Browsing by Subject "Huntington disease"
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Item Analysis of longitudinal censored semicontinuous data with application to the study of executive dysfunction: the Towers Task(Sage, 2017) Lourens, Spencer; Zhang, Ying; Long, Jeffrey D.; Paulsen, Jane S.; Biostatistics and Health Data Science, School of MedicineExecutive dysfunction is a deficiency in skills of planning and problem solving that characterizes many neuropsychiatric disorders. The Towers Task is a commonly used measure of planning and problem solving for assessing executive function. Towers Task data are usually zero-inflated and right-censored, and ignoring these features can result in biased inference for the disease characterization of executive dysfunction. In this manuscript, a mixed-effects model for longitudinal censored semicontinuous data is developed for analyzing longitudinal Towers Task data from the PREDICT-HD study. The model is contrasted with current practice and implications for general use are discussed.Item A clinical trial method to show delay of onset in Huntington disease(Wiley, 2019-02) Paulsen, Jane S.; Lourens, Spencer; Kieburtz, Karl; Zhang, Ying; Biostatistics, School of Public HealthBackground: Disease-modifying clinical trials in persons without symptoms are often limited in methods to assess the impact associated with experimental therapeutics. This study suggests sample enrichment approaches to facilitate preventive trials to delay disease onset in individuals with the dominant gene for Huntington disease. Methods: Using published onset prediction indexes, we conducted the receiver operating curve analysis for diagnosis within a 3-year clinical trial time frame. We determined optimal cut points on the indexes for participant recruitment and then conducted sample size and power calculations to detect varying effect sizes for treatment efficacy in reducing 3-year rates of disease onset (or diagnosis). Results: Area under the curve for 3 onset prediction indexes all demonstrated excellent value in sample enrichment methodology, with the best-performing index being the multivariate risk score (MRS). Conclusions: This study showed that conducting an intervention trial in premanifest and prodromal individuals with the gene expansion for Huntington disease is highly feasible using sample enrichment recruitment methods. Ongoing natural history studies are highly likely to indicate additional markers of disease prior to diagnosis. Statistical modeling of identified markers can facilitate participant enrichment to increase the likelihood of detecting a difference between treatment arms in a cost-effective and efficient manner. Such variations may expedite translation of emerging therapies to persons in an earlier phase of the disease.Item Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS)(Wiley, 2017-06) Quaid, Kimberly A.; Eberly, Shirley W.; Kayson-Rubin, Elise; Oakes, David; Shoulson, Ira; Huntington Study Group PHAROS Investigators; Medical and Molecular Genetics, School of MedicineHuntington disease (HD) is a late onset ultimately fatal neurodegenerative disorder caused by a cytosine-adenine-guanine ( CAG) triplet repeat expansion in the Huntingtin gene which was discovered in 1993. The PHAROS study is a unique observational study of 1001 individuals at risk for HD who had not been previously tested for HD and who had no plans to do so. In this cohort, 104 (10%) individuals changed their minds and chose to be tested during the course of the study but outside of the study protocol. Baseline behavioral scores, especially apathy, were more strongly associated with later genetic testing than motor and chorea scores, particularly among subjects with expanded CAG repeat length. In the CAG expanded group, those choosing to be tested were older and had more chorea and higher scores on the behavioral section of the unified Huntington's disease rating scale at baseline than those not choosing to be tested. Following genetic testing, 56% of subjects with CAG < 37 had less depression when compared to prior to testing, but depression generally stayed the same or increased for 64% of subjects in the expanded group. This finding suggests that approaches to testing must continue to be cautious, with appropriate medical, psychological and social support.Item Longitudinal diffusion changes in prodromal and early HD: Evidence of white-matter tract deterioration(Wiley, 2017-03) Shaffer, Joseph J.; Ghayoor, Ali; Long, Jeffrey D.; Kim, Regina Eun-Young; Lourens, Spencer; O’Donnell, Lauren J.; Westin, Carl-Fredrik; Rathi, Yogesh; Magnotta, Vincent; Paulsen, Jane S.; Johnson, Hans J.; Biostatistics, School of Public HealthINTRODUCTION: Huntington's disease (HD) is a genetic neurodegenerative disorder that primarily affects striatal neurons. Striatal volume loss is present years before clinical diagnosis; however, white matter degradation may also occur prior to diagnosis. Diffusion-weighted imaging (DWI) can measure microstructural changes associated with degeneration that precede macrostructural changes. DWI derived measures enhance understanding of degeneration in prodromal HD (pre-HD). METHODS: As part of the PREDICT-HD study, N = 191 pre-HD individuals and 70 healthy controls underwent two or more (baseline and 1-5 year follow-up) DWI, with n = 649 total sessions. Images were processed using cutting-edge DWI analysis methods for large multicenter studies. Diffusion tensor imaging (DTI) metrics were computed in selected tracts connecting