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

项目总结/摘要 亨廷顿舞蹈病（HD）患者的治疗正迅速进入一个新时代，基因- 沉默和疾病修饰疗法现在在临床试验中。虽然目前的研究包括患者 运动显性疾病，未来的临床试验将需要在症状前HD基因携带者中进行干预， 希望在运动症状出现之前改变疾病的进程。然而，关键的问题是， 仍然是如何针对潜在的治疗和衡量结果的大型和异质性人口， 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 在运动症状发作前几十年就出现了变化，但这些症状的全谱尚未出现。 已经很好地定义了，确切地说，哪些症状首先出现，以及如何测量它们仍然是问题， 辩论在外地。此外，关于18岁以下个人的数据基本上缺乏。 我们的初步数据表明，有患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， 神经精神症状，包括抑郁、焦虑和冲动行为。但 这些症状的神经生物学基础，社会和环境因素，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。 这个职业发展奖的目的是（1）调查CAG重复与 扩张，不良的童年经历，以及有HD风险的青少年的外化冒险行为;（2） 检查可能是该队列中冲动行为基础的反应抑制的改变;以及（3） 鉴定抑制控制神经生理学标志物，其可以代表可改变的治疗靶点， 未来的治疗试验 这项建议得到了一个多学科团队的支持，该团队的导师具有神经精神方面的专业知识。 神经退行性疾病的表现，儿童心理学和人类发展，以及 电生理学我的首要目标是成为一个独立的医生科学家与独特的专业知识 在评估前驱行为表现作为神经退行性疾病的早期标志物。 这项建议将建立在我以前的经验，并将提供一个独特的培训机会，以发展 神经生理学的新技能，纵向数据分析，以及当前神经发育的应用 心理障碍的模型，这将使我能够进行未来的独立调查， 在一个前瞻性的纵向队列中， 从青年到成年这项工作将填补一个关键的差距，我们的知识有关的最早表现的HD 并将有助于在疾病的预表现阶段更好地针对潜在的治疗。

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.