PROJECT SUMMARY / ABSTRACT Hazardous alcohol use has grown substantially in the aging population. It remains unknown whether Alcohol Use Disorder (AUD) and its alcohol-related cognitive and brain decline increases risk for diagnostic mild cognitive impairment (MCI) or even can result in classic irreversible dementia. Motivating the proposal are 1) our longitudinal findings of accelerated aging of selective brain structures in AUD; 2) results of an animal model of high alcohol exposure in old compared with young, well-nourished male and female rats; and 3) preliminary results from non-alcoholic individuals meeting MCI criteria compared with AUD with similar extent of cognitive deficits revealing different age-related patterns of brain degradation. The findings led us to consider factors of nutritional deficiency and cytokine dysregulation that occur in both AUD and MCI and have the potential to contribute to common and unique disruption, accelerated by aging, of selective brain circuitry and cognitive sequelae in each diagnosis. We will test 180 actively drinking men and women (60 AUD, 60 non-alcoholic MCI, and 60 age-matched controls) before and after 18-24 months with structural MRI and diffusion tensor imaging (DTI). Recognizing mnemonic compromise associated with AUD and MCI, primary hypotheses will target the integrity of nodes and connections of Papez (limbic) circuit; white matter integrity will be assessed with deterministic fiber tracking and node-to-node integrity with probabilistic fiber tracking. Causal modeling will test the influence of specific independent variables of alcohol, nutrition, age, and sex hypothesized to have direct effects on inflammation and thalamic-hippocampal or cingulate-entorhinal connectivity, which, in turn, exert mediating influences on episodic memory. In addition to quantification of alcohol use and nutritional and inflammatory markers, modifiable risk factors to be examined include smoking, licit and illicit drugs, obesity-BMI, blood pressure, and physical activity. The parallel animal study will focus on the interaction of alcohol binge exposure and nutritional challenge with graded levels of thiamine deficiency and resulting cytokine, brain structure and connectivity, and behavioral sequelae in rats. AIM 1: In cross-sectional study, model for each diagnosis the influence of independent variables (i.e., alcohol, nutrition, age, and sex) and hypothesized mediating factors (i.e., inflammation) affecting neurocircuitry substrates of episodic memory. AIM 2: In longitudinal study, use trajectory analysis to quantify interim change in targeted neurocircuitry as a function of age. Causal modeling will use longitudinal change data of the independent variables. AIM 3: In longitudinal study, determine whether nutritional (thiamine) deficits are sufficient to produce enduring MR-detectable responses to high blood alcohol levels in wild-type Wistar rats.

PROJECT NARRATIVE Among the aging population it remains unknown whether Alcohol Use Disorder (AUD) and its alcohol-related cognitive and brain decline increases risk for diagnostic mild cognitive impairment (MCI) or even can result in a classic irreversible dementia. Characterization of brain pathology and its relation to cognitive deficits in AUD compared with MCI and identification of modifiable risk factors may provide biological markers and enhance mechanistic understanding of these disorders. Development of a translational animal model of AUD brain pathology will permit discovery of biological factors in addition to alcohol itself that contribute to brain damage and inform intervention and treatment efforts for reversing pathology and impairment.