Serum Exosome Detection and Monitoring of Alcohol-Related White Matter Brain Pathology-Opportunities to Optimize Treatment and Monitoring of AUD-Related Organ and Tissue Damage in Diverse Populations

1 Chronic heavy or binge alcohol consumption damages the brain’s structural and functional integrity. These effects, in large measure, are caused by alcohol’s toxic and degenerative effects on white matter (WM). Consequences include declines in CNS neurobehavioral performance, reinforcement of dysfunctional activities, and multimodal

disabilities. Fortunately, growing evidence suggests that WM atrophy in alcohol-related brain degeneration (ARBD) may be partly reversible through abstinence, which could be effectuated by cognitive-behavioral, brief intervention, or neuro-modulatory strategies that reduce craving. However, to advance this aspect of alcohol use disorder (AUD)

research and patient care, efficient, non-invasive monitoring of treatment/intervention outcomes in relation to WM ARBD is needed. Our overarching hypothesis is that WM ARBD is rooted in oligodendrocyte dysfunction caused by oxidative stress, inflammation, and dysregulated signaling through insulin/IGF-1-PI3K-Akt-mTOR-mTORC.

These pathophysiological processes reduce mature oligodendrocyte populations and compact myelin, impair the maturation of immature oligodendroglia, and alter sphingolipid metabolism, resulting in sulfatide and sphingomyelin depletion and ceramide accumulation. Using established experimental rat models, we found that abstinence

partially reversed these pathologies, and more recently discovered that WM ARBD-related alterations in oligodendrocyte-myelin glycoprotein and lipid profiles can be detected in extracellular vesicles (EVs) isolated from brain and serum. Furthermore, we have preliminary evidence that comparable studies are feasible using human

samples. This R21 application leverages the gains achieved through ongoing research by logically extending an important sub-project included in Aim 3 of R01-AA028408. The main goal is to use our existing bank of human AUD and control serum from IRB-approved longitudinal studies in which samples were obtained before and after

either brief intervention counseling or short-term baclofen treatment. In addition, we have banked pre- and post- ghrelin treatment serum from a human laboratory study to assess the effects of craving on alcohol consumption. The approaches will include comparative biochemical and molecular analyses of EVs from AUD and control human

serum to characterize the effects of ethanol and different treatments on the expression of oligodendrocyte/myelin proteins, sphingolipids, and indices of stress. In addition, we plan to assess the sensitivity and specificity of analyzing total versus oligodendrocyte-derived (O4+) EVs to detect WM ARBD effects and responses to treatment.

This R21 proposal has the advantage of collecting relevant human data in parallel with ongoing experimental studies for potentially earlier clinical translation rather than awaiting the completion of rodent experiments, which already show promising results. Furthermore, the outcomes of this research will lead to insights into the utility of

EV-based serum-diagnostic aids for WM ARBD detection, responses to treatment, and accessible, inexpensive, prospective non-invasive monitoring that will especially benefit diverse underserved populations.