Alcohol-related Brain Damage Research Articles

Role of inflammation in alcohol-related brain abnormalities: a translational study.

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

Sex differences in cholinergic circuits and behavioral disruptions following chronic ethanol exposure with and without thiamine deficiency.

Few studies have investigated differences in the vulnerabilities of males and females to alcohol use disorder and alcohol-related brain damage (ARBD). According to epidemiological and clinical findings, females appear to be more sensitive to the effects of alcohol and thiamine deficiency and have a worse prognosis in recovery from neurocognitive deficits compared with males. This study aimed to characterize the effects of chronic ethanol (EtOH) toxicity and thiamine deficiency across the sexes using rodent models. Male and female Sprague Dawley rats were assigned to chronic forced EtOH treatment (CET), pyrithiamine-induced thiamine deficiency (PTD), combined CET-PTD, or pair-fed (PF) control treatment conditions. Following treatments, spatial working memory was assessed during a spontaneous alternation task while measuring acetylcholine (ACh) in the prefrontal cortex (PFC) and the hippocampus (HPC). The animals also underwent an operant-based attentional set-shifting task (ASST) for the analysis of behavioral flexibility. Female and male rats did not differ in terms of EtOH consumption; however, the CET and CET-PTD-treated female rats had lower BECs than male rats. Compared with the PF group, the CET, PTD, and CET-PTD groups exhibited spatial working memory impairments with corresponding reductions in ACh efflux in the PFC and HPC. The ASST revealed that CET-PTD-treated males and females displayed impairments marked by increased latency to make decisions. Thalamic shrinkage was prominent only in the CET-PTD and PTD treatment conditions, but no sex-specific effects were observed. Although the CET and CET-PTD-treated females had lower BECs than the males, they demonstrated similar cognitive impairments. These results provide evidence that female rats experience behavioral and neurochemical disruptions at lower levels of alcohol exposure than males and that chronic EtOH and thiamine deficiencies produce a unique behavioral profile.

Alcohol-related dementia – an overlooked entity?

IntroductionThe relationship between alcohol use and dementia is complex. There is a J-shaped relationship between alcohol use and cognitive impairment and evidence shows that one-quarter of the dementia population have alcohol related problems. It is estimated that alcohol-related dementia (ARD) contributes for about 10% of all cases of dementia, especially early-onset dementia, but is largely overlooked or seen as a comorbid factor.ObjectivesTo clarify the relationship between alcohol use, alcohol-related brain damage and dementia; to review the clinical features, neuropathology, nosology and neuropsychology of ARD and alcohol-induced persisting amnestic syndrome (Wernicke-Korsakoff syndrome- WKS).MethodsWe performed a review of systematic reviews from the last 10 years. A total of 28 systematic reviews were identified.ResultsHeavy alcohol use has been shown to be a contributory factor and necessary factor in the development of multiple brain diseases. It may cause brain damage in multiple ways: direct neurotoxic effect of acetaldehyde; thiamine deficiency. It is also a risk factor for other conditions, such as hepatic encephalopathy, epilepsy and head injury.ConclusionsClinical observation favors the diagnosis of ADR as a distinct entity, but broader evidence reflects significant commonality between ARD and WKS, tough neuropsychological studies have largely attempted to differentiate these syndromes. Repeated episodes of WKS may cause cognitive deterioration. In contrast to other common causes of dementia, the decline in cognitive functioning in ARD is relatively non-progressive if abstinence is maintained, or even partially reversible, as supported by neuroimaging evidence. Given the increase in per capita consumption, it is expected a disproportionate increase in ARD.

