Stress, Inflammation, and Neurocognitive Functioning in Adults with Huntington’s Disease - PROJECT SUMMARY Huntington’s disease (HD) is a chronic, fatal neurodegenerative disease characterized by impairments in multiple domains of neurocognitive functioning, particularly executive dysfunction (e.g., inhibitory control, working memory). Notably, levels of impairment in executive functioning within HD are highly heterogenous and the specific underlying mechanisms driving declines are not well understood. Evidence from seminal reviews and longitudinal empirical studies (e.g., Slavich & Irwin, 2014; Zainal & Newman, 2022), have identified chronic stress and inflammation as two important mechanisms that contribute to executive functioning deficits in other populations. However, little to no research has investigated how stress and inflammatory mechanisms may be contributing to declines in executive functioning in HD. The proposed study will fill this gap in the literature by examining the contribution of chronic stress, inflammation, and disease processes to impairments in executive functioning in a sample of adults with HD. The proposed study will leverage access to participants in an ongoing NIH grant (R01HD104188; m-PI’s: Compas & Claassen) testing the longitudinal associations among social connectedness and health behaviors in HD patients and their families as compared to a community sample of families. The primary goals of the proposed study are three- fold. First, this study will improve the quality of the measurement of stress in individuals with HD by adapting and using state-of the art methodology (i.e., stress interviews with a blind rating component) to assess general and disease specific stressful events in a sample of individuals with HD compared to a community sample of adults. It is hypothesized that individuals with HD will exhibit a greater number of general acute and chronic stressful events on average compared to a community sample of adults. Further, variability in disease specific acute and chronic stress within the HD sample will be associated with relevant demographic and disease characteristics (e.g., disease progression). Second, the proposed study will investigate two candidate mechanisms, chronic stress and CAG by Age Product (CAP) scores (a standardized marker of disease burden; Warner et al., 2022) that may contribute to heightened inflammatory processes in a HD sample. Lastly, direct and indirect path analyses will examine associations of stress, inflammatory cytokines, and CAP scores with impairments in executive functioning in a sample of individuals with HD. Because the proposed is embedded within a larger, longitudinal grant, a portion of analyses for the final aim will be tested both cross- sectionally and prospectively at 6-month follow-up. Training for the applicant will include development of new skills with biological methods (i.e., inflammatory cytokine assays), data management and analyses, along with an opportunity to expand knowledge on the biological underpinnings of stress and disease processes on an important indicator of functioning, executive function. Finally, evidence from this proposal yields potential important ramifications on treatment and intervention targets for supportive care in this population.
