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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.
