Wernicke–Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated with impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, either isolated or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation (TDD)), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior which appeared to be dependent on TDD. Additionally, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

Wernicke-Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated to impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, isolate or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation; TDD), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior, which appears to be dependent on TDD. Also, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

Background Apolipoprotein E (APOE)-4 isoform, Reelin and Clusterin share VLDLR and APOER2 receptors and are related to cognition in neuropsychiatric disorders. These proteins are expressed in plasma and brain but studies involving plasma expression and cognition are scarce. Methods We studied the peripheral expression (plasma and PBMCs) of these proteins in 24 Alcohol Use Disorder (AUD)-diagnosed middle-aged subjects at 4-12 weeks of abstinence (t=0) and 34 controls. Cognition was assessed using the 'Test of Detection of Cognitive Impairment in Alcoholism' (TEDCA). In a follow-up study (t=1), we measured Reelin levels and evaluated cognitive improvement at six months of abstinence. Results APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively, reaching similar plasma levels in ε4 carriers, regardless of whether they were AUD subjects or controls. Plasma Reelin and Clusterin were higher in the AUD group, and Reelin levels peaked inpatients expressing APOE4 (p<0.05, ⴄ 2=0.09), who showed reduced VLDLR and ApoER2 expression in PBMCs. APOE4 had a negative effect on Memory/Learning mainly in the AUD group (p<0.01, ⴄ 2=0.15).Multivariate logistic regression analyses identified plasma Reelin as a good indicator of AUD cognitive impairment at t=0.At t=1, AUD subjects showed lower Reelin levels versus controls, along with some cognitive improvement. Conclusions Reelin plasma levels are elevated during early abstinence in AUD subjects who express the APOE4 isoform, identifying cognitive deterioration to a great extent, and it may participate as a homeostatic signal for cognitive recovery in the long-term.

Background: Human apolipoprotein (APO)-E4 has been related to neuropsychiatric disorders such as Alzheimer disease and cognitive decline. Reelin and Clusterin share the VLDLR and ApoER2 receptors with APOE4. Here we checked the role of these components in Alcohol Use Disorder (AUD)-induced cognitive decline. Methods: This is a cross-sectional study with AUD-diagnosed patients (DSM-5) (n=24) recruited from an outpatient Alcohol Programme and matched controls (n=34). Participants were assessed by the validated Test of Detection of Cognitive Impairment in Alcoholism (TEDCA). APOE4 presence in plasma (distinguishing APOE4 carriers and no carriers subjects) and its levels were performed by e4Quant technique. The rest of biological markers were tested by Enzyme-Linked Immunosorbent Assay kits. Results: Plasma APOE4 isoform was present in 37.5% and 58.8% of patients and controls, respectively. Quantification analyses revealed that APOE4 reached similar plasma levels in carriers independently if they were AUD subjects or controls. Circulant plasma APOE4 had a negative effect on AUD cognition, specifically affecting Memory/Learning (p<0.01; eta2=0.15). Plasma Clusterin and Reelin increased in patients but, interestingly, Reelin plasma levels peaked in patients expressing APOE4 (p<0.05, lower case Greek eta2=0.09), who showed reduced VLDL and ApoER2 expression in peripheral blood mononuclear cells (PBMCs). Reelin was a good predictor of cognitive loss in patients, accounting for the 42.3% and 54.0% of general intelligence and executive function impairments, respectively. Conclusions: Reelin plasma levels are increased in AUD patients who express the APOE4 isoform, predicting cognitive deterioration to a great extent. Remarkably, plasma Reelin helps to differentiate between AUD patients with and without cognitive decline.