Inhibitory Control and Externalizing Behaviors in Youth at Risk for Huntington Disease

有亨廷顿病风险的青少年的抑制控制和外化行为

基本信息

批准号：
10674016
负责人：
Katherine McDonell
金额：
$ 17.68万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674016
关键词：
Adolescence Adolescent Adolescent and Young Adult Adult Affect Age Aggressive behavior Anxiety Attention Automobile Driving Award Behavior Behavioral Biological Markers Blinded CAG repeat Child Child Psychology Childhood Chronic stress Clinical Clinical Trials Cognitive Coping Skills Data Data Analyses Data Set Dedications Detection Development Developmental Course Diagnosis Disease Disease Marker Disease Progression Early identification Electroencephalography Electrophysiology (science)Equipment and supply inventories Event-Related Potentials Executive Dysfunction Exhibits Face Family Funding Future Gene Silencing Genes Genetic Genetic Status Goals Human Development Huntington Disease Huntington gene Impairment Impulsive Behavior Individual Intervention Investigation K-Series Research Career Programs Knowledge Lead Length Longitudinal Studies Longitudinal cohort Measures Mental Depression Mental disorders Mentors Mentorship Modeling Monitor Motor Nerve Degeneration Neurobiology Neurodegenerative Disorders Neurologist Outcome Measure Participant Patient Self-Report Patients Persons Phase Phenotype Physicians Population Positioning Attribute Prevalence Protocols documentation Psychological Models Questionnaires Reporting Research Risk Risk Behaviors Risk Taking Scientist Stress Substance abuse problem Symptoms Therapeutic Trials Time Training United States Work Youth adverse childhood events autosome behavior prediction career development cohort environmental stressor executive function experience externalizing behavior follow-up genetic testing improved motor symptom multidisciplinary mutant neural correlate neurodevelopment neurodevelopmental effect neurophysiology neuropsychiatric symptom neuropsychiatry novel novel therapeutics pediatric trauma prospective response skills social training opportunity young adult

项目摘要

PROJECT SUMMARY/ABSTRACT The treatment of patients with Huntington disease (HD) is quickly entering a new era, with gene- silencing and disease-modifying therapies now in clinical trials. While current studies include patients with motor manifest disease, future clinical trials will require interventions in presymptomatic HD gene carriers in the hope of altering the course of the disease prior to the onset of motor symptoms. However, the critical question remains how to target potential therapies and measure outcomes in the large and heterogenous population of youth and young adults at risk for HD. Recent longitudinal studies have shown that cognitive and behavioral changes emerge decades before motor symptom onset, but the full spectrum of these symptoms has not yet been well-defined, and precisely which symptoms occur first and how to measure them remain matters of debate in the field. Furthermore, data on individuals under age 18 are largely lacking. Our preliminary data demonstrate that children who are at risk for HD face a multitude of challenges, including executive dysfunction, chronic stress, impaired coping skills, and significantly elevated neuropsychiatric symptoms, including depression, anxiety, and impulsive behaviors. However, the neurobiological basis of these symptoms, social and environmental contributing factors, and the potential impacts of mutant huntingtin protein and aberrant neurodevelopment remain unknown. The aims of this career development award are (1) to investigate the association between CAG repeat expansion, adverse childhood experiences, and externalizing risk-taking behavior in youth at risk for HD; (2) to examine alterations in response inhibition that may underlie impulsive behaviors in this cohort; and (3) to identify neurophysiological markers of inhibitory control that may represent modifiable treatment targets for future therapeutic trials. This proposal is supported by a multidisciplinary team of mentors with expertise in neuropsychiatric manifestations of neurodegenerative disorders, child psychology and human development, and electrophysiology. My overarching goal is to become an independent physician-scientist with unique expertise in the assessment of prodromal behavioral manifestations as early markers of neurodegenerative conditions. This proposal will build on my previous experience and will provide a unique training opportunity to develop new skills in neurophysiology, longitudinal data analysis, and the application of current neurodevelopmental models of psychological disorders that will allow me to conduct future independent investigations examining the developmental course of aberrant behaviors and impulse control in a prospective, longitudinal cohort from youth to adulthood. This work will fill a critical gap in our knowledge regarding the earliest manifestations of HD and will help to better target potential treatments during the premanifest phase of the disease.

项目概要/摘要亨廷顿病 (HD) 患者的治疗正在迅速进入一个新时代，基因治疗沉默和疾病缓解疗法目前正在进行临床试验。虽然目前的研究包括患有以下疾病的患者运动明显疾病，未来的临床试验将需要对症状前 HD 基因携带者进行干预希望在运动症状出现之前改变病程。然而，关键问题仍然是如何针对大量异质人群的潜在治疗方法并衡量结果青少年和年轻人有患 HD 的风险。最近的纵向研究表明，认知和行为变化在运动症状出现前几十年就出现了，但这些症状的全部范围尚未出现已经明确定义了哪些症状首先出现以及如何测量它们仍然是问题场内辩论。此外，很大程度上缺乏 18 岁以下个人的数据。我们的初步数据表明，有 HD 风险的儿童面临着多种挑战，包括执行功能障碍、慢性压力、应对技能受损以及显着升高神经精神症状，包括抑郁、焦虑和冲动行为。然而，这些症状的神经生物学基础、社会和环境影响因素以及潜在的突变亨廷顿蛋白和异常神经发育的影响仍然未知。该职业发展奖的目的是 (1) 调查 CAG 重复之间的关联扩张、不良童年经历以及有 HD 风险的青少年的冒险行为外化； (2) 至检查反应抑制的变化，这可能是该群体冲动行为的基础； (3) 至识别抑制控制的神经生理学标志物，这些标志物可能代表可修改的治疗目标未来的治疗试验。该提案得到了具有神经精神病学专业知识的多学科导师团队的支持神经退行性疾病、儿童心理学和人类发育的表现，以及电生理学。我的首要目标是成为一名具有独特专业知识的独立医师科学家评估前驱行为表现作为神经退行性疾病的早期标志。该提案将建立在我之前的经验基础上，并将提供独特的培训机会来发展神经生理学、纵向数据分析以及当前神经发育学应用的新技能心理障碍模型将使我能够进行未来的独立调查前瞻性纵向队列中异常行为和冲动控制的发展过程青年期到成年期。这项工作将填补我们关于 HD 最早表现的知识空白并将有助于在疾病的前期阶段更好地针对潜在的治疗。