Professional Perspectives on Supporting Those with Alcohol-Related Neurocognitive Disorders: Challenges & Effective Treatment

ABSTRACT We interviewed health and social care professionals (n = 17) supporting those with Alcohol-Related Neurocognitive Disorders (ARNDs) to better understand the challenges they face and garner recommendations for effective treatment. Thematic qualitative content analysis was used to systematically analyze interview transcripts. Key challenges associated with treating ARNDs included the challenging behaviors of those with the disorders, their significant physical and mental health needs, stigmatization from others, and a general lack of understanding and awareness of ARNDs. Multiple recommendations for effective treatment were proposed, including first ensuring a comprehensive assessment and diagnostic process is undertaken that informs treatment, multidisciplinary input, and person-specific interventions. ABBREVIATIONS: ARBD: Alcohol-related brain damage: ARND: Alcohol-related neurocognitive disorder: ARD: Alcohol-related dementia: AUD: Alcohol use disorder: DSM: diagnostic & statistical manual of mental disorders: KS: Korsakoff’s syndrome: NICE: National Institute for Health and Clinical Excellence: WE: Wernicke’s Encephalopathy: WKS: Wernicke’s Korsakoff syndrome

Biochemical Features and Physiological Roles of hNP22 in the Central Nervous System.

hNP22, a novel neuron-specific protein that interacts with both actin filaments and microtubules, was found to be highly homologous to the smooth muscle cell cytoskeleton-associated proteins human SM22α and rat acidic calponin. In recent years, functions of hNP22 such as the promotion of neural differentiation and enhancement of neural plasticity, have been described, as well as potential roles of hNP22 in schizophrenia and alcohol-related brain damage (ARBD). Because of the potential roles of hNP22 in neuronal processes and its potential implications in diseases, hNP22 has emerged as a research target. In this paper, we review the gene structure, possible modifications, and functions of the hNP22 protein, as well as its potential clinical significance. Based on its physical structure and previous studies, we speculate that hNP22 has potential biological functions in neurological disorders, such as schizophrenia and ARBD.

Alcohol use and dementia: new research directions.

Alcohol is gaining increased recognition as an important risk factor for dementia. This review summarises recent evidence on the relationship between alcohol use and dementia, focusing on studies published from January 2019 to August 2020. Epidemiological data continues to yield results consistent with protective effects of low-to-moderate alcohol consumption for dementia and cognitive function. However, recent literature highlights the methodological limitations of existing observational studies. The effects of chronic, heavy alcohol use are clearer, with excessive consumption causing alcohol-related brain damage. Several pathways to this damage have been suggested, including the neurotoxic effects of thiamine deficiency, ethanol and acetaldehyde. Future research would benefit from greater implementation of analytical and design-based approaches to robustly model the alcohol use-dementia relationship in the general population, and should make use of large, consortia-level data. Early intervention to prevent dementia is critical: thiamine substitution has shown potential but requires more research, and psychosocial interventions to treat harmful alcohol use have proven effective. Finally, diagnostic criteria for alcohol-related dementia require formal validation to ensure usefulness in clinical practice.

The Effect of Chronic Ethanol Exposure and Thiamine Deficiency on Myelin-related Genes in the Cortex and the Cerebellum.

Long-term alcohol consumption has been linked to structural and functional brain abnormalities. Furthermore, with persistent exposure to ethanol (EtOH), nutrient deficiencies often develop. Thiamine deficiency is a key contributor to alcohol-related brain damage and is suspected to contribute to white matter pathology. The expression of genes encoding myelin proteins in several cortical brain regions is altered with EtOH exposure. However, there is limited research regarding the impact of thiamine deficiency on myelin dysfunction. A rat model was used to assess the impact of moderate chronic EtOH exposure (CET; 20% EtOH in drinking water for 1 or 6months), pyrithiamine-induced thiamine deficiency treatment (PTD), both conditions combined (CET-PTD), or CET with thiamine injections (CET+T) on myelin-related gene expression (Olig1, Olig2, MBP, MAG, and MOG) in the frontal and parietal cortices and the cerebellum. The CET-PTD treatments caused the greatest suppression in myelin-related genes in the cortex. Specifically, the parietal cortex was the region that was most susceptible to PTD-CET-induced alterations in myelin-related genes. In addition, PTD treatment, with and without CET, caused minor fluctuations in the expression of several myelin-related genes in the frontal cortex. In contrast, CET alone and PTD alone suppressed several myelin-related genes in the cerebellum. Regardless of the region, there was significant recovery of myelin-related genes with extended abstinence and/or thiamine restoration. Moderate chronic EtOH alone had a minor effect on the suppression of myelin-related genes in the cortex; however, when combined with thiamine deficiency, the reduction was amplified. There was a suppression of myelin-related genes following long-term EtOH and thiamine deficiency in the cerebellum. However, the suppression in the myelin-related genes mostly occurred 24h after EtOH removal or following thiamine restoration; within 3weeks of abstinence or thiamine recovery, gene expression rebounded.

