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Background: Theoretical and empirical contributions have identified insula as key in addiction. However, anatomical modifications of the insula in addictive states, and their variations across substance use disorders (SUDs), remain to be specifically explored. We therefore explored the specificities and commonalities of insula gray matter (GM) alterations in severe alcohol use disorder (sAUD) and severe cocaine use disorder (sCUD)., Methods: We explored insula GM volume through a refined parcellation in 12 subregions (six bilateral): anterior inferior cortex (AIC), anterior short gyrus, middle short gyrus, posterior short gyrus, anterior long gyrus (ALG), and posterior long gyrus (PLG). Using a linear mixed model analysis, we explored the insula volume profiles of 50 patients with sAUD, 61 patients with sCUD, and 36 healthy controls (HCs)., Results: In both sAUD and sCUD, we showed overall insular lower volume with a right-sided lateralization effect, and a major volume deficit in bilateral ALG. Moreover, differences emerged across groups, with higher left AIC and PLG volume deficits in sCUD compared to sAUD and HC., Conclusions: We offered the first joint exploration of GM insular volumes in two SUD through refined parcellation, thus unveiling the similarities and dissimilarities in volume deficit profiles. Our results bring evidence complementing prior ones suggesting the core role of the right and posterior insula in craving and interoception, two crucial processes in addiction. Left AIC and PLG group differences also show that, while insula is a region of interest in SUD, sCUD and sAUD generate distinct insular profiles, which might parallel clinical differences across SUD.

Advances in single-cell technologies have led to the discovery and characterization of new brain cell types, which in turn lead to a better understanding of the pathogenesis of Alzheimer's disease (AD). Here, we present a detailed analysis of single-nucleus (sn)RNA-seq data for three stages of AD from middle temporal gyrus and compare it with snRNA-seq data from the prefrontal cortices from individuals with alcohol use disorder (AUD). We observed a significant decrease in both inhibitory and excitatory neurons, in general agreement with previous reports. We observed several cell-type-specific gene expressions and pathway dysregulations that delineate AD stages. Endothelial and vascular leptomeningeal cells showed the greatest degree of gene expression changes. Cell-type-specific evidence of neurodegeneration was seen in multiple neuronal cell types particularly in somatostatin and Layer 5 extratelencephalic neurons, among others. Evidence of inflammatory responses was seen in non-neuronal cells, particularly in intermediate and advanced AD. We observed common perturbations in AD and AUD, particularly in pathways, like transcription, translation, apoptosis, autophagy, calcium signaling, neuroinflammation, and phosphorylation, that imply shared transcriptional pathogenic mechanisms and support the role of excessive alcohol intake in AD progression. Major AUD gene markers form and perturb a network of genes significantly associated with intermediate and advanced AD. Master regulator analysis from AUD gene markers revealed significant correlation with advanced AD of transcription factors that have implications in intellectual disability, neuroinflammation, and other neurodegenerative conditions, further suggesting a shared nexus of transcriptional changes between AD and AUD., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Joshi et al.)

The thalamus, with its reciprocal connections to and from cortical, subcortical, and cerebellar regions, is a central active participant in multiple functional brain networks. Structural MRI studies measuring the entire thalamus without respect to its regional or nuclear divisions report volume shrinkage in diseases including HIV infection, alcohol use disorder (AUD), and their comorbidity (HIV+AUD). Here, we examined relations between thalamic subregions (anterior, ventral, medial, and posterior) and neuropsychological functions (attention/working memory, executive functioning, episodic memory, and motor skills). Volumes of thalamic subregions were derived from automatic segmentations of standard T1 weighted MRIs of 65 individuals with HIV, 189 with AUD, 80 with HIV+AUD comorbidity, and 141 healthy controls (CTRL). Total thalamic volume was smaller and cognitive and motor composite scores were lower in the three diagnostic groups relative to the CTRL group. The AUD and HIV+AUD groups had significantly smaller thalamic subregional volumes than the CTRL group. The HIV+AUD group had smaller anterior thalamic volume than the HIV-only group and smaller ventral thalamic volume than the AUD-only group. In the HIV+AUD group, memory scores correlated with anterior thalamic volumes, attention/working memory scores correlated with posterior and medial thalamic volumes, and motor skill scores correlated with posterior thalamic volumes. Exploratory analyses focused on the HIV+AUD group indicated that within the posterior thalamic region, the pulvinar and medial geniculate nuclei were related to attention/working memory scores, and the pulvinar was related to motor skills scores. This study is novel in locating volume deficits in specific thalamic subregions, in addition to the thalamus as a whole, in HIV, AUD, and their comorbidity and in identifying functional ramifications of these deficits. Taken together, this study highlights the relevance of thalamic subregional volume deficits to dissociable cognitive and motor processes., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both postural instability and brain white matter hyperintensities (WMHs) are noted markers of normal aging and alcohol use disorder (AUD). Here, we questioned what variables contribute to the sway path-WMH relationship in individuals with AUD and healthy control participants., Methods: The data comprised 404 balance platform sessions, yielding sway path length and magnetic resonance imaging data acquired cross-sectionally or longitudinally in 102 control participants and 158 participants with AUD ages 25 to 80 years. Balance sessions were typically conducted on the same day as magnetic resonance imaging fluid-attenuated inversion recovery acquisitions, permitting WMH volume quantification. Factors considered in multiple regression analyses as potential contributors to the relationship between WMH volumes and postural instability were age, sex, socioeconomic status, education, pedal 2-point discrimination, systolic and diastolic blood pressure, body mass index, depressive symptoms, total alcohol consumed in the past year, and race., Results: Initial analysis identified diagnosis, age, sex, and race as significant contributors to observed sway path-WMH relationships. Inclusion of these factors as predictors in multiple regression analyses substantially attenuated the sway path-WMH relationships in both AUD and healthy control groups. Women, irrespective of diagnosis or race, had shorter sway paths than men. Black participants, irrespective of diagnosis or sex, had shorter sway paths than non-Black participants despite having modestly larger WMH volumes than non-Black participants, which is possibly a reflection of the younger age of the Black sample., Conclusions: Longer sway paths were related to larger WMH volumes in healthy men and women with and without AUD. Critically, however, age almost fully accounted for these associations., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Previous studies have established a connection between adverse childhood experiences (ACE) and alcohol use disorder (AUD), both of which are associated with alterations in grey matter volume (GMV) and cortical thickness (CT). The current study aimed to assess the neurobiological impact of ACE specifically in the context of AUD, as well as the role of maltreatment type (i.e., abuse or neglect) and timing., Methods: Structural MRI data were collected from 35 adults with AUD (mean age: 40; 31% female) and 28 healthy controls (mean age: 36; 61% female). ACE were assessed retrospectively using the Childhood Trauma Questionnaire, and the Maltreatment and Abuse Chronology interview. Global and regional GMV and CT were estimated using voxel- and surface-based morphometry., Results: Relative to the healthy controls, the AUD group had significantly reduced CT in the left inferior frontal gyrus, left circular sulcus of the insula and subcentral gyrus and sulci (cluster C1), and in the central sulcus and precentral gyrus (cluster C2). Within the AUD group, a reduction of CT in cluster C1 was significantly associated with higher severity of ACE and AUD. Type and timing analyses revealed a significant association between higher levels of abuse at ages 13 to 15 and reduced CT in cluster C1 within the AUD group., Conclusions: In adults with AUD, abuse experienced during early adolescence is associated with reduced CT in regions involved in inhibitory control, indicating the potential relevance of cognitive pathways in the association between ACE and AUD. Longitudinal studies are needed to confirm and expand upon current findings., (© 2024 The Author(s). Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Alcohol use disorder (AUD) has been associated with changes in the processing of internal body signals, known as interoception. Changes in brain structure, particularly in the insula, are thought to underlie impaired interoception. As studies specifically investigating this association are largely lacking, this analysis takes an approach that compares meta-analytic results on interoception with recently published meta-analytic results on gray matter reduction in AUD. A systematic literature search identified 25 eligible interoception studies. Activation likelihood estimation (ALE) was used to test for spatial convergence of study results. Overlap between interoception and AUD clusters was tested using conjunction analysis. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity were used to identify the functional network of interoception and to test where this network overlapped with AUD meta-analytic clusters. The results were characterized using behavioral domain analysis. The interoception ALE identified a cluster in the left middle insula. There was no overlap with clusters of reduced gray matter in AUD. MACM analysis of the interoception cluster revealed a large network located in the insulae, thalami, basal nuclei, cingulate and medial frontal cortices, and pre- and postcentral gyri. Resting state analysis confirmed this result, showing the strongest connections to nodes of the salience- and somatomotor network. Five of the eight clusters that showed a structural reduction in AUD were located within these networks. The behavioral profiles of these clusters were suggestive of higher-level processes such as salience control, somatomotor functions, and skin sensations. The results suggest an altered salience mapping of interoceptive signals in AUD, consistent with current models. Connections to the somatomotor network may be related to action control and integration of skin sensations. Mindfulness-based interventions, pleasurable touch, and (deep) transcranial magnetic stimulation may be targeted interventions that reduce interoceptive deficits in AUD and thus contribute to drug use reduction and relapse prevention., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

