# Molecular and biochemical correlates of frontal lobe white matter degeneration in humans with alcohol use disorder

## TL;DR

This study explores how alcohol use disorder causes white matter damage in the frontal lobe by affecting oligodendrocytes and myelin in human brain tissue.

## Contribution

The study identifies specific molecular and biochemical changes in oligodendrocyte and astrocyte function linked to alcohol-related white matter degeneration in humans.

## Key findings

- AUD frontal lobe tissue shows myelin loss and altered oligodendrocyte/myelin glycoprotein expression.
- Reduced mRNA for insulin/IGF and Notch signaling components were observed in AUD samples.
- Neuroinflammatory and Alzheimer’s disease markers were largely unchanged in AUD tissue.

## Abstract

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.

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.

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.

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.

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.