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

项目摘要/摘要 亨廷顿病(HD)患者的治疗正迅速进入一个新时代，基因- 沉默和疾病修改疗法目前正在进行临床试验。虽然目前的研究包括患有 运动显性疾病，未来的临床试验将需要干预症状前HD基因携带者在 希望在出现运动症状之前改变病程。然而，关键的问题是 仍然是如何针对潜在的治疗方法并在庞大的异种人群中衡量结果 青少年和有患HD风险的年轻人。最近的纵向研究表明，认知和行为 这些变化在运动症状出现前几十年就出现了，但这些症状的全谱还没有。 已经很好地定义了，以及哪些症状首先出现以及如何衡量它们仍然是问题所在 在田野上的辩论。此外，关于18岁以下个人的数据在很大程度上是缺乏的。 我们的初步数据显示，患有HD风险的儿童面临着一系列挑战， 包括执行功能障碍、慢性压力、应对技能受损，以及显著升高 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，社会和环境因素，以及潜在的 突变的亨廷顿蛋白和异常神经发育的影响尚不清楚。 这一职业发展奖的目的是(1)调查CAG重复之间的联系 HD高危青少年的扩展、不良童年经历和外化冒险行为；(2) 检查反应抑制的变化，这些变化可能是该队列中冲动行为的基础；以及(3) 确定抑制控制的神经生理标记物，这些标记物可能代表可修改的治疗目标 未来的治疗试验。 这项提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。 神经退行性疾病的表现、儿童心理和人类发展，以及 电生理学。我的首要目标是成为一名拥有独特专业知识的独立内科科学家 在评估前驱行为表现作为神经退行性疾病的早期标志方面。 这项建议将建立在我以前的经验基础上，并将提供一个独特的培训机会来发展 神经生理学、纵向数据分析和现代神经发育的应用方面的新技能 心理障碍的模型，这将使我能够进行未来的独立调查 儿童异常行为和冲动控制的发展过程 从年轻到成年。这项工作将填补我们对HD最早表现的认识上的一个关键空白 并将有助于在疾病的显性前期更好地针对潜在的治疗方法。

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.