Aims: Widespread brain metabolite abnormalities in those with alcohol use disorder (AUD) were reported in numerous studies, but the effects of the pro-atherogenic conditions of hypertension, type 2 diabetes mellitus, hepatitis C seropositivity, and hyperlipidemia on metabolite levels were not considered. These conditions were associated with brain metabolite abnormalities in those without AUD. We predicted treatment-seeking individuals with AUD and pro-atherogenic conditions (Atherogenic+) demonstrate lower regional metabolite markers of neuronal viability [N-acetylaspartate (NAA)] and cell membrane turnover/synthesis [choline-containing compounds (Cho)], compared with those with AUD without pro-atherogenic conditions (Atherogenic-) and healthy controls (CON)., Methods: Atherogenic+ (n = 59) and Atherogenic- (n = 51) and CON (n = 49) completed a 1.5 T proton magnetic resonance spectroscopic imaging study. Groups were compared on NAA, Cho, total creatine, and myoinositol in cortical gray matter (GM), white matter (WM), and select subcortical regions., Results: Atherogenic+ had lower frontal GM and temporal WM NAA than CON. Atherogenic+ showed lower parietal GM, frontal, parietal and occipital WM and lenticular nuclei NAA level than Atherogenic- and CON. Atherogenic- showed lower frontal GM and WM NAA than CON. Atherogenic+ had lower Cho level than CON in the frontal GM, parietal WM, and thalamus. Atherogenic+ showed lower frontal WM and cerebellar vermis Cho than Atherogenic- and CON., Conclusions: Findings suggest proatherogenic conditions in those with AUD were associated with increased compromise of neuronal integrity and cell membrane turnover/synthesis. The greater metabolite abnormalities observed in Atherogenic+ may relate to increased oxidative stress-related compromise of neuronal and glial cell structure and/or impaired arterial vasoreactivity/lumen viability., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

People living with HIV and those diagnosed with alcohol use disorders (AUD) relative to healthy individuals commonly have low levels of serum albumin, substantiated as an independent predictor of cardiovascular events. White matter hyperintensities (WMH)-a neuroimaging feature of cerebral small vessel disease-are also related to cardiovascular disease. Despite consensus regarding associations between high levels of urine albumin and WMH prevalence, and low serum albumin levels and impaired cognitive functioning, relations between serum albumin and WMH burdens have rarely been evaluated. Here, a sample including 160 individuals with AUD, 142 living with HIV, and 102 healthy controls was used to test the hypothesis that serum albumin would be inversely related to WMH volumes and directly related to cognitive performance in the two diagnostic groups. Although serum albumin and periventricular WMH volumes showed an inverse relationship in both AUD and HIV groups, this relationship persisted only in the HIV group after consideration of traditional cardiovascular (i.e., age, sex, body mass index (BMI), nicotine use, hypertension, diabetes), study-relevant (i.e., race, socioeconomic status, hepatitis C virus status), and disease-specific (i.e., CD4 nadir, HIV viral load, HIV duration) factors. Further, serum albumin contributed more significantly than periventricular WMH volume to variance in performance on a verbal learning and memory composite score in the HIV group only. Relations in both HIV and AUD groups between albumin and hematological red blood cell markers (e.g., hemoglobin, hematocrit) suggest that in this sample, serum albumin reflects hematological abnormalities. Albumin, a simple serum biomarker available in most clinical settings, may therefore help identify periventricular WMH burden and performance levels in specific cognitive domains in people living with HIV. Whether serum albumin contributes mechanistically to periventricular WMH in HIV will require additional investigation., (© 2024. The Author(s).)

Ethanol is one of the psychoactive substances most used by young individuals, usually in an intermittent and episodic manner, also called binge drinking. In the adolescent period, brain structures undergo neuromaturation, which increases the vulnerability to psychotropic substances. Our previous studies have revealed that ethanol binge drinking during adolescence elicits neurobehavioral alterations associated with brain damage. Thus, we explored the persistence of motor function impairment and cerebellum damage in the context of ethanol withdrawal periods (emerging adulthood and adult life) in adolescent female rats. Female Wistar rats (35 days old) received orally 4 cycles of ethanol (3.0 g/kg/day) or distilled water in 3 days on-4 days off paradigm (35th until 58th day of life). Motor behavioral tests (open field, grip strength, beam walking, and rotarod tests) and histological assays (Purkinje's cell density and NeuN-positive cells) were assessed on the 1-, 30-, and 60-days of binge alcohol exposure withdrawal. Our findings demonstrate that the adolescent binge drinking exposure paradigm induced cerebellar cell loss in all stages evaluated, measured through the reduction of Purkinje's cell density and granular layer neurons. The cerebellar tissue alterations were accompanied by behavioral impairments. In the early withdrawal, the reduction of spontaneous movement, incoordination, and unbalance was seen. However, the grip strength reduction was found at long-term withdrawal (60 days of abstinence). The cerebellum morphological changes and the motor alterations persisted until adulthood. These data suggest that binge drinking exposure during adolescence causes motor function impairment associated with cerebellum damage, even following a prolonged withdrawal, in adult life., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Alcohol dependence is a disorder with a high recurrence rate that leads to a considerable public health burden. The risk of relapse appears to be related to a complex interplay of multiple factors. Herein, we aimed to explore the potential neural predictors of relapse in Chinese male patients with alcohol dependence. This study enrolled 58 male patients with alcohol dependence who had undergone acute detoxification. General demographic information and clinical features were collected. Magnetic resonance imaging data were used to measure cortical thickness across 34 regions of the brain. Patients were followed up at six months, and 51 patients completed the follow-up visit. These patients were divided into a relapser and an abstainer group. A binary logistic regression analysis was performed to investigate the potential risk factors of relapse. Compared to abstainers, relapsers showed higher inattention and non-planning impulsivity on the 11th version of the Barratt Impulsive Scale. The cortical thicknesses of the inferior-parietal lobules were significantly higher in abstainers compared with those in relapsers. Furthermore, binary logistic regression analysis showed that the thickness of the inferior parietal lobule predicted relapse, and lower non-planning impulse was a protective factor against relapse. Relapsers show poorer impulse control than abstainers, and structural magnetic resonance imaging revealed a decreased thickness of the inferior parietal lobule in relapsers. Our results indicate the thickness of the inferior parietal lobule as a potential relapse predictor in male patients with alcohol dependence., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The cerebellum plays a vital role in the aging process. With the aging of the cerebellum, there is a decline in balance and motor function, particularly fine motor skills, and an increased risk of falling. However, in recent years, numerous studies have revealed that the cerebellum has several roles besides balance and fine motor skills, such as cognitive function and memory. It also plays a role in many neurodegenerative diseases. Interestingly, the cerebellum ages more rapidly than other brain regions, including the hippocampus. With increasing studies reporting that the cerebellum has a more prominent and interconnected role in the brain, it is essential to understand why aging affects it more, leading to solutions to help curb the accelerated decline. Here, we summarize the cerebellum's function and look at how it ages at the cellular, molecular, and functional levels. Additionally, we explore the the effects of alcoholism on the aging cerebellum as well as the role of the cerebellum in diseases such as Alzheimer's, Parkinson's, and Multiple Sclerosis.

