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.