Human alcohol-related neuropathology

Abstract

Alcohol-related diseases of the nervous system are caused by excessive exposures to alcohol, with or without co-existing nutritional or vitamin deficiencies. Toxic and metabolic effects of alcohol (ethanol) vary with brain region, age/developmental stage, dose, and duration of exposures. In the mature brain, heavy chronic or binge alcohol exposures can cause severe debilitating diseases of the central and peripheral nervous systems, and skeletal muscle. Most commonly, long-standing heavy alcohol abuse leads to disproportionate loss of cerebral white matter and impairments in executive function. The cerebellum (especially the vermis), cortical-limbic circuits, skeletal muscle, and peripheral nerves are also important targets of chronic alcohol-related metabolic injury and degeneration. Although all cell types within the nervous system are vulnerable to the toxic, metabolic, and degenerative effects of alcohol, astrocytes, oligodendrocytes, and synaptic terminals are major targets, accounting for the white matter atrophy, neural inflammation and toxicity, and impairments in synaptogenesis. Besides chronic degenerative neuropathology, alcoholics are predisposed to develop severe potentially life-threatening acute or subacute symmetrical hemorrhagic injury in the diencephalon and brainstem due to thiamine deficiency, which exerts toxic/metabolic effects on glia, myelin, and the microvasculature. Alcohol also has devastating neurotoxic and teratogenic effects on the developing brain in association with fetal alcohol spectrum disorder/fetal alcohol syndrome. Alcohol impairs function of neurons and glia, disrupting a broad array of functions including neuronal survival, cell migration, and glial cell (astrocytes and oligodendrocytes) differentiation. Further progress is needed to better understand the pathophysiology of this exposure-related constellation of nervous system diseases and better correlate the underlying pathology with in vivo imaging and biochemical lesions.

Astrocyte Dysfunction Induced by Alcohol in Females but Not Males

“…Dysregulated ubiquitination contributes to the development of Alzheimer's disease and other neurodegenerative disorders [for review, see (8)], and is associated with demyelination and white matter degeneration (123). Myelin degradation has been associated with ethanol abuse (2,28,68), but to our knowledge males and females have not been examined separately. Though complex, TNF production has been associated with enhanced demyelination (66), while Tgfb1 expression reduces demyelination (33).…”

Understanding the addiction cycle: A complex biology with distinct contributions of genotype vs. sex at each stage

“…During the abstinence phase, analysis identified atherosclerosis signaling as the top pathway in the low response WSR model. In contrast, in the WSP model phosphatidylethanolamine biosynthesis was significant during abstinence, which may reflect the complex effects of alcohol toxicity on myelin synthesis (de la Monte and Kril, 2014). Combined, these results suggest that optimal targets for the treatment of alcohol dependence are complex and likely to be distinct in males and females and also at each stage of addiction.…”

Fetal Alcohol Syndrome, Chemo-Biology and OMICS: Ethanol Effects on Vitamin Metabolism During Neurodevelopment as Measured by Systems Biology Analysis

“…T he maternal consumption of alcohol, especially during the initial 3-6 weeks of brain development, can lead to abnormal fetal nervous system changes during pregnancy, resulting in fetal alcohol syndrome (FAS) and fetal alcohol syndrome disorders (FASD) (de la Monte and Kril, 2014;Jaurena et al, 2011;O'Leary, 2004;Wentzel and Eriksson, 2009;Zhou et al, 2011). Although alcohol abstinence is recommended during pregnancy, more than 20% of pregnant women worldwide continue to abuse alcohol (van der Wulp et al, 2013).…”