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Alcohol-related brain damage in humans.

ABSTRACT: Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin ? II, and ?- and ?-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in ?-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in ?-spectrin protein levels, and a significant increase in transmembranous ?3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of ?-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic ?- and ?-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.

SUBMITTER: Erdozain AM

PROVIDER: S-EPMC3974765 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Alcohol-related brain damage in humans.

Erdozain Amaia M AM Morentin Benito B Bedford Lynn L King Emma E Tooth David D Brewer Charlotte C Wayne Declan D Johnson Laura L Gerdes Henry K HK Wigmore Peter P Callado Luis F LF Callado Luis F LF Carter Wayne G WG

PloS one 20140403 4

Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homoge ...[more]

PMID: 24699688

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Project description:BACKGROUND:Alcohol-related brain damage (ARBD) is associated with neurotoxic effects of heavy alcohol use and nutritional deficiency, in particular thiamine deficiency (TD), both of which induce inflammatory responses in brain. Although neuroinflammation is a critical factor in the induction of ARBD, few studies have addressed the specific contribution(s) of ethanol (EtOH) versus TD. METHODS:Adult rats were randomly divided into 6 conditions: chronic EtOH treatment (CET) where rats consumed a 20% v/v solution of EtOH for 6 months; CET with injections of thiamine (CET + T); severe pyrithiamine-induced TD (PTD); moderate PTD; moderate PTD during CET; and pair-fed controls. After the treatments, the rats were split into 3 recovery phase time points: the last day of treatment (time point 1), acute recovery (time point 2: 24 hours posttreatment), and delayed recovery (time point 3: 3 weeks posttreatment). At these time points, vulnerable brain regions (thalamus, hippocampus, frontal cortex) were collected and changes in neuroimmune markers were assessed using a combination of reverse transcription polymerase chain reaction and protein analysis. RESULTS:CET led to minor fluctuations in neuroimmune genes, regardless of the structure being examined. In contrast, PTD treatment led to a profound increase in neuroimmune genes and proteins within the thalamus. Cytokine changes in the thalamus ranged in magnitude from moderate (3-fold and 4-fold increase in interleukin-1? [IL-1?] and I?B?) to severe (8-fold and 26-fold increase in tumor necrosis factor-? and IL-6, respectively). Though a similar pattern was observed in the hippocampus and frontal cortex, overall fold increases were moderate relative to the thalamus. Importantly, neuroimmune gene induction varied significantly as a function of severity of TD, and most genes displayed a gradual recovery across time. CONCLUSIONS:These data suggest an overt brain inflammatory response by TD and a subtle change by CET alone. Also, the prominent role of TD in the immune-related signaling pathways leads to unique regional and temporal profiles of induction of neuroimmune genes.

Project description:BackgroundAn understanding of alcohol's acute neural effects could augment our knowledge of mechanisms underlying alcohol-related cognitive/motor impairment and inform interventions for addiction. Focusing on studies employing event-related brain potential methods, which offer a direct measurement of neural activity in functionally well-characterized brain networks, we present the first meta-analysis to explore acute effects of alcohol on the human brain.MethodsDatabases were searched for randomized laboratory alcohol-administration trials assessing brain activity using event-related potentials. Hedges' g coefficients were pooled using 3-level random-effects meta-regression.ResultsSixty independent randomized controlled trials met inclusion (total N = 2149). Alcohol's effects varied significantly across neural systems, with alcohol leading to reductions in event-related potential components linked with attention (P3b), g = -0.40, 95% CI (-0.50, -0.29), automatic auditory processing (mismatch negativity), g = -0.44, 95% CI (-0.66, -0.22), and performance monitoring (error-related negativity), g = -0.56, 95% CI (-0.79, -0.33). These effects were moderated by alcohol dose, emerging as significant at doses as low as 0.026% blood alcohol concentration and increasing to moderate/large at 0.12%. In contrast, irrespective of dose, relatively small or nonsignificant alcohol effects emerged in other processing domains, including those linked to executive control (N2b responses) and stimulus classification (N2c responses).ConclusionsContrary to traditional conceptualizations of alcohol as a "dirty drug" with broad central nervous system depressant effects, results instead support accounts positing targeted alcohol effects in specific processing domains. By identifying alcohol effects on brain systems involved in performance monitoring and attention, results move toward the identification of mechanisms underlying alcohol-related impairment as well as factors reinforcing addiction.

Project description:Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver-brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.

Dataset Information

Alcohol-related brain damage in humans.

Publications

Alcohol-related brain damage in humans.

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