Alcohol use disorder (AUD) is characterized by cycles of abuse, withdrawal, and relapse. Neuroadaptations in the basal ganglia are observed in AUD; specifically in the putamen, globus pallidus (GP), and ventral pallidum (VP). These regions are associated with habit formation, drug-seeking behaviors, and reward processing. While previous studies have shown the crucial role of glial cells in drug seeking, it remains unknown whether glial cells in the basal ganglia are altered in AUD. Glial cells in the putamen, GP, and VP were examined in human post-mortem tissue of AUD and alcohol remission cases. Immunohistochemistry was performed to analyze cell count, staining intensity, and morphology of microglia and astrocytes, using markers Iba-1 and GFAP. Morphological analysis revealed a significant decrease in microglia cell size and process retraction, indicating activation or a dystrophic microglia phenotype in individuals with AUD compared to controls. Microglia staining intensity was also higher in the GP and VP in AUD cases, whereas microglia staining intensity and cell size in remission cases were not different to control cases. In contrast, no astrocyte changes were observed in examined brain regions for both AUD and remission cases compared to controls. These results suggest alcohol exposure alters microglia, potentially contributing to dysfunctions in the basal ganglia that maintain addiction, and abstinence from alcohol may reverse microglia changes and associated dysfunctions. Overall, this study further characterizes AUD neuropathology and implicates microglia in the putamen, GP, and VP as a potential target for therapy., (© 2024 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19., Methods: Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA., Results: 48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue., Conclusions: The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature., Competing Interests: Declaration of competing interest None of the authors have relevant conflict of interests to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: To study morphological changes of cerebral cortex in young people under the conditions of chronic alcohol intoxication (CAI)., Material and Methods: Morphometric examination of cerebral cortex fragments obtained from 28 persons who died with a CAI diagnosis (average age was 38 years), and 25 subjects who died from other causes, which are not associated with alcohol consumption (average age was 39 years), was carried out., Results: It was shown that neurons of pathological shapes, including hypo- and hyperchromic, pyknotic and «shadow-like», were dominant in group of CAI. There was an increase in the glial index and a greater intensity of perivascular and pericellular edema compared to the control group., Conclusion: Morphological changes of cerebral cortex under the conditions of CAI are non-specific and largely similar to neurodegenerative alterations in other pathological conditions, senile dementia. Clearer histological criteria for alcoholic encephalopathy are needed, including with the use of immunohistochemical methods.

Background and Aims: Recently, we demonstrated that a distinct pattern of structural covariance networks (SCN) from magnetic resonance imaging (MRI)-derived measurements of brain cortical thickness characterized young adults with alcohol use disorder (AUD) and predicted current and future problematic drinking in adolescents relative to controls. Here, we establish the robustness and value of SCN for identifying heavy alcohol users in three additional independent studies., Design and Setting: Cross-sectional and longitudinal studies using data from the Pediatric Imaging, Neurocognition and Genetics (PING) study (n = 400, age range = 14-22 years), the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA) (n = 272, age range = 17-22 years) and the Human Connectome Project (HCP) (n = 375, age range = 22-37 years)., Cases: Cases were defined based on heavy alcohol use patterns or former alcohol use disorder (AUD) diagnoses: 50, 68 and 61 cases were identified. Controls had none or low alcohol use or absence of AUD: 350, 204 and 314 controls were selected., Measurements: Graph theory metrics of segregation and integration were used to summarize SCN., Findings: Mirroring our prior findings, and across the three data sets, cases had a lower clustering coefficient [area under the curve (AUC) = -0.029, P = 0.002], lower modularity (AUC = -0.14, P = 0.004), lower average shortest path length (AUC = -0.078, P = 0.017) and higher global efficiency (AUC = 0.007, P = 0.010). Local efficiency differences were marginal (AUC = -0.017, P = 0.052). That is, cases exhibited lower network segregation and higher integration, suggesting that adjacent nodes (i.e. brain regions) were less similar in thickness whereas spatially distant nodes were more similar., Conclusion: Structural covariance network (SCN) differences in the brain appear to constitute an early marker of heavy alcohol use in three new data sets and, more generally, demonstrate the utility of SCN-derived metrics to detect brain-related psychopathology., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Anxiety and depression are psychopathological states frequently co-occurring with severe alcohol use disorder (SAUD). These symptoms generally disappear with abstinence but may persist in some patients, increasing the relapse risk., Methods: The cerebral cortex thickness of 94 male patients with SAUD was correlated with symptoms of depression and anxiety, both measured at the end (2-3 weeks) of the detoxification treatment. Cortical measures were obtained using surface-based morphometry implemented with Freesurfer., Results: Depressive symptoms were associated with reduced cortical thickness in the superior temporal gyrus of the right hemisphere. Anxiety level was correlated with lower cortical thickness in the rostral middle frontal region, inferior temporal region, and supramarginal, postcentral, superior temporal, and transverse temporal regions of the left hemisphere, as well as with a large cluster in the middle temporal region of the right hemisphere., Conclusions: At the end of the detoxification stage, the intensity of depressive and anxiety symptoms is inversely associated with the cortical thickness of regions involved in emotions-related processes, and the persistence of the symptoms could be explained by these brain deficits., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

We aimed to investigate the clinico-radiologic features of acute Marchiafava-Bignami disease (MBD) and its evolutionary process after effective treatment through subgroup comparison. The clinical and MRI data of 23 patients with acute MBD were retrospectively analyzed and divided into type A (12 cases, with entire callosal involvement) and type B (11 cases, with focal callosal involvement). The clinical assessments and MRI findings (before and after treatment) were compared between the two subtypes. Compared with type B, type A had lower MoCA (Montreal Cognitive Assessment) scores at admission (16.50 ± 1.73 vs 18.27 ± 1.68, P = 0.021) and were more common with extracallosal involvement (66.67% vs 18.18%, P = 0.036) and longer illness duration (18.3 ± 2.1 days vs 15.6 ± 2.4 days, P = 0.012). During the treatment, the residual lesion in the splenium was more common in type A (58.33% vs 9.09%, P = 0.027). After treatment, the MoCa scores of both subtypes gradually increased (P < 0.001), and the callosal and extracallasal lesions disappeared completely. Clinico-radiologic typing of acute MBD is related to the severity of early symptoms, but not to the prognosis. Complete clinico-radiologic recovery is possible for both subtypes with combined treatment. The clinico-radiologic reversibility is helpful for accurate diagnosis and therapeutic evaluation., (© 2023. The Author(s).)

