Compared with dementia patients, Korsakoff patients have relatively intact intellectual abilities (Butters and Cermak 1980; Parsons et al. 1987). Other important differences between the two groups found by Cutting (1978) were that patients with alcoholic dementia had gradual rather than acute onset of symptoms, longer drinking history, and less evidence of ocular abnormalities, and that dementia occurred more often in women. Patients tended to show improvement with abstinence. The third neuropsychologically defined group of chronic alcoholics, variously referred to as "neurologically intact" (Ryan and Butters 1986), “intermediate duration organic mental disorder" (Grant 1987), and "neurologically asymptomatic" (Bowden 1990), show no overt behavioral signs of profound cognitive dysfunction. Their deficits are subtle in nature and more related to the demographic variables listed earlier (for instance, age, education, pattern and duration of drinking, length of sobriety, and medical complications). The deficits typically include impairments in abstraction ability and problem solving, impairments in visuoperceptual abilities, and mild learning and memory deficits (Grant 1987; Parsons et al. 1987; Ryan and Butters 1986; Salmon and Butters 1987). As in the other two groups, there is significant recovery following abstinence (Brandt et al. 1983; Goldman 1987; Grant 1987; Ryan and Butters 1986). While it is possible to make neuropsychological distinctions among subgroups of chronic alcoholics, whether this division is justified on the basis of neuropathological lesions has been the subject of debate (Bowden 1990; Butters and Stuss 1988; Lishman 1990). Initially, WernickeKorsakoff patients' amnesia was attributed to lesions produced by thiamine deficiency in subcortical structures, specifically the diencephalon, mammillary bodies (Victor et al. 1971, 1989), and basal forebrain (Arendt et al. 1983; Butters 1985). The abstracting and problem-solving difficulties most prominent in nonamnesic alcoholics were thought to be caused by alcohol-induced damage to the frontal cortex (Butters 1985; Jacobson and Lishman 1990; Ron 1987; Wilkinson 1987). However, postmortem analyses (Harper et al. 1986; Torvik et al. 1982), in vivo MRI (Jernigan, Butters et al. 1991; Jernigan, Schafer et al. 1991), and local cerebral blood flow studies (Hata et al. 1987) have shown that subcortical diencephalic and basal forebrain lesions associated with Wernicke-Korsakoff patients are also found in nonamnesic chronic alcoholics with undetect able or mild neurological and neuropsychological deficits. Individuals diagnosed as having alcoholic dementia also show the same pattern of brain changes as Wernicke-Korsakoff patients (Besson et al. 1989; Torvik et al. 1982). Furthermore, all three groups demonstrate significant reversibility of structural or functional brain changes following periods of abstinence that range from 2 to 28 weeks (Besson et al. 1989; Hata et al. 1987; Jernigan et al. 1992; Zipursky et al. 1989). Because Wernicke-Korsakoff patients show a pattern of cortical and subcortical changes similar to nonamnesic alcoholics as well as a heterogeneous presentation of the clinical signs (eye movement changes and memory and intellectual impairment) (Jacobson and Lishman 1987; Jacobson et al. 1990; Reuler et al. 1985; Victor and Adams 1985), it has been suggested that alcoholics progress through stages of brain damage caused by numerous bouts of subclinical thiamine deficiency or alcohol neurotoxicity or both (Bowden 1990; Harper et al. 1986; Lishman 1990). However, the factors that contribute to individual susceptibility to brain damage induced by alcohol or by thiamine deficiency, as well as the exact location and extent of cerebral damage that must be exceeded to produce severe neurological and memory impairments, is still an open question. Gender differences in susceptibility to alcohol-related brain damage have also been described (Jacobson 1986; Jacobson et al. 1990; Kroft et al. 1991; Pfefferbaum et al. 1992), but more research in this area is needed. Since the new functional imaging techniques (PET and SPECT) are potentially very sensitive to subtle alcohol-induced changes and allow simultaneous study of behavior, it may be possible to follow the development of lesions from reversible physiological changes to irreversible structural damage and to correlate these regional metabolic changes with the emergence of cognitive deficits (Jagust 1992). Furthermore, the capability of PET and SPECT to evaluate neurochemical differences between alcohol-related organic brain syndromes and other dementia complexes (e.g., Alzheimer's disease, multiinfarct dementia) has important treatment implications, since there is some suggestion that different pharmacological treatment strategies may be warranted (Eckardt et al. 1990; Martin and Eckardt 1985). Finally, the observation of subclinical brain and behavioral changes in chronic alcoholics has significant treatment implications. Nutritional supplements should be administered to alcoholics at risk for nutritional deficiencies, and assessment techniques should be developed to help identify chronic alcoholics' milder processing deficits (Cermak 1990). Relationship between alcohol-induced liver damage and cognitive deficits The liver, which is the primary site of alcohol metabolism in the body, can be damaged by chronic alcohol abuse. The types of liver injury produced by chronic