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Alcohol-related dementia (ARD) is one of the most common dementing disorders in middle-aged people and occurs in heavy drinkers who are estimated to be 10 - 15 % of the adult men in a community. While the concept of ARD is multifactorial and includes all cognitive deficits in alcoholics, the central clinical manifestations are exemplified by Korsakoff's syndrome (KS), a persistent neuropsychiatric syndrome, characterized by amnesia and disorientation that is caused by thiamine deficiency along with excessive alcohol consumption. Antemortem detection of intracranial changes has been made possible by MRI and many studies have revealed that alcoholics have atrophic changes in frontal lobe, cerebellum, medial temporal lobe and hippocampus. However, these brain regions are vulnerable to excessive alcohol and seem to be independent of cognitive deficits in alcoholics. This review shows the regional differences in gray matter volumes between cognitively normal alcoholics and patients with KS. By employing a 3-dimensional MRI method for voxel-based morphometry that enables an automated, unbiased, comprehensive assessment, we demonstrate that parahippocampal/hippocampal atrophy is specific to KS and thalamic atrophy and the third ventricle enlargement are more severe in patients with KS than in cognitively normal alcoholics.

Recent clinical neuroimaging studies have revealed the possible relation between morphological brain changes, and memory, cognitive impairment in the course of alcoholism and depression. In the previous studies, we have been analyzing the mechanism of neural network disruption by ethanol using postmortem human brain and cultured cells, and identified the sensitive effect of ethanol on the neural stem cell (NSC) differentiation rather than the influence on neuronal cell survival. Furthermore, to develop a novel method for reconstruction of the neural network damaged by ethanol, we tried to analyze the usefulness of intravenous NSC transplantation in fetal alcohol syndrome spectrum disorder (FASD) model rats. In the in vitro studies, we have found the suppressive effect of ethanol on NSC differentiation to neurons, through alteration of transcription factor, CREB and NRSF/REST activities, by the cellular signaling cascade changes including trophic factors and endoplasmic reticulum (ER) function. In the in vivo studies, we have shown the effective migration of labeled NSCs into the brain of FASD model rats, and revealed the therapeutic potential of this transplantation for the treatment of anxiety/cognitive dysfunction and behavioral abnormalities in alcohol-induced brain neural network damage. We are going to the next step for analysis of transplanted NSC dynamics in the brain, which must play a pivotal role in the effective induction of behavioral recoveries.

In this article, we reviewed brain damage seen in patients with alcohol dependence briefly focusing on neuroimaging studies. In uncomplicated alcoholic patients, a high incidence of cortical shrinkage and ventricular dilatation were reported using brain CT scans. In older alcoholics, prefrontal gray matter deficits were especially marked when compared with younger alcoholics. Reversibility of brain shrinkage is a common neuroimaging finding in patients with alcohol dependence and a study by Gazdinski et al. reported more rapid brain tissue gain during the first month of sobriety than in the following months. Another MRI study using deformation-based morphometry revealed significant shrinkage in the frontal and temporal lobes within 1 week of abstinence of alcoholic patients. This study followed participants for 8 months longitudinally and revealed that abstaining alcoholics recovered tissue volumes significantly faster than nonalcoholic controls in the parietal and frontal lobes and this study also revealed that when abstaining alcoholics were compared with relapsed alcoholics, additional regions with significantly greater recovery in abstainers were the temporal lobes, thalamus, brainstem, cerebellum, corpus callosum, anterior cingulate, insula, and subcortical white matter. Finally we introduced a MR spectroscopy (MRS) study on alcoholic patients. This study using proton MRS indicated that with short-term abstinence, cerebellar choline and frontomesial N-acetylaspartate (NAA) were significantly increased. Findings showing that a cerebellar choline increase and a frontomesial NAA increase were detected at stable water integrals and creatine concentrations, serum electrolytes and red blood cell indices suggest that early brain recovery through abstinence does not simply reflect rehydration. This might indicate that even the adult brain has capacities for regrowth and further understanding of the mechanisms of recovery of alcoholics' brains may result in a valuable model of brain regeneration with relevance for other disorders.

We report an autopsy case of fatal acute alcoholism showing myoglobinuria and myocardial damage. The victim was a 29-year-old male, who was found drunk at his home. Although he was once brought to a hospital following a police officer's advice, he was taken into custody without effective medical care due to his violent behavior, and died about 16 hours later. Autopsy revealed marked congestion of the viscera and fatty liver. Histologically, skeletal muscle and myocardium showed focal degeneration and necrosis. Immunohistochemical investigation revealed a diffuse myoglobin loss from muscle fibers. Alcohol concentrations were 0.54 mg/ml, 0.79 mg/ml and 2.53 mg/ml in the left, right heart blood and urine, respectively. No other drugs or poisons were detected. The urine was dark brown, showing marked myoglobinuria. Cardiac troponin T, I and CK-MB in the pericardial fluid showed elevated levels even when postmortem influence was taken into consideration. From these observations, the cause of death was determined as myocardial damage from advanced acute alcoholic myopathy accompanied by myoglobinuria, possibly with underlying alcohol abuse. The present case suggests that careful clinical observation and adequate management are essential for an alcoholic patient with neurological symptoms.

Mallory bodies, the intra-cytoplasmic inclusions in hepatocytes, are thought to be a pathognomonic feature of alcoholic liver disease, particularly of alcoholic hepatitis. The presence of Mallory bodies is considered as a reflection of serious illness in alcoholic liver disease. Mallory bodies are thought to disappear relatively rapidly with the use of therapeutic agents after giving up alcohol drinking. However, histological vicissitudes of Mallory bodies have not been studied extensively. In the present study, 19 autopsied cases with a history of heavy drinking were clinicopathologically evaluated. All patients were admitted to our hospital, and stopped alcohol drinking. These period of non-drinking ranged from one day to 150 days (group A: 1-7 days, group B: 8-30 days, group C: 31-150 days). Histological evaluation was performed by hematoxylin and eosin staining, Luxol Fast blue staining and chromotrope aniline blue staining of formalin-fixed paraffin-embedded liver sections. Hepatocytes including Mallory bodies were counted. The incidence of Mallory body formation was as follows: Group A (50%), group B (100%), and group C (100%) respectively. Average count of Mallory bodies: Group A (12.3/10 fields), group B (141.4/10 fields), and group C (188.3/10 fields). Fatty change was more significant in group A than in group B or C, and bile stasis was more significant in group B or C than in group A. These findings suggest that Mallory bodies may remain for several months after giving up drinking.

The brains of 8 patients with chronic alcoholism were neuropathologically examined. The findings obtained in the cerebellum of case 1 (male, aged 52) were in agreement with the restricted form of cerebellar cortical degeneration which was described by Victor et al (1958). The clinicopathological report on the cerebellar degeneration of this type was very rare in Japan. The cerebellar changes were more pronounced in the anterior vermis than in the posterior vermis and hemisphere. Furthermore, some old lesions of Wernicke's encephalopathy were found in this brain. 7 other cases showed very mild cerebellar degeneration. Partial loss of Purkinje cells was found near the tops of cerebellar folia. But their distribution and intensity had no individual variation and there was no tendency that the anterior vermis was more affected. This fact suggests that the alcoholic cerebellar degeneration may have some other cause than the direct toxic effect of ethylalcohol or its metabolites. The etiology of this disease was discussed with reference to thiamine deficiency and mal-nutrition.