To follow our 2016 study of chronic traumatic encephalopathy neuropathologic change (CTE-NC) in our forensic autopsy service, we prospectively screened all cases with clinical histories of multiple concussions, persistent post-head injury symptoms, or ≥3 hospital investigations for head injuries from 2016 to 2022 inclusive using hyperphosphorylated tau (p-tau) immunostaining. The cases had routine brain sampling plus 4-6 additional lateral hemisphere samples. When "pathognomonic" CTE-NC lesions were identified, additional p-tau immunostaining was done for CTE-NC staging. Of ∼1100 adult brains aged 18-65 years examined, 85 were screened, and 16 were positive for CTE-NC (2 women, 14 men, ages 35-61 years, median 47 years). Alcohol abuse was documented in 14 of 16 (8 in combination with other substances); 5 had developmental brain anomalies (2 presumed genetic, 3 from acquired perinatal insults). Widespread p-tau deposits (high CTE-NC) were found in 7 of 16. Old brain contusions were present in 9 of 16, but CTE-NC did not colocalize. Of particular interest were (1) a man with FGFR3 mutation/hypochondroplasia and life-long head banging, (2) a woman with cerebral palsy and life-long head banging, and (3) a man with bilateral peri-Sylvian polymicrogyria, alcohol abuse, and multiple head injuries. Thus, CTE-NC occurs in association with repeated head trauma outside contact sports. Substance abuse is a common determinant of risk behavior. The utility of diagnosing mild-/low-stage CTE-NC in this population remains to be determined., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc.)

Recent evidence suggests that alcohol use disorder (AUD) may manifest itself differently in women compared to men. Women experience AUDs on an accelerated timeline and may have certain regional vulnerabilities. In male rats, neuronal cell death and astrocyte reactivity are noted following induction of alcohol dependence in an animal model of an AUD. However, the regional and temporal patterns of neurodegeneration and astrocyte reactivity have yet to be fully examined in females using this model. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by different periods of abstinence. Histological markers for FluoroJade B, a label of degenerating neurons, and vimentin, a marker for reactive astrocytes, were utilized. The expression of these markers in cortical and limbic regions was quantified immediately after their last dose (e.g., T0), or 2, 7, and 14 days later. Significant neuronal cell death was noted in the entorhinal cortex and the hippocampus, similar to previous reports in males, but also in several cortical regions not previously observed. Vimentin immunoreactivity was noted in the same regions as previously reported, in addition to three novel regions. Vimentin immunoreactivity also occurred at earlier and later time points in some cortical and hippocampal regions. These data suggest that both neuronal cell death and astrocyte reactivity could be more widespread in females compared to males. Therefore, this study provides a framework for specific regions and time points which should be examined in future studies of alcohol-induced damage that include female rats., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: The diagnosis of alcoholic steatohepatitis (ASH) is based on liver biopsy, which is costly and invasive with non-negligible morbidity. The aim of this study was to evaluate the accuracy of circulating cytokeratin 18 M65 fragment (K18-M65) alone or in association with other markers for the non-invasive diagnosis of ASH in patients ongoing alcohol withdrawal., Methods: This study examined the serum level of K18-M65 in a test cohort of 196 patients. All patients underwent liver biopsy, transient elastography (TE) and serum collection. The diagnostic accuracy of K18-M65 alone or combined with clinico-biological data was assessed and the best defined cut-offs were validated in an independent validation cohort of 58 patients., Results: K18-M65 had an area under the curve (AUC) of 0.82 (test cohort) and 0.90 (validation cohort). Using two cut-off decision points, K18-M65 was able to classify 46.9% (test cohort) and 34.5% (validation cohort) of patients with 95% sensitivity or specificity. Combining K18-M65, alpha-2-macroglobulin, TE, body mass index, and age, we created a score allowing accurate diagnosis of ASH with an AUC of 0.93 (test cohort) and 0.94 (validation cohort). This new score was able to rule out or rule in the diagnosis of steatohepatitis for probability ≤0.135 or ≥0.667 respectively in more than two-thirds of patients., Conclusions: We propose a new validated non-invasive score for the diagnosis of ASH in patients ongoing alcohol withdrawal. This score can help to identify patients that may benefit from potential therapeutics or motivate them to reduce alcohol consumption., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Automated alcohol craving and habitual alcohol consumption characterize the later stages of alcohol use disorder (AUD). This study reanalyzed previously collected functional neuroimaging data in combination with the Craving Automated Scale for Alcohol (CAS-A) questionnaire to investigate the neural correlates and brain networks underlying automated drinking characterized by unawareness and nonvolition., Methods: We assessed 49 abstinent male patients with AUD and 36 male healthy control participants during a functional magnetic resonance imaging-based alcohol cue-reactivity task. We performed whole-brain analyses examining the associations between CAS-A scores and other clinical instruments and neural activation patterns in the alcohol versus neutral contrast. Furthermore, we performed psychophysiological interaction analyses to assess the functional connectivity between predefined seed regions and other brain areas., Results: In patients with AUD, higher CAS-A scores correlated with greater activation in dorsal striatal, pallidal, and prefrontal regions, including frontal white matter, and with lower activation in visual and motor processing regions. Between-group psychophysiological interaction analyses showed extensive connectivity between the seed regions inferior frontal gyrus and angular gyrus and several frontal, parietal, and temporal brain regions in AUD versus healthy control participants., Conclusions: The present study applied a new lens to previously acquired alcohol cue-reactivity functional magnetic resonance imaging data by correlating neural activation patterns with clinical CAS-A scores to elucidate potential neural correlates of automated alcohol craving and habitual alcohol consumption. Our results support previous findings showing that alcohol addiction is associated with hyperactivation in habit-processing regions, with hypoactivation in areas mediating motor and attention processing, and with general hyperconnectivity., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alcohol use disorder is a major public health concern in the United States. Recent work has suggested a link between chronic alcohol consumption and the development of tauopathy disorders, such as Alzheimer's disease and frontotemporal dementia. However, relatively little work has investigated changes in neural circuitry involved in both tauopathy disorders and alcohol use disorder. The locus coeruleus (LC) is the major noradrenergic nucleus in the brain and is one of the earliest sites to be affected by tau lesions. The LC is also implicated in the rewarding effects of ethanol and alcohol withdrawal. In this study we assessed effects of long-term ethanol consumption and tauopathy on the physiology of LC neurons. Male and female P301S mice, a humanized transgenic mouse model of tauopathy, underwent 16 weeks of intermittent access to 20% ethanol from 3 to 7 months of age. We observed higher total alcohol consumption in female mice regardless of genotype. Male P301S mice consumed more ethanol and had a greater preference for ethanol than wild-type (WT) males. At the end of the drinking study, LC function was assessed using ex vivo whole cell electrophysiology. We found significant changes in excitatory inputs to the LC due to both ethanol and genotype. We found significantly increased excitability of the LC due to ethanol with greater effects in female P301S mice than in female WT mice. Our study identifies significant changes in the LC due to interactions between tauopathy and long-term ethanol use. These findings could have important implications regarding LC activity and changes in behavior due to both ethanol- and tauopathy-related dementia., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Studies universally find early age of drinking onset is linked to lifelong risks of alcohol problems and alcohol use disorder (AUD). Assessment of the lasting effect of drinking during adolescent development in humans is confounded by the diversity of environmental and genetic factors that affect adolescent development, including emerging personality disorders and progressive increases in drinking trajectories into adulthood. Preclinical studies using an adolescent intermittent ethanol (AIE) exposure rat model of underage binge drinking avoid the human confounds and support lifelong changes that increase risks. AIE increases adult alcohol drinking, risky decision-making, reward-seeking, and anxiety as well as reductions in executive function that all increase risks for the development of an AUD. AIE causes persistent increases in brain neuroimmune signaling high-mobility group box 1 (HMGB1), Toll-like receptor, receptor for advanced glycation end products, and innate immune genes that are also found to be increased in human AUD brain. HMGB1 is released from cells by ethanol, both free and within extracellular vesicles, that act on neurons and glia, shifting transcription and cellular phenotype. AIE-induced decreases in adult hippocampal neurogenesis and loss of basal forebrain cholinergic neurons are reviewed as examples of persistent AIE-induced pathology. Both are prevented and reversed by anti-inflammatory and epigenetic drugs. Findings suggest AIE-increased HMGB1 signaling induces the RE-1 silencing transcript blunting cholinergic gene expression, shifting neuronal phenotype. Inhibition of HMGB1 neuroimmune signaling, histone methylation enzymes, and galantamine, the cholinesterase inhibitor, both prevent and reverse AIE pathology. These findings provide new targets that may reverse AUD neuropathology as well as other brain diseases linked to neuroimmune signaling. SIGNIFICANCE STATEMENT: Adolescent underage binge drinking studies find that earlier adolescent drinking is associated with lifelong alcohol problems including high levels of lifetime alcohol use disorder (AUD). Preclinical studies find the underage binge drinking adolescent intermittent ethanol (AIE) model causes lasting changes in adults that increase risks of developing adult alcohol problems. Loss of hippocampal neurogenesis and loss of basal forebrain cholinergic neurons provide examples of how AIE-induced epigenetic and neuroimmune signaling provide novel therapeutic targets for adult AUD., (Copyright © 2023 by The Author(s).)

