Laura Orio

Alcohol use disorder (AUD) is linked to cognitive deficits that can persist even after prolonged abstinence. Research highlighted associations between plasma apolipoproteins and cognition in AUD. This study examines the longitudinal evolution of plasma apolipoproteins and inflammation in AUD patients during early and prolonged abstinence and their association with cognitive recovery. Thirty‐three AUD patients from an outpatient hospital alcoholism programme were evaluated at baseline ( t = 0), 6 months ( t = 1) and 12 months ( t = 2), along with 34 healthy controls. Cognitive performance was assessed using the TEDCA test, which measures general cognitive function (GCF). Biological assessments included plasma pro‐inflammatory biomarkers (LPS and LBP) and several apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ and APOM). AUD patients showed elevated plasma LPS, APOAI, APOE, APOJ and downregulated APOM, which all normalized at t = 1, whereas cognitive improvement was significant at t = 2 compared to controls. Mixed‐effects models including all covariates and within‐between person decomposition, followed by correlation matrix and reduced mixed models sensitivity analysis support robust associations between better GCF and (1) the duration of abstinence and (2) within‐person reductions in LPS, although apolipoprotein changes should be considered exploratory at this level. Prolonged abstinence in AUD patients normalizes plasma peripheral inflammation and apolipoprotein levels and improves cognition. Although APOAI and APOM showed opposite trajectories, as opposite biomarkers in AUD diagnosis reported previously, only the duration of abstinence and normalization of within‐person blood LPS levels over time emerged as predictors of cognitive recovery.

A sex perspective in the behavioural effects induced by alcohol binge exposure during youth or early adulthood remain limited. This study aimed to evaluate the effects of high doses of ethanol on emotional behaviour and cognition in 8-weeks old rats, from a sex perspective. Male and female animals were exposed to ethanol binges (3 g/kg, i.g.; 3 times/day x 4 days) in a 2days on-2days off paradigm and assessed in the elevated plus maze (EPM), forced swimming test (FST), saccharin preference test (SPT), Morris water maze (MWM) and novel object recognition (NOR) test. Baseline differences between control male and females were observed in emotional, motivational and cognitive tasks. Additionally, Intensive Alcohol Exposure (IAE) exerted sex-specific effects in: a) EPM: males showed anxiety and no effect in females; b) FST: depressive-like symptoms in both sexes but more pronounce immobility time in females; c) NOR test: impairment in a short-term memory in both sexes but females displayed improved performance in a long-term versus their controls. No IAE-related effects were found in the SPT or MWM. These results suggest inherent sex-differences in rodent performance in behavioural tests assessing emotional, motivational and cognitive behaviours. Additionally, IAE may impact male and females differently during abstinence in early adulthood. These findings underscore the importance of considering sex as a critical variable for preclinical studies.

Wernicke's encephalopathy (WE) is caused by thiamine deficiency (TD) whose main risk factor is alcohol use disorder. Pathogenic mechanisms associated with WE include mitochondrial dysfunction, oxidative stress and neuroinflammation. This study aims to explore the gene expression signature of certain candidate genes related to neuroinflammation, mitochondrial dysfunction and thiamine metabolism in the hippocampus from animals exposed to chronic alcohol consumption, thiamine deficiency or the combination of both. Male Wistar rats (n=42) were randomly assigned to 4 experimental groups: control (C) receiving tap water or tap water plus thiamine (0.2 g/L), chronic alcohol (CA) forced ingestion for 36 weeks, TD diet and pyrithiamine for 12 days (TDD) and CA combined with TDD. The relative gene expression of neurotrophic factors (Ptn, Mdk, Ptprz), proinflammatory molecules (Tlr4, Ccl2 and Hmgb1), mitochondrial homeostatic factors (Mfn1 and Mfn2) and thiamine metabolism (Tpk1) was analyzed in RNA isolated from the hippocampus across all experimental groups. Differences in gene expression were assessed using non-parametric tests (Kruskal-Wallis). Ptprz mRNA levels tended to be downregulated in the TDD group compared to controls (p=0.06, non-significant) and levels were significantly decreased related to the CA+TDD group (p<0.05). TDD group showed the lowest expression levels of Ptn across all experimental groups, and this decrease was statistically significant compared to the control and CA groups (p<0.05). Our findings indicate a differential gene expression profile of the PTN-MDK-PTPRZ axis in the hippocampus of rats receiving a TD diet but not in the rest of the WE models analyzed (CA and CA+TDD).

