Background Alcohol-related brain damage caused by heavy alcohol misuse is associated with cognitive-motor impairment and white matter (WM) degeneration. Oligodendrocytes and myelin are major targets, but the underlying mechanisms remain incompletely characterized, particularly in humans. Purpose This study investigates the nature of oligodendrocyte dysfunction in anterior frontal lobe tissue from humans with alcohol use disorder (AUD), focusing on molecular and biochemical pathologies that may underlie WM ARBD. Methods Cores of fresh frozen human postmortem frontal lobe WM from adults with AUD or no history of substance use disorder (N = 6/group) were analyzed with duplex enzyme-linked immunosorbent assays, multiplex immunoassays, and multiplex RNA hybridization panels. Results AUD anterior frontal lobe WM tissue exhibited myelin loss with significant changes in oligodendrocyte/myelin glycoprotein immunoreactivity and mRNA expression, increased glial fibrillary acidic protein, and reduced expression of mRNA transcripts encoding upstream components of the insulin and insulin-like growth factor networks, aspartyl-asparaginyl-β-hydroxylase, and the Notch signaling pathway. In contrast, neuroinflammatory mediators and Alzheimer’s disease (AD) biomarkers were largely unaffected. Conclusion Human AUD anterior frontal lobe WM pathology is accompanied by significant alterations in oligodendrocyte and astrocyte function, with alterations in Notch and insulin/IGF signaling. The findings provide new information on the mechanisms of AUD-mediated WM degeneration as well as potential strategies for diagnosing ARBD in humans.
Monte et al. (Tue,) studied this question.