Alcohol use disorder (AUD) is one of the most common preventable mental health disorders and can result in pathology within the CNS, including the cerebellum. Cerebellar alcohol exposure during adulthood has been associated with disruptions in proper cerebellar function. However, the mechanisms regulating ethanol-induced cerebellar neuropathology are not well understood. High-throughput next generation sequencing was performed to compare control versus ethanol-treated adult C57BL/6J mice in a chronic plus binge model of AUD. Mice were euthanized, cerebella were microdissected, and RNA was isolated and submitted for RNA-sequencing. Down-stream transcriptomic analyses revealed significant changes in gene expression and global biological pathways in control versus ethanol-treated mice that included pathogen-influenced signaling pathways and cellular immune response pathways. Microglial-associated genes showed a decrease in homeostasis-associated transcripts and an increase in transcripts associated with chronic neurodegenerative diseases, while astrocyte-associated genes showed an increase in transcripts associated with acute injury. Oligodendrocyte lineage cell genes showed a decrease in transcripts associated with both immature progenitors as well as myelinating oligodendrocytes. These data provide new insight into the mechanisms by which ethanol induces cerebellar neuropathology and alterations to the immune response in AUD.

The brain's ability to strengthen or weaken synaptic connections is often termed synaptic plasticity. It has been shown to function in brain remodeling following different types of brain damage (e.g., drugs of abuse, alcohol use disorders, neurodegenerative diseases, and inflammatory conditions). Although synaptic plasticity mechanisms have been extensively studied, how neural plasticity can influence neurobehavioral abnormalities in alcohol use disorders (AUDs) is far from being completely understood. Alcohol use during pregnancy and its harmful effects on the developing offspring are major public health, social, and economic challenges. The significant attribute of prenatal alcohol exposure on offspring is damage to the central nervous system (CNS), causing a range of synaptic structural, functional, and behavioral impairments, collectively called fetal alcohol spectrum disorder (FASD). Although the synaptic mechanisms in FASD are limited, emerging evidence suggests that FASD pathogenesis involves altering a set of molecules involved in neurotransmission, myelination, and neuroinflammation. These studies identify several immediate and long-lasting changes using many molecular approaches that are essential for synaptic plasticity and cognitive function. Therefore, they can offer potential synaptic targets for the many neurobehavioral abnormalities observed in FASD. In this review, we discuss the substantial research progress in different aspects of synaptic and molecular changes that can shed light on the mechanism of synaptic dysfunction in FASD. Increasing our understanding of the synaptic changes in FASD will significantly advance our knowledge and could provide a basis for finding novel therapeutic targets and innovative treatment strategies.

The CNS manifestation of chronic liver disease can include magnetic resonance (MR) signal hyperintensities in basal ganglia structures. Here, relations between liver (serum-derived fibrosis scores) and brain (regional T1-weighted signal intensities and volumes) integrity were evaluated in a sample of 457 individuals including those with alcohol use disorders (AUD), people living with human immunodeficiency virus (HIV), those comorbid for AUD and HIV, and healthy controls. Liver fibrosis was identified from cutoff scores as follows: aspartate aminotransferase to platelet ratio index (APRI) > 0.7 in 9.4% (n = 43) of the cohort; fibrosis score (FIB4) > 1.5 in 28.0% (n = 128) of the cohort; and non-alcoholic fatty liver disease fibrosis score (NFS) > -1.4 in 30.2% (n = 138) of the cohort. Presence of serum-derived liver fibrosis was associated with high signal intensities selective to basal ganglia (i.e., caudate, putamen, and pallidum) structures. High signal intensities in the pallidum, however, explained a significant portion of the variance in APRI (25.0%) and FIB4 (23.6%) cutoff scores. Further, among the regions evaluated, only the globus pallidus showed a correlation between greater signal intensity and smaller volume (r = -0.44, p <.0001). Finally, higher pallidal signal intensity correlated worse ataxia (eyes open ρ = -0.23, p =.0002; eyes closed ρ = -0.21, p =.0005). This study suggests that clinically relevant serum biomarkers of liver fibrosis such as the APRI may identify individuals vulnerable to globus pallidus pathology and contribute to problems with postural balance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Structural alterations in cortical thickness and the microstructural organization of white matter are independently associated with non-dependent alcohol consumption and bipolar disorder (BD). Identifying their interactive and network-level effects on brain topology may identify the impact of alcohol on reward and emotion circuitry, and its contribution to relapse in BD. Materials and Methods: Thirty-four BD-I (DSM-IV-TR) and 38 healthy controls (HC) underwent T1 and diffusion-weighted magnetic resonance imaging scanning, and the Alcohol Use Disorders Identification Test-Consumption to assess alcohol use. Connectomes comprising 34 cortical and 9 subcortical nodes bilaterally (Freesurfer v5.3) connected by fractional anisotropy-weighted edges derived from non-tensor based deterministic constrained spherical deconvolution tractography (ExploreDTI v4.8.6) underwent permutation-based topological analysis (NBS v1.2) and were examined for the effects of alcohol use and diagnosis-by-alcohol use accounting for age, sex, and diagnosis. Results: Alcohol was significantly related to a subnetwork, encompassing connections between fronto-limbic, basal ganglia, and temporal nodes ( F range  = 5-8.4, p  = 0.031) and it was not detected to have an effect on global brain integration or segregation. A portion of this network (18%), involving cortico-limbic and basal ganglia connections, was differentially impacted by alcohol in the BD relative to the control group ( F range  = 5-8.8, p  = 0.033), despite the groups' consuming similar amounts of alcohol (BD: mean ± standard deviation 4.95 ± 3.0; HC 3.62 ± 3.0, T  = 1.88, p  = 0.06). Discussion: Non-dependent alcohol use impacts brain architectural organization and connectivity within salience, reward, and affective circuitry. The relationship between alcohol use and topology of the network in BD suggests an interactive effect between specific biological vulnerability and alcohol use, which may explain the susceptibility to an increased risk of relapse in the disorder. Impact statement The association between non-dependent alcohol use and neural architecture in bipolar disorder (BD) is unknown, despite the poor clinical trajectory and increased likelihood of relapse associated with alcohol use in BD. We demonstrate that together alcohol and a diagnosis of BD is associated with a subnetwork involving nodes of the cortico-limbic and reward networks. This subnetwork, demonstrated in BD and absent in controls, differentially involves nodes that are specific to reward and emotion processes. This suggests a diagnosis-specific biological vulnerability for alcohol use and may be consistent with known mood lability and thus relapse associated with alcohol use in BD.