the primary motor, primary somato-sensory, and premotor areas of the cortex with the subcortical caudate and putamen. Pre-HD participants were divided into three CAG-Age Product (CAP) score groups reflecting clinical diagnosis probability (low, medium, or high probabilities). Baseline and longitudinal group differences were examined using linear mixed models. RESULTS: Cross-sectional and longitudinal differences in DTI measures were present in all three CAP groups compared with controls. The high CAP group was most affected. CONCLUSIONS: This is the largest longitudinal DWI study of pre-HD to date. Findings showed DTI differences, consistent with white matter degeneration, were present up to a decade before predicted HD diagnosis. Our findings indicate a unique role for disrupted connectivity between the premotor area and the putamen, which may be closely tied to the onset of motor symptoms in HD. Hum Brain Mapp 38:1460-1477, 2017. © 2017 Wiley Periodicals, Inc.Item Motor onset and diagnosis in Huntington disease using the diagnostic confidence level(Springer, 2015-12) Liu, Dawei; Long, Jeffrey D.; Zhang, Ying; Raymond, Lynn A.; Marder, Karen; Rosser, Anne; McCusker, Elizabeth A.; Mills, James A.; Paulsen, Jane S.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthHuntington disease (HD) is a neurodegenerative disorder characterized by motor dysfunction, cognitive deterioration, and psychiatric symptoms, with progressive motor impairments being a prominent feature. The primary objectives of this study are to delineate the disease course of motor function in HD, to provide estimates of the onset of motor impairments and motor diagnosis, and to examine the effects of genetic and demographic variables on the progression of motor impairments. Data from an international multisite, longitudinal observational study of 905 prodromal HD participants with cytosine-adenine-guanine (CAG) repeats of at least 36 and with at least two visits during the followup period from 2001 to 2012 was examined for changes in the diagnostic confidence level from the Unified Huntington's Disease Rating Scale. HD progression from unimpaired to impaired motor function, as well as the progression from motor impairment to diagnosis, was associated with the linear effect of age and CAG repeat length. Specifically, for every 1-year increase in age, the risk of transition in diagnostic confidence level increased by 11% (95% CI 7-15%) and for one repeat length increase in CAG, the risk of transition in diagnostic confidence level increased by 47% (95% CI 27-69%). Findings show that CAG repeat length and age increased the likelihood of the first onset of motor impairment as well as the age at diagnosis. Results suggest that more accurate estimates of HD onset age can be obtained by incorporating the current status of diagnostic confidence level into predictive models.Item Mutant huntingtin does not cross the mitochondrial outer membrane(Oxford University Press, 2020-10-10) Hamilton, James; Brustovetsky, Tatiana; Khanna, Rajesh; Brustovetsky, Nickolay; Pharmacology and Toxicology, School of MedicineMutant huntingtin (mHTT) is associated with mitochondria, but the exact mitochondrial location of mHTT has not been definitively established. Recently, it was reported that mHTT is present in the intermembrane space and inhibits mitochondrial protein import by interacting with TIM23, a major component of mitochondrial protein import machinery, but evidence for functional ramifications were not provided. We assessed mHTT location using synaptic and nonsynaptic mitochondria isolated from brains of YAC128 mice and subjected to alkali treatment or limited trypsin digestion. Mitochondria were purified either with discontinuous Percoll gradient or with anti-TOM22-conjugated iron microbeads. We also used mitochondria isolated from postmortem brain tissues of unaffected individuals and HD patients. Our results demonstrate that mHTT is located on the cytosolic side of the mitochondrial outer membrane (MOM) but does not cross it. This refutes the hypothesis that mHTT may interact with TIM23 and inhibit mitochondrial protein import. The levels of expression of nuclear-encoded, TIM23-transported mitochondrial proteins ACO2, TUFM, IDH3A, CLPP and mitochondrially encoded and synthesized protein mtCO1 were similar in mitochondria from YAC128 mice and their wild-type littermates as well as in mitochondria from postmortem brain tissues of unaffected individuals and HD patients, supporting the lack of deficit in mitochondrial protein import. Regardless of purification technique, mitochondria from YAC128 and WT mice had similar respiratory activities and mitochondrial membrane potentials. Thus, our data argue against mHTT crossing the MOM and entering into the mitochondrial intermembrane space, making it highly unlikely that mHTT interacts with TIM23 and inhibits protein import in intact mitochondria.Item NEURAL CORRELATES AND PROGRESSION OF SACCADE IMPAIRMENT IN PREMANIFEST AND MANIFEST HUNTINGTON DISEASE(2010-10-15) Rupp, Jason Douglas; Foroud, Tatiana; Conneally, P. Michael; Kareken, David A.; Saykin, Andrew J.; Wojcieszek, JoanneHuntington disease (HD) is an autosomal dominant disorder characterized by progressive decline of motor, cognitive, and behavioral function. Saccades (rapid, gaze-shifting eye movements) are affected before a clinical diagnosis of HD is certain (i.e. during the premanifest period of the disease). Fundamental questions remain regarding the neural substrates of abnormal saccades and