Midline Thalamic Damage Associated with Alcohol-Use Disorders: Disruption of Distinct Thalamocortical Pathways and Function.

The thalamus, a significant part of the diencephalon, is a symmetrical and bilateral central brain structure. The thalamus is subdivided into three major groups of nuclei based on their function: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Anatomically, nuclei within the thalamus are described by their location, such as anterior, medial, lateral, ventral, and posterior. In this review, we summarize the role of medial and midline thalamus in cognition, ranging from learning and memory to flexible adaptation. We focus on the discoveries in animal models of alcohol-related brain damage, which identify the loss of neurons in the medial and midline thalamus as drivers of cognitive dysfunction associated with alcohol use disorders. Models of developmental ethanol exposure and models of adult alcohol-related brain damage and are compared and contrasted, and it was revealed that there are similar (anterior thalamus) and different (intralaminar [adult exposure] versus ventral midline [developmental exposure]) thalamic pathology, as well as disruptions of thalamo-hippocampal and thalamo-cortical circuits. The final part of the review summarizes approaches to recover alcohol-related brain damage and cognitive and behavioral outcomes. These approaches include pharmacological, nutritional and behavioral interventions that demonstrated the potential to mitigate alcohol-related damage. In summary, the medial/midline thalamus is a significant contributor to cognition function, which is also sensitive to alcohol-related brain damage across the life span, and plays a role in alcohol-related cognitive dysfunction.

The effect of alcohol withdrawal syndrome severity on sleep, brain and cognition.

In alcohol use disorder, drinking cessation is frequently associated with an alcohol withdrawal syndrome. Early in abstinence (within the first 2 months after drinking cessation), when patients do not exhibit physical signs of alcohol withdrawal syndrome anymore (such as nausea, tremor or anxiety), studies report various brain, sleep and cognitive alterations, highly heterogeneous from one patient to another. While the acute neurotoxicity of alcohol withdrawal syndrome is well-known, its contribution to structural brain alterations, sleep disturbances and neuropsychological deficits observed early in abstinence has never been investigated and is addressed in this study. We included 54 alcohol use disorder patients early in abstinence (from 4 to 21 days of sobriety) and 50 healthy controls. When acute physical signs of alcohol withdrawal syndrome were no longer present, patients performed a detailed neuropsychological assessment, a T1-weighted MRI and a polysomnography for a subgroup of patients. According to the severity of the clinical symptoms collected during the acute withdrawal period, patients were subsequently classified as mild alcohol withdrawal syndrome (mild-AWS) patients (Cushman score ≤ 4, no benzodiazepine prescription, N = 17) or moderate alcohol withdrawal syndrome (moderate-AWS) patients (Cushman score > 4, benzodiazepine prescription, N = 37). Patients with severe withdrawal complications (delirium tremens or seizures) were not included. Mild-AWS patients presented similar grey matter volume and sleep quality as healthy controls, but lower processing speed and episodic memory performance. Compared to healthy controls, moderate-AWS patients presented non-rapid eye movement sleep alterations, widespread grey matter shrinkage and lower performance for all the cognitive domains assessed (processing speed, short-term memory, executive functions and episodic memory). Moderate-AWS patients presented a lower percentage of slow-wave sleep, grey matter atrophy in fronto-insular and thalamus/hypothalamus regions, and lower short-term memory and executive performance than mild-AWS patients. Mediation analyses revealed both direct and indirect (via fronto-insular and thalamus/hypothalamus atrophy) relationships between poor sleep quality and cognitive performance. Alcohol withdrawal syndrome severity, which reflects neurotoxic hyperglutamatergic activity, should be considered as a critical factor for the development of non-rapid eye movement sleep alterations, fronto-insular atrophy and executive impairments in recently detoxified alcohol use disorder patients. The glutamatergic activity is involved in sleep-wake circuits and may thus contribute to molecular mechanisms underlying alcohol-related brain damage, resulting in cognitive deficits. Alcohol withdrawal syndrome severity and sleep quality deserve special attention for a better understanding and treatment of brain and cognitive alterations observed early in abstinence, and ultimately for more efficient relapse prevention strategies.

