prodromal Huntington disease.
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    Oxidative metabolism in YAC128 mouse model of Huntington's disease
    (Oxford University Press, 2015-09-01) Hamilton, James; Pellman, Jessica J.; Brustovetsky, Tatiana; Harris, Robert A.; Brustovetsky, Nickolay; Department of Pharmacology and Toxicology, IU School of Medicine
    Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month-old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mm glucose and 15 mm pyruvate. In the medium with 2.5 mm glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis.
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    A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease
    (2017-01) McGarry, Andrew; McDermott, Michael; Kieburtz, Karl; de Blieck, Elisabeth A.; Beal, Flint; Marder, Karen; Ross, Christopher; Shoulson, Ira; Gibert, Peter; Mallonee, William M.; Guttman, Mark; Wojcieszek, Joanne; Kumar, Rajeev; LeDoux, Mark S.; Jenkins, Mary; Rosas, H. Diana; Nance, Martha; Biglan, Kevin; Como, Peter; Dubinsky, Richard M.; Shannon, Kathleen M.; O'Suilleabhain, Padraig; Chou, Kelvin; Walker, Francis; Martin, Wayne; Wheelock, Vicki L.; McCusker, Elizabeth; Jankovic, Joseph; Singer, Carlos; Sanchez-Ramos, Juan; Scott, Burton; Suchowersky, Oksana; Factor, Stewart A.; Higgins, Donald S., Jr.; Molho, Eric; Revilla, Fredy; Caviness, John N.; Friedman, Joseph H.; Perlmutter, Joel S.; Feigin, Andrew; Anderson, Karen; Rodriguez, Ramon; McFarland, Nikolaus R.; Margolis, Russell L.; Farbman, Eric S.; Raymond, Lynn A.; Suski, Valerie; Kostyk, Sandra; Colcher, Amy; Seeberger, Lauren; Epping, Eric; Esmail, Sherali; Diaz, Nancy; Fung, Wai Lun Alan; Diamond, Alan; Frank, Samuel; Hanna, Philip; Hermanowicz, Neal; Dure, Leon S.; Cudkowicz, Merit; Department of Neurology, School of Medicine
    Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD.
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