We investigated the presence of myocardial apoptosis on isoproterenol (ISO)-induced myocardial injury (MI) after long-term high dose alcohol consumption and examined the antiapoptotic role of calpain inhibitor 1. Male Wistar Albino rats ( n  = 108) were divided into six groups: Control, alcohol (ethanol was given during 30 days for chronic alcohol consumption), MI (150 mg/kg ISO injection at last two days of alcohol consumption), alcohol + MI, alcohol + MI + calpain inhibitor 1 (10 mg/kg inhibitor was injected at 15 min before ISO injections) and Dimethyl Sulfoxide (DMSO) groups. Biochemical, histological, and morphometric methods determined apoptosis levels in the heart tissue of rats. Cytochrome c, caspase 3, and calpain levels were significantly high in alcohol, MI, and alcohol + MI groups. In contrast, mitochondrial cardiolipin content was found to be low in alcohol, MI, and alcohol + MI groups. These parameters were close to the control group in the therapy group. Histological and morphometric data have supported biochemical results. As a result of our biochemical data, myocardial apoptosis was seen in the alcohol, MI, and especially alcohol after MI groups. Calpain inhibitor 1 reduced apoptotic cell death and prevented myocardial tissue injury in these groups. The efficiency of calpain inhibitor was very marked in MI after long-term high dose alcohol consumption.

Comorbid pathology, high mortality and disability remain an urgent problem for people with the development of an immunodeficiency state, including women of reproductive age. Prognostic triggers could help to improve management of preneoplastic injury of cervical epithelium., Aim: The aim of this study was to identify the cytological features of the cervical epithelium in women with immunodeficiency status and alcoholism, depending on the level of CD4-lymphocytes., Materials and Methods: The study involved cytological analysis of women, who were divided into 3 groups (group consisted of patients with confirmed HIV infection and chronic alcoholism; group consisted of women with chronic alcoholism; comparison group). Determination of CD4 lymphocytes was carried out with gradation of indicators of 500- 350-100 cells per microliter. The relationship between the number of lymphocytes in a smear and changes in epithelial cells was carried out., Results: Microscopic examination revealed koilocytosis, binuclear and multinuclear cells, keratinocytes, parakeratosis, cytoplasmic amphiphilia in all women of the two studied groups. In addition, epithelial cells were characterized by large size, displacement of the nucleus to the periphery, uneven staining of the cytoplasm, karyopyknosis, karyorrhexis, karyolysis, and dyskeratosis. The inflammatory type of smear was detected in all women of these groups with the presence of neutrophils, eosinophils, lymphocytes, plasmocytes, histiocytes, macrophages and microflora. At the same time, in the comparison group, the inflammatory type of smear was detected only in 36.6%. When studying the relationship between the level of CD4 cells and the degree of damage to the cervical epithelium in the study groups, a strong correlation was established (r=0.824 and r=0.801)., Conclusions: With the development of immunodeficiency status, the number of CD4 cells below 100 per mm3 should be considered as an unfavorable prognostic factor for the development of neoplastic transformation of the cervix., (© 2022 MEDPRESS.)

Aims: Alcohol use disorder (AUD) is associated with alterations within the default mode network (DMN) at rest. Also, impaired white matter structures have been observed in individuals with AUD. This study developed a workflow for examining the relation between functional and structural connectivity, exemplary for nodes of the DMN within a sample of non-treatment seeking individuals with AUD. Furthermore, AUD severity was correlated with both measures independently., Methods: The functional magnetic resonance imaging (fMRI) protocol included anatomical, resting state and diffusion weighted imaging measurements. Independent component analyses and deterministic fiber tracking as well as correlation analyses, including the severity of AUD, were performed. N = 18 out of 23 adult study participants took part in the fMRI examination, and N = 15 were included in the final analyses., Results: Established resting-state networks were reliably identified in our sample. Structural connections were found between several nodes of the DMN, whereas only fibers between the medial prefrontal cortex and the posterior cingulate cortex were reliably detected in all individuals. A negative correlation was observed between brain activation during rest and AUD severity in left parietal and temporal regions and the putamen. A more severe AUD predicted impairments in white matter integrity of the cingulum., Conclusion: In AUD, information obtained from a combination of resting-state, diffusion weighted data and clinical information has great potential to provide a more profound understanding of the disorder since alterations may already become apparent at earlier stages of the disorder, e.g. in non-treatment seeking individuals., Summary: Alcohol use disorder leads to alterations in the default mode network of the resting brain that is associated with the severity of the disorder. Following our workflow, white matter impairments can be observed between some of the nodes of the default mode network using diffusion tensor imaging. Both, resting-state functional and structural connectivity relate to the severity of alcohol use disorder., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Context.—: Basal vacuolization (BV) in renal tubules is a histopathologic hallmark of advanced ketoacidosis that enables us to retrospectively diagnose these cases., Objective.—: To clarify the pathologic background and serologic findings of ketoacidosis with BV, and to reveal the pathologic findings by each pathologic background., Design.—: We examined 664 serial autopsy cases. A systemic histopathologic examination and measurement of serum β-hydroxybutyrate concentration were performed for the cases with BV. The extent of steatosis and fibrosis in the organs and the degree of coronary artery stenosis were semiquantitatively investigated. Immunohistochemistry for adipophilin was also performed to analyze its usefulness for the pathologic diagnosis., Results.—: Basal vacuolization was found in 16 cases, all of which showed a pathologic serum β-hydroxybutyrate concentration. The main background of ketoacidosis was considered as alcohol abuse in 6 cases, diabetes in 5, malnutrition in 3, and hypothermia and infection in 1 case each. Severe hepatic fibrosis was observed only in the alcohol-abuser group. Moreover, cardiac steatosis was more severe in patients with possible alcohol abuse than in those with other causes. Immunohistochemistry for adipophilin showed immunoreactivity consistent with BV in 13 of 16 cases. There was no correlation between β-hydroxybutyrate concentration and either the postmortem or storage interval., Conclusions.—: Basal vacuolization may be a useful finding for detecting ketoacidosis cases in a postmortem investigation. Serum β-hydroxybutyrate was a stable and reliable compound for the definitive diagnosis of ketoacidosis in such cases. The present study showed that pathologic changes in some organs may vary by each pathologic background of ketoacidosis with BV.

M2b monocytes commonly isolated from patients with unhealthy alcohol use (Alc) have been described as cells that make the host susceptible to opportunistic infections. CD34 + CD10 + CD19 - cells are multilineage progenitors of CD19 + cells, and we show that the effect of these cells from the peripheral blood on M2b monocyte polarization differed between healthy donors and Alc in this study. In healthy donors, these cells consistently differentiated into high-mobility group box-1 (HMGB1)-nonproducing cells (CD19 + cells) in response to retinoic acid (RA). However, owing to the lack of expression of RA receptor (RAR), these cells from Alc failed to differentiate into CD19 + cells under the same RA stimulation. Conditioned medium (CM) of these cells from Alc induced the polarization of M2b monocytes, which increases the susceptibility of hosts to opportunistic infections in Alc. When the alcoholic individuals were subjected to 2 weeks of abstinence from alcohol, these cells from Alc recovered their RAR expression and differentiated into CD19 + cells. Moreover, the CM of these cells from Alc after abstinence lost its ability to induce M2b monocyte polarization. These results indicate that these cells from Alc have different properties from those of healthy donors. In Alc, these cells without RAR stimulate M2b monocyte polarization through the production of HMGB1.