Alcohol-related brain damage: diagnosis, treatment and medical management

Alcohol misuse is often a hidden problem and alcohol-related brain damage is thought to account for around 10% of cases of dementia ( Gupta and Warner, 2008 ; Brust, 2010 ). In England, an estimated 589 101 adults are alcohol-dependent and 24% of adults in England and Scotland regularly drink more than Department of Health and Social Care (DHSC) guidelines ( Burton et al, 2016 ). Alcohol misuse can affect many aspects of health and can lead to alcohol-related brain damage (ARBD). This article explains about the pathophysiology and clinical features of ARBD, and how it is diagnosed, treated and managed.

Dementia 5. Alcohol-related brain damage (ARBD): diagnosis, treatment and medical management

Alcohol misuse is often a hidden problem and alcohol-related brain damage is thought to account for around 10% of cases of dementia ( Brust, 2010 ; Gupta and Warner, 2008 ). In England, an estimated 589 101 adults are alcohol-dependent and 24% of adults in England and Scotland regularly drink more than Department of Health and Social Care (DHSC) guidelines ( Burton et al, 2016 ). Alcohol misuse can affect many aspects of health and can lead to alcohol-related brain damage (ARBD). This article, the fifth in a series on dementia, explains about the pathophysiology and clinical features of ARBD, and how it is diagnosed, treated and managed.

Applicability of the ACE-III and RBANS Cognitive Tests for the Detection of Alcohol-Related Brain Damage.

Background and AimsRecent investigations have highlighted the value of neuropsychological testing for the assessment and screening of Alcohol-Related Brain Damage (ARBD). The aim of the present study was to evaluate the suitability of the Addenbrooke’s Cognitive Examination (ACE-III) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) for this purpose.MethodsComparing 28 participants with ARBD (11 with Korsakoff’s Syndrome and 17 with the umbrella “ARBD” diagnosis) and 30 alcohol-dependent participants without ARBD (ALs) we calculated Area Under the Curve (AUC) statistics, sensitivity and specificity values, base-rate adjusted predictive values, and likelihood ratios for both tests.ResultsHigh levels of screening accuracy were found for the total scores of both the ACE-III (AUC = 0.823, 95% CIs [0.714, 0.932], SE = 0.056; optimal cut-off ≤86: sensitivity = 82%, specificity = 73%) and RBANS (AUC = 0.846, 95% CIs [0.746, 0.947], SE = 0.052; optimal cut-off ≤83: sensitivity = 89%, specificity = 67%) at multiple cut-off points. Removing participants with a history of polysubstance from the samples (10 ALs and 1 ARBD) improved the diagnostic capabilities of the RBANS substantially (AUC = 0.915, 95% CIs [0.831, 0.999], SE = 0.043; optimal cut-off ≤85: sensitivity = 98%, specificity = 80%), while only minor improvements to the ACE-III’s accuracy were observed (AUC = 0.854, 95% CIs [0.744, 0.963], SE = 0.056; optimal cut-off ≤88: sensitivity = 85%, specificity = 75%).ConclusionOverall, both the ACE-III and RBANS are suitable tools for ARBD screening within an alcohol-dependent population, though the RBANS is the superior of the two. Clinicians using these tools for ARBD screening should be cautious of false-positive outcomes and should therefore combine them with other assessment methods (e.g., neuroimaging, clinical observations) and more detailed neuropsychological testing before reaching diagnostic decisions.

Therapeutic Prospects of Cannabidiol for Alcohol Use Disorder and Alcohol-Related Damages on the Liver and the Brain.