heavy alcohol consumption range from a benign reversible condition known as fatty liver to the more severe disorders of hepatitis and cirrhosis. When the liver becomes diseased, the functioning of other systems that depend on normal liver activity, such as the kidneys, the gastrointestinal system, and the brain, also become impaired. Identification of chemical pathways in the brain that may be affected in Wernicke-Korsakoff syndrome and alcoholic dementia could lead to the development of pharmacological treatments. The most common brain dysfunction associated with hepatitis and cirrhosis is primary hepatic encephalopathy. This syndrome, which is considered a potentially reversible metabolic disorder, is characterized by impaired intellectual functioning, altered emotions, and psychomotor disturbances (Jones and Gammal 1988). Although not all chronic drinkers show evidence of liver damage, 15 to 30 percent of alcoholics develop cirrhosis (Lelbach 1975). Given the prevalence of cirrhosis among nonabstinent alcoholics, researchers have been interested in determining the relative contribution of impaired liver functioning to the cognitive deficits found in the alcoholic population. In a recent study, alcoholic and nonalcoholic individuals with cirrhosis showed similar patterns and severity of impairments on tests of motor speed, abstraction, and visuospatial ability, thus suggesting that cirrhosis, rather than alcoholism per se, may be the most important factor underlying the neuropsychological deficits (Tarter et al. 1988). However, more recent preliminary findings comparing alcoholics with and without cirrhosis support the hypothesis that alcohol and liver disease may act con jointly to produce the memory impairments in alcoholics (Arria et al. 1990). Several laboratories have studied the relationship between biochemical indices of liver dysfunction and neuropsychological status in order to determine the role of liver function in alcoholrelated cognitive impairment. Significant correlations have been found between cognitive performance and serum albumin (an index of liver protein synthesis) (Gilberstadt et al. 1980), y-glutamyltransferase (a measure of production of liver enzymes) (Irwin et al. 1989; Richardson et al. 1991), and fasting blood ammonia levels (an indicator of liver metabolic function) (Tarter and Edwards 1985) in detoxified alcoholics. In a recent longitudinal study (Schafer et al. 1991), the neuropsychological status of alcoholics was examined on their admission and discharge from an inpatient treatment program and at 3-month followups. Multiple factors were measured, including indices of depression, liver function, nutrition, drinking history, and family history. While depression and liver function were important predictors of neuropsychological performance on admission, the role of these factors diminished with length of stay in treatment. At followup, only the severity of depressive symptoms and the amount of drinking after discharge were major predictors of cognitive performance. These findings emphasize the importance of studying the collective contribution of multiple factors, including liver function, to a patient's cognitive deficits at various points in the clinical course. Finally, although there has been considerable speculation about possible aberrant metabolic pathways that may cause hepatic encephalopathy (see Arria et al. 1990 for a review), the specific biochemical mechanisms or neurotoxins associated with liver injury and their relationship to alcohol-induced cognitive deficits is unknown. Biochemical aspects of alcohol-related cognitive deficits Identification of chemical pathways in the brain that may be affected in Wernicke-Korsakoff syndrome and alcoholic dementia could lead to the development of pharmacological treatments. To date, three neurotransmitters (chemical substances that enable nerve cells to communicate) have been implicated in the memory loss of patients with Wernicke-Korsakoff syndrome-the catecholaminergic, cholinergic, and serotonergic systems (see Charness et al. 1989; Joyce 1987; McEntee and Mair 1990 for reviews). Several lines of evidence link the memory deficits in Wernicke-Korsakoff syndrome to decreased transmission of the catecholamine norepinephrine. First, an area of the brain frequently damaged in Korsakoff patients, the locus ceruleus, is the origin of the norepinephrine pathway (Mayes et al. 1988; Victor et al. 1971). Second, norepinephrine metabolism is decreased in Korsakoff patients (McEntee and Mair 1978; McEntee et al. 1984), and reduced norepinephrine activity is correlated with severity of neuropsychological impairment in these patients (Mair et al. 1985). Finally, treatment with clonidine, a drug that restores norepinephrine activity in the brain, transiently improves memory in Korsakoff patients (Mair and McEntee 1986; Martin et al. 1984). The assumption that the cholinergic system is involved in the memory loss of WernickeKorsakoff syndrome is largely based on the finding that there is cell loss in the basal forebrain area (particularly the nucleus basalis of Meynert), the major source of acetylcholine to brain areas responsible for learning and memory (Arendt et al. 1983). Several studies have found deficiencies in precursors of the neurotransmitter acetylcholine in Korsakoff patients and chronic alcoholics (Antuono et al. 1980; Lal et al. 1985; Nordberg et al. 1982), as well as reduced cholinergic