the course of premanifest disease. This work addressed these questions using magnetic resonance imaging (MRI) and a longitudinal study of premanifest disease progression. Gray matter atrophy is a characteristic of HD that can be reliably detected during the premanifest period, but it is not known how such changes influence saccadic behavior. We evaluated antisaccades (AS) and memory guided saccades (MG) in premanifest and manifest HD, then tested for associations between impaired saccadic measures and gray matter atrophy in brain regions involved in these saccadic tasks. The results suggest that slowed vertical AS responses indicate cortical and subcortical atrophy and may be a noninvasive marker of atrophic changes in the brain. We also investigated the brain changes that underlie AS impairment using an event-related AS design with functional MRI (fMRI). We found that, in premanifest and manifest HD, blood oxygenation level dependent (BOLD) response was abnormally absent in the pre-supplementary motor area and dorsal anterior cingulate cortex following incorrect AS responses. These results are the first to suggest that abnormalities in an error-related response network underlie early disease-related saccadic changes, and they emphasize the important influence of regions outside the striatum and frontal cortex in disease manifestations. Though saccadic abnormalities have been repeatedly observed cross sectionally, they have not yet been studied longitudinally in premanifest HD. We found different patterns of decline; for some measures the rate of decline increased as individuals approached onset, while for others the rate was constant throughout the premanifest period. These results establish the effectiveness of saccadic measures in tracking premanifest disease progression, and argue for their use in clinical trials. Together, these studies establish the utility of saccade measures as a marker of HD neurodegeneration and suggest that they would be a valuable component of batteries evaluating the efficacy of neuroprotective therapies.Item Phenotype Characterization of HD Intermediate Alleles in PREDICT-HD(IOS Press, 2016-12-15) Downing, Nancy R.; Lourens, Spencer; De Soriano, Isabella; Long, Jeffrey D.; Paulsen, Jane S.; PREDICT-HD Investigators and Coordinators of the Huntington Study Group; Biostatistics, School of Public HealthBACKGROUND: Huntington disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion on chromosome 4. Pathology is associated with CAG repeat length. Prior studies examining people in the intermediate allele (IA) range found subtle differences in motor, cognitive, and behavioral domains compared to controls. OBJECTIVE: The purpose of this study was to examine baseline and longitudinal differences in motor, cognitive, behavioral, functional, and imaging outcomes between persons with CAG repeats in three ranges: normal (≤26), intermediate (27-35), and reduced penetrance (36-39). METHODS: We examined longitudinal data from 389 participants in three allele groups: 280 normal controls (NC), 21 intermediate allele [IA], and 88 reduced penetrance [RP]. We used linear mixed models to identify differences in baseline and longitudinal outcomes between groups. Three models were tested: 1) no baseline or longitudinal differences; 2) baseline differences but no longitudinal differences; and 3) baseline and longitudinal differences. RESULTS: Model 1 was the best fitting model for most outcome variables. Models 2 and 3 were best fitting for some of the variables. We found baseline and longitudinal trends of declining performance across increasing CAG repeat length groups, but no significant differences between the NC and IA groups. CONCLUSION: We did not find evidence to support differences in the IA group compared to the NC group. These findings are limited by a small IA sample size.Item Two Decades of Huntington Disease Testing: Patient’s Demographics and Reproductive Choices(2013-10) Krukenberg, Rebekah C; Koller, Daniel L; Weaver, David D; Dickerson, Jennifer N; Quaid, Kimberly APredictive testing for Huntington disease (HD) has been available in the United States (US) since 1987, and the Indiana University Predictive Testing Program has been providing this testing since 1990. To date there has been no published description of those who present for such testing in the US. Here we describe demographics of 141 individuals and reproductive decision making of a subset of 16 of those individuals who underwent predictive HD testing between 1990 and 2010 at one site in the US. This study is a retrospective chart review of the “Personal History Questionnaire” participants completed prior to testing. As seen in other studies, most participants were female (64.5 %), in their mid-30s (mean = 34), and had at least one child prior to testing (54 %). Multiple demographic datum points are described, and the reproductive decision making of these at-risk individuals was analyzed using Fisher’s Exact Tests. Of those women who had children before learning of their risk to inherit HD, those who attended church more frequently, had three or more children total, or whose mother was affected with HD were more likely to be comfortable with their choice to have children. We conclude that these demographic factors influence the reproductive decision-making of individuals at risk for HD. Psychologists, clinical geneticists, and genetic counselors may be able to use this information to help counsel at-risk patients regarding current or past reproductive decision making.