Background: Cannabidiol (CBD) is a natural component of cannabis that possesses a widespread and complex immunomodulatory, antioxidant, anxiolytic, and antiepileptic properties. Much experimental data suggest that CBD could be used for various purposes in alcohol use disorder (AUD) and alcohol-related damage on the brain and the liver. Aim: To provide a rationale for using CBD to treat human subjects with AUD, based on the findings of experimental studies. Methods: Narrative review of studies pertaining to the assessment of CBD efficiency on drinking reduction, or on the improvement of any aspect of alcohol-related toxicity in AUD. Results: Experimental studies find that CBD reduces the overall level of alcohol drinking in animal models of AUD by reducing ethanol intake, motivation for ethanol, relapse, anxiety, and impulsivity. Moreover, CBD reduces alcohol-related steatosis and fibrosis in the liver by reducing lipid accumulation, stimulating autophagy, modulating inflammation, reducing oxidative stress, and by inducing death of activated hepatic stellate cells. Finally, CBD reduces alcohol-related brain damage, preventing neuronal loss by its antioxidant and immunomodulatory properties. Conclusions: CBD could directly reduce alcohol drinking in subjects with AUD. Any other applications warrant human trials in this population. By reducing alcohol-related steatosis processes in the liver, and alcohol-related brain damage, CBD could improve both hepatic and neurocognitive outcomes in subjects with AUD, regardless of the individual’s drinking trajectory. This might pave the way for testing new harm reduction approaches in AUD, in order to protect the organs of subjects with an ongoing AUD.

Chronic alcohol causes alteration of lipidome profiling in brain

Much efforts have been tried to clarify the molecular mechanism of alcohol-induced brain damage from the perspective of genome and protein; however, the effect of chronic alcohol exposure on global lipid profiling of brain is unclear. In the present study, by using Q-TOF/MS-based lipidomics approach, we investigated the comprehensive lipidome profiling of brain from the rats orally administrated with alcohol daily, continuously for one year. Through systematically analysis of all lipids in prefrontal cortex (PFC) and striatum region, we found that long-term alcohol exposure profoundly modified brain lipidome profiling. Notably, three kinds of lipid classes, glycerophospholipid (GP), glycerolipid (GL) and fatty acyls (FA), were significantly increased in these two brain regions. Interestingly, most of the modified lipids were involved in synthetic pathways of endoplasmic reticulum (ER), which may result in ER stress-related metabolic disruption. Moreover, alcohol-modified lipid species displayed long length of carbon chain with high degree of unsaturation. Taken together, our results firstly present that chronic alcohol exposure markedly modifies brain lipidomic profiling, which may activate ER stress and eventually result in neurotoxicity. These findings provide a new insight into the mechanism of alcohol-related brain damage.

Effects of Chronic Voluntary Alcohol Drinking on Thiamine Concentrations, Endoplasmic Reticulum Stress, and Oxidative Stress in the Brain of Crossed High Alcohol Preferring Mice.

Chronic alcohol drinking can damage the central nervous system via many mechanisms. One of these may involve a deficiency of an essential nutrient, thiamine, as a result of chronic alcohol exposure. Although thiamine deficiency (TD) has often been linked to the neuropathology of alcohol-related brain damage, the underlying mechanisms remain to be investigated. The crossed high alcohol preferring (cHAP) mice prefer alcohol to water when they have free access. In this study, we used cHAP mice to determine the effect of chronic voluntary alcohol exposure on thiamine levels and neuropathological changes in the brain. The male cHAP mice were given free-choice access to 10% ethanol (EtOH) and water for 7months, sacrificed, and thiamine concentrations in the blood plasma and brain were determined by liquid chromatography-mass spectrometry (LC-MS). The expression of thiamine transporters was examined by immunoblotting. In addition, oxidative stress, endoplasmic reticulum (ER) stress, active caspase-3-dependent apoptosis, and neurogenesis in the brain were evaluated. The results indicated that chronic alcohol exposure decreased thiamine levels and thiamine transporters, and increased oxidative stress, ER stress, and neuronal apoptosis in the brains. Interestingly, alcohol exposure also stimulated neurogenesis in the hippocampus which may serve as a compensatory mechanism in response to alcohol-induced brain damage. Our data have demonstrated that cHAP mice are a useful model to study the interaction between chronic alcohol consumption and TD, as well as TD's contributions to the neuropathological processes resulting in alcohol-related brain damage.