receptors in brains of chronic alcohol abusers (Freund and Ballinger 1988, 1989a, 1989b). Furthermore, transient memory enhancement was found in Korskoff patients following chronic treatment with the acetylcholine precursor choline chloride (O'Donnell et al. 1986). However, more studies in humans are needed to reliably assess the role of cholinergic systems in memory loss associated with alcoholism and the potential of cholinergic drugs to reverse this disorder. Evidence for involvement of the neurotransmitter serotonin in the amnesia of WernickeKorsakoff syndrome comes in part from the proximity of neuronal pathways of this neurochemical system to the sites of neuropathological lesions in these patients (Joyce 1987; McEntee and Mair 1990). Recently, the administration of fluvoxamine, a drug that increases serotonin activity, was found to improve memory for recently acquired information in Korsakoff patients, but not in patients with more global cognitive impairment (alcoholic dementia) (Martin et al. 1989). In addition, the alcoholic dementia and Wernicke-Korsakoff patients could be distinguished by concentrations of somatostatin (a hormone that also can act like a neurotransmitter) in cerebrospinal fluid (CSF). Lower CSF somatostatin concentrations (similar to those seen in Alzheimer's disease) were found in the alcoholic dementia patients but not the Korsakoff patients. These findings suggest that the cognitive deficits associated with these two disorders could be mediated by different, if not multiple, neurochemical systems and underscore the need for diverse modes of treatment based on cognitive differences among the alcoholic groups. Summary The consequences of alcohol abuse affect almost every part of the body. Because the liver is the primary site of alcohol metabolism, it is severely affected by alcohol abuse. The major types of injury are fatty liver, alcoholic hepatitis and fibrosis, and cirrhosis. The risk of alcoholic liver damage depends on factors such as the quantity and pattern of alcohol consumed, gender, nutrition, and hormones. Recent research has focused on the role of free radicals, reactive oxygen molecules that oxidize lipids in various liver cell constituents. In alcoholics, the normal antioxidant protective mechanisms appear to be impaired. Activation of cytokines, hormone-like proteins, may also contribute to the pathogenesis of alcoholic liver disease. Acetaldehyde, the major metabolite of alcohol, appears to damage the cellular microstructure of the liver, induce fibrosis, and affect energy metabolism as well as generate free radicals. Other factors that play a role in alcohol-induced liver injury include immune mechanisms and oxygen deficiency. An experimental drug, propylthiouracil, may have some benefit in treating alcoholic liver disease. Liver transplantation has succeeded as well in alcoholic as in nonalcoholic cirrhotic patients. Moderate alcohol intake may decrease the risk of coronary heart disease, possibly by increasing the level of high-density lipoproteins, interfering with thrombosis, and, in postmenopausal women, increasing estrogen levels. However, heavy drinking is linked with hypertension, weakened heart muscle, and arrhythmias (disturbances in the normal heart rhythm). The high incidence of sudden death in alcoholics may be explained in part by arrhythmias. Heavy drinking is also associated with an increased risk of hemorrhagic stroke. By interfering with thrombosis, alcohol may increase the likelihood of hemorrhage. Chronic alcohol abuse depresses the immune system and results in a predisposition to infectious diseases. This effect of alcohol may be significant in immunocompromised patients, such as those with HIV infection. Some studies have suggested that alcohol may increase susceptibility to HIV infection itself. There is also a strong association between alcohol abuse and some forms of cancer. Although several hypotheses could account for this association, mechanisms for the possible carcinogenic effect of alcohol are incompletely understood. Numerous studies have found adverse effects of alcohol on the endocrine system and reproductive function. In men, alcohol can suppress testosterone levels, among other effects. Menstrual cycle disturbances are associated with chronic alcohol abuse in women of childbearing age. In animal models, alcohol can impair fertility either by preventing pregnancy or increasing the risk for spontaneous abortion; it can also delay puberty. Alcohol also stimulates the production of some steroid hormones that in turn stimulate the adrenal glands to secrete hormones that affect metabolism. The most dramatic result of this hormone excess is pseudo-Cushing's syndrome. Both acute and chronic alcohol use have multiple neurologic effects, including disruptive effects on cognitive and motor functioning, nutritional diseases of the nervous system, and neurologic disorders consequent to alcoholic liver disease. With the advent of new, noninvasive imaging techniques, it is becoming possible to correlate the cognitive, neurochemical, and neuroanatomical changes associated with varying degrees of alcohol use. Alcohol withdrawal has effects on many neurotransmitters and neuroendocrine systems, and medical treatment of withdrawal symptoms appears warranted. Pharmacologic interventions also show some promise in treating alcohol-related neuropsychological impairment. 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