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

• 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
• 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

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.

项目摘要/摘要 亨廷顿疾病（HD）患者的治疗迅速进入了一个新时代，基因 现在在临床试验中进行沉默和调整疾病改良疗法。目前的研究包括患者 运动表现疾病，未来的临床试验将需要在预症状HD基因携带者中进行干预 希望在运动症状发作之前改变疾病的过程。但是，关键问题 仍然是如何靶向潜在疗法并测量大量和异源种群的结果 青年和年轻人有高清风险。最近的纵向研究表明，认知和行为 运动症状发作前几十年出现的变化，但这些症状的全部范围尚未 定义明确，准确地说是首先发生哪些症状，如何测量它们仍然是 在场上的辩论。此外，在很大程度上缺乏有关18岁以下个人的数据。 我们的初步数据表明，面临高清风险的孩子面临许多挑战， 包括执行功能障碍，慢性压力，应对技巧受损以及显着提高 神经精神症状，包括抑郁，焦虑和冲动行为。但是， 这些症状的神经生物学基础，社会和环境促成因素以及潜力 突变亨廷汀蛋白和异常神经发育的影响尚不清楚。 该职业发展奖的目的是（1）调查CAG重复的关联 扩展，不利的童年经历以及外在的高清风险年轻人冒险行为； （2）至 检查反应抑制作用的改变，这可能是该队列中冲动行为的基础； （3）到 确定抑制性控制的神经生理标记，可能代表可修改的治疗靶标的 未来的治疗试验。 该建议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展的表现以及 电生理学。我的总体目标是成为具有独特专业知识的独立医师科学家 在评估前驱行为​​表现为神经退行性疾病的早期标志物中。 该建议将以我以前的经验为基础，并将提供独特的培训机会来发展 神经生理学，纵向数据分析和当前神经发育的应用 心理疾病的模型，这将使​​我能够进行未来的独立调查检查 从 青年到成年。这项工作将填补我们关于高清最早表现的知识的关键空白 并将有助于在疾病的前阶段更好地靶向潜在治疗。