A Pivotal Role for Thiamine Deficiency in the Expression of Neuroinflammation Markers in Models of Alcohol-Related Brain Damage.

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

Aging with alcohol-related brain damage: Critical brain circuits associated with cognitive dysfunction.

Alcoholism is associated with brain damage and impaired cognitive functioning. The relative contributions of different etiological factors, such as alcohol, thiamine deficiency and age vulnerability, to the development of alcohol-related neuropathology and cognitive impairment are still poorly understood. One reason for this quandary is that both alcohol toxicity and thiamine deficiency produce brain damage and cognitive problems that can be modulated by age at exposure, aging following alcohol toxicity or thiamine deficiency, and aging during chronic alcohol exposure. Pre-clinical models of alcohol-related brain damage (ARBD) have elucidated some of the contributions of ethanol toxicity and thiamine deficiency to neuroinflammation, neuronal loss and functional deficits. However, the critical variable of age at the time of exposure or long-term aging with ARBD has been relatively ignored. Acute thiamine deficiency created a massive increase in neuroimmune genes and proteins within the thalamus and significant increases within the hippocampus and frontal cortex. Chronic ethanol treatment throughout adulthood produced very minor fluctuations in neuroimmune genes, regardless of brain region. Intermittent "binge-type" ethanol during the adolescent period established an intermediate neuroinflammatory response in the hippocampus and frontal cortex, that can persist into adulthood. Chronic excessive drinking throughout adulthood, adolescent intermittent ethanol exposure, and thiamine deficiency all led to a loss of the cholinergic neuronal phenotype within the basal forebrain, reduced hippocampal neurogenesis, and alterations in the frontal cortex. Only thiamine deficiency results in gross pathological lesions of the thalamus. The behavioral impairment following these types of treatments is hierarchical: Thiamine deficiency produces the greatest impairment of hippocampal- and prefrontal-dependent behaviors, chronic ethanol drinking ensues mild impairments on both types of tasks and adolescent intermittent ethanol exposure leads to impairments on frontocortical tasks, with sparing on most hippocampal-dependent tasks. However, our preliminary data suggest that as rodents age following adolescent intermittent ethanol exposure, hippocampal functional deficits began to emerge. A necessary requirement for the advancement of understanding the neural consequences of alcoholism is a more comprehensive assessment and understanding of how excessive alcohol drinking at different development periods (adolescence, early adulthood, middle-aged and aged) influences the trajectory of the aging process, including pathological aging and disease.

Protective effect of taurine on cellular structures in rat hippocampus following ethanol intoxication.

Background. Distinct brain structures, in particular, the hippocampus, have a selective sensitivity to acute and chronic alcohol intoxication. Study of the pathogenesis of alcohol-related brain damage with a view to the development of methods of prevention and treatment is an urgent task.Objective.Our main interest was in elucidating the effects of the biologically active substance, such as taurine on cellular structures in the hippocampus following ethanol intoxication.Methods.We applied a histochemical method to estimate the Ca2 + -dependent acid phosphatase activity. The present study was carried out in female albino rats. All experimental animals received an ethanol (15%) diet as their sole source of fluid at various time points.To study the effect of taurine on cellular structures of the rat brain following short-term and chronic alcohol consumption, rats were given daily injections of taurine solution for 7 days. Results. The morphological picture of the hippocampus is characterized by swelling of granular cells in the dentate gyrus that undergo chromatolysis, as well as a decrease in numerical density and a weak expression of processes of pyramidal neurons in the early stages of alcohol consumption. Degenerative changes occur in pyramidal cells in the hippocampus in the middle periods of alcohol consumption. The density of neurons is decreased; pyramidal cells lose their characteristic shape. In the conditions of long-term alcohol consumption, not only changes in the size and number of pyramidal neurons but also in the volume of the hippocampus and its regions are observed. The morphological picture of hippocampal neurons is a morphological proof of the disorders of their metabolism. In rats treated with taurine, there are positive changes in the structural properties of neurons and an increase in phosphatase activity (increased metabolism) in the hippocampus, which determines cell survival and functional recovery of irritated neurons. Conclusion. The results indicate that taurine has a neuroprotective effect on cellular structures in rat hippocampus.