Aims: Alcohol consumption influences the water balance in the brain. While the impact of chronic alcohol misuse on cerebral water content has been the subject of several studies, less is known about the effects of acute alcohol misuse, with contradictory results in the literature. Therefore, we investigated the effects of acute alcohol intoxication on cerebral water content using a precise quantitative magnetic resonance imaging (MRI) sequence., Methods: In a prospective study, we measured cerebral water content in 20 healthy volunteers before alcohol consumption and after reaching a breath alcohol concentration of 1 ‰. A quantitative MRI water mapping sequence was conducted on a clinical 3 T system. Non-alcoholic fluid input and output were documented and accounted for. Water content was assessed for whole brain, grey and white matter and more specifically for regions known to be affected by acute or chronic alcohol misuse (occipital and frontal lobes, thalamus and pons). Changes in the volume of grey and white matter as well as the whole brain were examined., Results: Quantitative cerebral water content before and after acute alcohol consumption did not differ significantly (P ≥ 0.07), with changes often being within the range of measurement accuracy. Whole brain, white and grey matter volume did not change significantly (P ≥ 0.12)., Conclusion: The results of our study show no significant water content or volume change in the brain after recent alcohol intake in healthy volunteers. This accounts for the whole brain, grey and white matter, occipital and frontal lobes, thalamus and pons., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Abstract: Central pontine myelinolysis is most commonly associated with rapid correction of hyponatremia and has historically been associated with alcoholism. In this case report, 2 deaths with gross findings of central pontine lesions led to the possibility that CPM may have been a potential mechanism of death. Subsequent analysis revealed that these lesions were incidental findings. This case report discusses the importance of appropriate microscopic and immunohistochemical analysis of suspected CPM cases., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation., (© 2022. The Author(s).)

There are many studies on changes in cervix, however, there are no data about property of cervical tissue to keep potential for regeneration under influence of immunodeficiency, which is very important since it allows escaping severe irreversible changes in tissue. CD34 stem cells are one of significant indicator for property of tissual regeneration. So, the purpose of our study was to identify amount of CD34 stem cells in the cervix under influence of immunodeficiency of infectious and non-infectious origin. Sectional material of reproductive women was studied. All subjects were divided into 3 groups: women who were diagnosed with HIV infection; women who have identified anamnestic and postmortem signs of alcohol abuse; group of comparison. After routine testing and immunohistochemical (IHC) staining to CD34, morphometric measure was performed. We evaluate presence activities of stromal cells for detection of connection and relationship between expression of CD34 and the thickness of the cervical epithelium, relative volumes of condyloma, cervical dysplasia severity, degree of infiltration of the mucosal lamina propria by immunocompetent cells. The obtained digital data were statistically processed. Morphological investigation revealed changes of thickness of the cervical stratified squamous nonkeratinized epithelium up to 714.23±59.21 x 10-6 m in group of HIVinfected women. Relative volumes of condylomas were 44 increased in both investigated groups with presence of pointed, flat and inverted types. Both low- and high-grade squamous intraepithelial lesions were detected more often in investigated goups. Assessment of the degree of infiltration of the mucosal lamina propria by immunocompetent cells was changed unevenly with reducing in HIV-group and increasing in alcohol group. Results of ICH reaction CD34 realized in cytoplasmic staining with membranous accentuation in all cases of control group with strong, but reduced level in investigated groups. Most close connection was observed for cervical dysplasia severity and CD34 expression. HIV infection and alcohol abuse have pronounced pathological effects with cervical changes. The expression of CD34 is present in 96% of women with immunodeficiency mainly with strong reaction. It is statistically likely that it does not depend on such morphological indicators as thickness of the cervical epithelium, relative volumes of condyloma, degree of infiltration of the mucosal lamina propria by immunocompetent cells. The expression of CD34 has statistically close negative connection with cervical dysplasia severity (r=-0,81) and can be used for detection of early potential of tissual transformation in women with immunodeficiency.

Hepatic disease is common in severe COVID-19. This study compared the histologic/molecular findings in the liver in fatal COVID-19 (n = 9) and age-matched normal controls (n = 9); three of the fatal COVID-19 livers had pre-existing alcohol use disorder (AUD). Controls showed a high resident population of sinusoidal macrophages that had variable ACE2 expression. Histologic findings in the cases included periportal/lobular inflammation. SARS-CoV2 RNA and nucleocapsid protein were detected in situ in 2/9 COVID-19 livers in low amounts. In 9/9 cases, there was ample in situ SARS-CoV-2 spike protein that co-localized with viral matrix and envelope proteins. The number of cells positive for spike/100× field was significantly greater in the AUD/COVID-19 cases (mean 5.9) versus the non-AUD/COVID-19 cases (mean 0.4, p < 0.001) which was corroborated by Western blots. ACE2+ cells were 10× greater in AUD/COVID-19 livers versus the other COVID-19/control liver samples (p < 0.001). Co-expression experiments showed that the spike protein localized to the ACE2 positive macrophages and, in the AUD cases, hepatic stellate cells that were activated as evidenced by IL6 and TNFα expression. Injection of the S1, but not S2, subunit of spike in mice induced hepatic lobular inflammation in activated macrophages. It is concluded that endocytosed viral spike protein can induce hepatitis in fatal COVID-19. This spike induced hepatitis is more robust in the livers with pre-existing AUD which may relate to why patients with alcohol abuse are at higher risk of severe liver disease with SARS-CoV2 infection., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: To evaluate chronological changes on serial magnetic resonance imaging (MRI) examinations and clinical prognosis in patients with status epilepticus (SE), as well as the effect of alcohol abuse and heavy alcohol use on clinicoradiological findings., Materials and Methods: This retrospective, single-centre study was approved by the institutional review board. Among 345 patients with seizures between January 2010 and October 2021, 27 patients with SE who had undergone both initial MRI (within a week after onset) and follow-up MRI (within 1 month after the initial MRI) were included. Five and three patients with concurrent or previous alcohol abuse and heavy alcohol-use history were included, respectively, and they were classified into the AL (Alcohol use) group. The remaining 19 patients were classified into the non-AL group. Two neuroradiologists independently evaluated both initial and follow-up MRI examinations of each patient; MRI findings were compared between the AL and non-AL groups using Fisher's exact test. In 15 patients, including four patients from the AL group, clinical information 6 months after the onset of SE was available; this information was compared between the two groups., Results: Brain atrophy (5/8 versus 2/19, p=0.011; odds ratio, 12.29 [95% confidence interval, 1.32-189.2]) and unfavourable clinical course with uncontrollable seizures (3/4 versus 1/11, p=0.033; odds ratio, 30[1.43-638.19]) were significantly more frequent in the AL group than in the non-AL group., Conclusion: Among patients with SE, alcohol abuse and heavy alcohol-use history were associated with unfavourable seizure control and brain atrophy., (Copyright © 2022 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Abnormal resting-state functional connectivity, as measured by functional magnetic resonance imaging (MRI), has been reported in alcohol use disorders (AUD), but findings are so far inconsistent. Here, we exploited recent developments in graph-theoretical analyses, enabling improved resolution and fine-grained representation of brain networks, to investigate functional connectivity in 35 recently detoxified alcohol dependent patients versus 34 healthy controls. Specifically, we focused on the modular organization, that is, the presence of tightly connected substructures within a network, and on the identification of brain regions responsible for network integration using an unbiased approach based on a large-scale network composed of more than 600 a priori defined nodes. We found significant reductions in global connectivity and region-specific disruption in the network topology in patients compared with controls. Specifically, the basal brain and the insular-supramarginal cortices, which form tightly coupled modules in healthy subjects, were fragmented in patients. Further, patients showed a strong increase in the centrality of the anterior insula, which exhibited stronger connectivity to distal cortical regions and weaker connectivity to the posterior insula. Anterior insula centrality, a measure of the integrative role of a region, was significantly associated with increased risk of relapse. Exploratory analysis suggests partial recovery of modular structure and insular connectivity in patients after 2 weeks. These findings support the hypothesis that, at least during the early stages of abstinence, the anterior insula may drive exaggerated integration of interoceptive states in AUD patients with possible consequences for decision making and emotional states and that functional connectivity is dynamically changing during treatment., (© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Alcohol is globally the leading risk factor for cirrhosis and is subsumed under the term alcohol-related liver disease (ALD). However, only ca. 10% of people with harmful alcohol consumption (>40 gram alcohol per day) develop cirrhosis, while 15% have normal liver histology. Unfortunately, laboratory parameters and ultrasound hold little value to neither rule-in nor rule out alcohol related liver fibrosis. While several indices with combinations of liver associated markers such as FIB4 seem to be promising, non-invasive test strategies are urgently needed with cut-off's that can be applied to guide clinical decision making. The aims of this review article are to highlight novel developments for the diagnosis of ALD and to identify topics of controversy and potential future directions. In the last 15 years, elastography to measure liver stiffness (LS) has significantly improved our screening strategies for cirrhosis. LS values below 6 kPa are considered as normal and exclude ALD. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis. Especially, transient elastography (TE) has been assessed in numerous studies, but similar performance can be obtained with point shear wave elastography, 2 SD shear wave elastography or MR elastography. Important confounders of elevated LS such as inflammation should also be considered and alcohol withdrawal not only improves liver inflammation but also LS. Liver stiffness measurement has signficiantly improved early diagnosis and follow-up of fibrosis in patients with ALD and patients with diagnosed manifest but clinically compensated cirrhosis should undergo further clinical examinations to rule out complications of portal hypertension. In addition, surveillance for the occurrence of hepatocellular carcinoma is recommended in all cirrhotic patients., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Decreased punishment sensitivity in alcohol use disorder (AUD) might reflect a reduction in the typical human tendency to overweigh negative choice outcomes compared with equivalent positive ones, that is, 'loss aversion.' While this hypothesis is supported by previous reports of reduced loss aversion in AUD, it is still unknown whether such decreased sensitivity to prospective losses represents a specific facet of altered decision-making or a secondary effect of executive/working-memory impairments. We addressed this issue by assessing whether lower loss aversion in 22 AUD patients compared with 19 healthy controls is explained by their differential executive or working-memory performance and by investigating its neural basis in terms of grey matter density and cortical thickness via voxel- and surface-based morphometry, respectively. A significant decrease of loss aversion in patients, unrelated to their impaired executive/working-memory performance, reflected the reduction of posterior fronto-medial grey matter density and right frontopolar cortical thickness. Rather than their executive deficits, patients' reduced loss aversion reflects the structural damage of the posterior fronto-medial cortex previously associated with solving conflicts at the response level, where earlier functional magnetic resonance imaging (fMRI) studies have shown a 'neural loss aversion' pattern of steeper deactivation for losses than activation for gains, and of the frontopolar cortex in charge of managing competing goals. These findings highlight possible directions for addressing AUD patients' high relapse rate, for example, cognitive-behavioural rehabilitative interventions enhancing the awareness of the adverse outcomes of addiction or neurostimulation protocols targeting the regions processing their salience., (© 2021 Society for the Study of Addiction.)

