Sex Differences in Alcohol Use Disorder Neurodegeneration using Multimodal PET and DTI Neuroimaging

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Project Summary/Abstract The program of research and training described in this K01 application will provide the candidate with the requisite skills to become an independent investigator understanding sex differences in neurodegeneration (i.e., microglia and white matter tracts) and neurocognition in alcohol use disorder (AUD) to identify novel treatment targets that address sex differences. The research component of this 5-year plan involves the application of: (1) positron emission tomography (PET) imaging to examine sex differences in neurocognitive function that underlie sex differences in microglia levels in AUD; (2) diffusion tensor magnetic resonance imaging (DTI) to examine sex differences in white matter tract integrity in AUD and; (3) PET and DTI multimodal integration analysis to determine the relationship between microglia levels, white matter tract integrity, and neurocognitive function in women and men with AUD. Sixty (15 male and 15 female) individuals with AUD and 30 age-, sex-, and smoking-matched healthy controls will participate in both PET and DTI scanning to facilitate PET, DTI, and PET/DTI integration analysis. To systematically identify sex differences in patterns of white matter tract integrity, the candidate will also examine data from a large, archived, neuroimaging DTI dataset (The Human Connectome Project), to generate publications and productivity during data collection. This combination of novel data collection and secondary data analyses is designed to maximize the candidate's training via provision of hands-on experience in both: (1) the theory and conduct of her own combined multimodal neuroimaging study under guided supervision of recognized experts; and, (2) the analysis and interpretation of large-scale neuroimaging datasets. In pursuit of these goals, the candidate proposes to undertake further training in four primary areas: (1) the neurobiology of AUD, (2) treatment outcomes research and clinical corelates of AUD, (3) DTI and multimodal neuroimaging, and (4) biostatistical approaches. The opportunities afforded by the K01 mechanism would enable the candidate to embark on a rigorous, structured 5-year program of training and research, designed to provide her with the necessary skills in the four areas highlighted above. This program of study will combine formal didactic courses, directed readings, one-on-one tutorials, specialized workshops, attendance of scientific research conferences, and mentored research experience. The research and training proposed in this K01 provides an ideal interdisciplinary opportunity to achieve the candidate's long-term career goal of becoming an independent scientist with a particular focus on sex as a biological variable in the neurobiology of AUD. The team of mentors and collaborators are leaders in these fields and, together with the stimulating and collaborative environment of the Yale School of Medicine, will facilitate the candidate's growth and prepare her for an independent career at the interface of AUD neuroscience and neuroimaging research.