Identification and Evaluation of Neuropsychological Tools Used in the Assessment of Alcohol-Related Cognitive Impairment: A Systematic Review.

Background: Neuropsychological assessment is central to identifying and determining the extent of Alcohol-Related Cognitive Impairment (ARCI). The present systematic review aimed to synthesize and discuss the evidence appraising the neuropsychological tests used to assess ARCI in order to support clinicians and researchers in selecting appropriate tests for use with this population.Methods: We searched for studies investigating the psychometric, diagnostic and practical values of tools used in the screening, diagnosis, and assessment of Korsakoff's Syndrome (KS), Alcohol-Related Dementia (ARD), and those with a specific diagnosis of Alcohol-Related Brain Damage (ARBD). The following databases were searched in March 2016 and again in August 2018: MEDLINE, EMBASE, Psych-INFO, ProQuest Psychology, and Science Direct. Study quality was assessed using a checklist designed by the authors to evaluate the specific factors contributing to robust and clearly reported studies in this area. A total of 43 studies were included following the screening of 3646 studies by title and abstract and 360 at full-text. Meta-analysis was not appropriate due to heterogeneity in the tests and ARCI samples investigated in the studies reviewed. Instead, review findings were narratively synthesized and divided according to five domains of assessment: cognitive screening, memory, executive function, intelligence and test batteries, and premorbid ability. Effect sizes (d) were calculated to supplement findings.Results: Overall, several measures demonstrated sensitivity to the cognitive deficits associated with chronic alcoholism and an ability to differentiate between gradations of impairment. However, findings relating to the other psychometric qualities of the tests, including those important for the accurate assessment and monitoring of ARCI (e.g., test-retest reliability), were entirely absent or limited. Additionally, the synthesis of neuropsychological outcomes presented here supports the recent impetus for a move away from discrete diagnoses (e.g., KS, ARD) and the distinctions between them toward more broad and inclusive diagnostic conceptualizations of ARCI, thereby recognizing the heterogeneity in presentation.Conclusions: Based on the evidence reviewed, provisional recommendations for appropriate tests in each domain of assessment are presented, though further validation of most tests is warranted. Review findings can support efficient and evidenced-based test-selection and guide future research in this area.

Acetate Mediates Alcohol Excitotoxicity in Dopaminergic-like PC12 Cells.

Neuronal excitotoxicity is the major cause of alcohol-related brain damage, yet the underlying mechanism remains poorly understood. Using dopaminergic-like PC12 cells, we evaluated the effect of N-methyl-d-aspartate receptors (NMDAR) on acetate-induced changes in PC12 cells: cell death, cytosolic calcium, and expression levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα). Treatment of PC12 cells with increasing concentrations of acetate for 4 h caused a dose-dependent increase in the percentage of cells staining positive for cell death using propidium iodide (PI) exclusion and cytosolic reactive oxygen species (ROS) using cell ROX detection analyzed via flow cytometry. The EC50 value for acetate was calculated and found to be 4.40 mM for PI and 1.81 mM for ROS. Ethanol up to 100 mM had no apparent changes in the percent of cells staining positive for PI or ROS. Acetate (6 mM) treatment caused an increase in cytosolic calcium measured in real-time with Fluo-4AM, which was abolished by coapplication with the NMDAR blocker memantine (10 μM). Furthermore, cells treated with acetate (6 mM) for 4 h had increased expression levels of TNFα relative to control, which was abolished by coapplication of memantine (10 μM). Co-application of acetate (6 mM) and memantine had no apparent reduction in acetate-induced cell death. These findings suggest that acetate is capable of increasing cytosolic calcium concentrations and expression levels of the pro-inflammatory cytokine TNFα through an NMDAR-dependent mechanism. Cell death from acetate was not reduced through NMDAR blockade, suggesting alternative pathways independent of NMDAR activation for excitotoxicity.