A study of the influence of chronic alcohol intoxication, constant illumination and their combined effects on the morphofunctional state of the rat liver and the circadian rhythms (CR) of the studied parameters of the organism was carried out. It was found that both alcohol and constant illumination caused significant changes in the structure of the liver, as well as in the circadian rhythmicity of micromorphometric parameters of hepatocytes, ALT, and total and direct bilirubin rhythms; however, the combined effects of ethanol and constant illumination had the most significant effect on the studied parameters of the organism. These two factors caused disturbances in the circadian rhythms of the micromorphometric parameters of hepatocytes, disruption of the circadian rhythms of total protein, albumin, AST, ALT, and direct and total bilirubin, as well as disturbances in the expression and rhythmicity of the studied clock genes against a background of the development of an inflammatory process in the liver.

Heavy alcohol use is one of the top causes of disease and death in the world. The brain is a key organ affected by heavy alcohol use. Here, our aim was to measure changes caused by heavy alcohol use in the human brain metabolic profile. We analyzed human postmortem frontal cortex and cerebrospinal fluid (CSF) samples from males with a history of heavy alcohol use (n = 74) and controls (n = 74) of the Tampere Sudden Death Series cohort. We used a nontargeted liquid chromatography mass spectrometry-based metabolomics method. We observed differences between the study groups in the metabolite levels of both frontal cortex and CSF samples, for example, in amino acids and derivatives, and acylcarnitines. There were more significant alterations in the metabolites of frontal cortex than in CSF. In the frontal cortex, significant alterations were seen in the levels of neurotransmitters (e.g., decreased levels of GABA and acetylcholine), acylcarnitines (e.g., increased levels of acylcarnitine 4:0), and in some metabolites associated with alcohol metabolizing enzymes (e.g., increased levels of 2-piperidone). Some of these changes were also significant in the CSF samples (e.g., elevated 2-piperidone levels). Overall, these results show the metabolites associated with neurotransmitters, energy metabolism and alcohol metabolism, were altered in human postmortem frontal cortex and CSF samples of persons with a history of heavy alcohol use., (© 2021 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Substance use disorders (SUDs) are conditions in which the use of legal or illegal substances, such as nicotine, alcohol or opioids, results in clinical and functional impairment. SUDs and, more generally, substance use are genetically complex traits that are enormously costly on an individual and societal basis. The past few years have seen remarkable progress in our understanding of the genetics, and therefore the biology, of substance use and abuse. Various studies - including of well-defined phenotypes in deeply phenotyped samples, as well as broadly defined phenotypes in meta-analysis and biobank samples - have revealed multiple risk loci for these common traits. A key emerging insight from this work establishes a biological and genetic distinction between quantity and/or frequency measures of substance use (which may involve low levels of use without dependence), versus symptoms related to physical dependence., (© 2021. Springer Nature Limited.)

Studies of inflammation in alcohol use disorder (AUD) are overwhelmingly preclinical, and translation to clinical samples is necessary. Endotoxin administration has been used successfully in humans to study mood disorders, offering a translational, reliable and safe model that may be validated in AUD research. We argue for the use of endotoxin challenge to elucidate the interplay between AUD and inflammation., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Aims: Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis., Methods: We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase., Results: Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells., Conclusion: Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed., (© The Author(s) 2021. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background: Alcohol use disorder (AUD) not only influences individuals and families but also has a lasting social impact on communities at the national level. Dopaminergic neurotransmission is involved in excessive alcohol consumption. Phosphatidylinositol-5-phosphate-4-kinase type 2 α (PIP4K2A) plays an important role in the regulation of ascending dopamine pathways. In this study; we determined possible associations between nine polymorphisms in PIP4K2A and AUD in Russian men., Methods: 279 Russian men with AUD were investigated. The control group consisted of 222 healthy men from the general Russian population. Genotyping of DNA samples for nine polymorphic variants of PIP4K2A was carried out by the Applied Biosystems™ QuantStudio™ 5 Real-Time PCR System with use of the TaqMan1 Validated SNP Genotyping Assay (Applied Biosystems; CIIIA)., Results: Carriage of the PIP4K2A rs2230469*TT/T genotype/allele was a relative risk factor for developing AUD in men ( p = 0.026 and p = 0.0084 accordingly). Moreover; men with AUD had a higher frequency of PIP4K2A rs746203*T allele ( p = 0.023) compared to healthy men., Conclusions: For the first time; we demonstrated different PIP4K2A polymorphisms to be associated with AUD presumably due to dopamine system modulation resulting from regulation of the lateral habenula.