Background: Memory impairment is frequent among alcohol use disorder (AUD) patients, and we lack specific biomarkers to detect it. Certain apolipoproteins were linked to cognition, and carrying the APOE4 gene is a vulnerability factor to memory impairment in AUD patients. We explored memory deficits in alcohol‐dependent male mice and humans versus controls, and their relationship to Apolipoprotein AI (APOAI), apolipoprotein B (APOB), and apolipoprotein E (APOE) plasma levels.Methods: Male C57BL/6J mice underwent voluntary alcohol drinking (two‐bottle choice, 2BC) and chronic intermittent ethanol vapor exposure (CIE) as a model of alcohol dependence; memory was assessed by the Object Location Test (OLT) and Novel Object Recognition Test (NORT). Additionally, male AUD‐diagnosed patients were recruited in Spain during an alcohol dishabituation program and assessed by the Wechsler Memory Scale‐IV (WMS‐IV). Plasma APOAI, APOB, and APOE levels were checked in mice and humans by ELISA kits and Luminex immunoassay technology. APOAI immunolabeling was quantified in mouse brain in early withdrawal and following alcohol consumption.Results: CIE‐2BC mice (n = 8) escalated alcohol consumption compared to Air‐2BC controls (n = 11) and showed deficits in spatial memory (OLT) and recognition memory (NORT) while AUD patients (n = 12) showed deficits in verbal and visual memory (WMS‐IV) versus controls (n = 16). Higher plasma levels of APOAI were detected in CIE‐2BC mice and AUD patients, with no differences in APOB and APOE in animals and humans. Significant negative correlations were found between levels of APOAI, APOB, and APOE and memory function tests/scales in the entire sample, with APOAI showing consistent results in both animals and humans. APOAI immunoreactivity was detected in the mice subfornical organ, but the signal did not differ between experimental groups.Conclusions: Both CIE‐2BC mice and AUD patients exhibited elevated plasma levels of APOAI during early abstinence. APOAI correlated with poorer memory performance in both species, suggesting a potential role for this apolipoprotein in the context of alcohol‐induced cognitive impairment.

Background: Alcohol use disorder (AUD) courses with inflammation and cognitive decline. Apolipoproteins have emerged as novel target compounds related to inflammatory processes and cognition. Methods: A cross-sectional study was performed on abstinent AUD patients with at least 1 month of abstinence (n = 33; 72.7% men) and healthy controls (n = 34; 47.1% men). A battery of plasma apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ, and APOM), plasma inflammatory markers (LPS, LBP), and their influence on cognition and presence of the disorder were investigated. Results: Higher levels of plasma APOAI, APOB, APOE, and APOJ, as well as the proinflammatory LPS, were observed in the AUD group, irrespective of sex, whereas APOM levels were lower vs controls. Hierarchical logistic regression analyses, adjusting for covariates (age, sex, education), associated APOM with the absence of cognitive impairment in AUD and identified APOAI and APOM as strong predictors of the presence or absence of the disorder, respectively. APOAI and APOM did not correlate with alcohol abuse variables or liver status markers, but they showed an opposite profile in their associations with LPS (positive for APOAI; negative for APOM) and cognition (negative for APOAI; positive for APOM) in the entire sample. Conclusions: The HDL constituents APOAI and APOM were differentially regulated in the plasma of AUD patients compared with controls, playing divergent roles in the disorder identification and associations with inflammation and cognitive decline.