What is the Korsakoff syndrome? - a paper in tribute to Prof Alwyn Lishman.

INTRODUCTION: Alwyn Lishman was interested in how memory research could be applied to clinical psychiatry. After a brief review of his major contributions, this paper will focus on his research on the alcoholic Korsakoff syndrome. It will consider how his findings relate to contemporary debates, particularly on how the syndrome should be defined, and its relationship to broader alcohol-induced cognitive impairments. METHODS: A review of the contribution of Alwyn Lishman, Robin Jacobson and colleagues to our knowledge of Korsakoff's syndrome, together with a review of the pertinent recent literature. RESULTS: Lishman and colleagues followed earlier authors in defining the Korsakoff syndrome in terms of disproportionate memory impairment, but they also noted a variable degree of IQ, frontal-executive, and timed visuo-spatial impairment in their cases. More recent authors have included such features in their definitions of the syndrome. Lishman also argued for a specific "alcoholic dementia". The present paper argues that recent definitions of the Korsakoff syndrome confound its core and associated features, and also fail to recognise the multifactorial basis of alcohol-related brain damage. CONCLUSIONS: Korsakoff's syndrome is best defined in terms of disproportionate memory impairment, and more widespread cognitive impairment is best encompassed within "alcohol-related brain damage".

Participation of cAMP/PKA-Mediated Signaling Pathways in Functional Activity of Regeneration-Competent Cells in the Nervous Tissue under Conditions of Ethanol-Induced Neurodegeneration.

We studied the involvement of cAMP/PKA signaling in the realization of the growth potential of neural progenitors and secretion of neurotrophic growth factors by glial elements under conditions of ethanol-induced neurodegeneration in vitro and in vivo. The stimulating role of cAMP and PKA in cell cycle progression of the neural progenitor cells and in production of neurotrophins by the cells in nervous tissue under the optimal conditions to vital activity was demonstrated. Ethanol inverted the role of cAMP/PKA signaling pathways in determination of the proliferation-differentiation status of neural stem cells. Selective blockade of adenylate cyclase or PKA in neural stem cells increased the rate of their division against the background of relative decrease in differentiation rate. In addition, cAMP/PKA signaling does not longer participate in neurotrophin production by glial cells in neurodegeneration. These findings suggest that inhibitors of activity/expression of adenylate cyclase and PKA can be considered as possible drugs with regenerative activity for the treatment of nervous system pathologies provoked by alcohol.

Forgetting the new locations of one's keys: spatial-memory interference in Korsakoff's amnesia.

The present study focused on interference in a group of patients with amnesia due to Korsakoff's syndrome (KS) within the domain of spatial memory. An object-location memory task was used in which participants first learned an array of objects on a computer screen, followed by a reconstruction of the object positions. Next a trial was given in which the same objects were presented only now in different locations. Participants had to place the objects a second time but at the new locations. This was repeated for seven pairs of baseline/interference trials. Both Korsakoff patients and matched controls did worse on the interference trials than on the baseline trials, indicating that it is difficult to relearn new spatial locations for objects that previously were remembered in other locations. When computing relative interference effects (that is the percentage change from baseline in the interference trials), Korsakoff patients were less affected than controls. It is discussed in how far interference depends on the strength of the original memories, which are markedly lower in KS patients.

Blackouts among male and female youth seeking emergency department care.

BACKGROUND: Alcohol-related blackouts are a common consequence of heavy drinking, and these blackouts pose risk for injury and other adverse health outcomes. OBJECTIVE: To examine the prevalence and correlates of blackouts among underage drinkers. METHODS: Youth (ages 14-20) presenting to a suburban Emergency Department (ED) completed screening surveys. Among those reporting past-year alcohol consumption, we examined past 3-month blackouts in relation to: background characteristics (e.g., demographics, fraternity/sorority involvement), substance use, sexual risk behaviors and incapacitated sexual assault (unaware/unable to consent due to alcohol/drugs), forced sexual assault, positive depression screening, and reason for ED visit (injury vs. medical). RESULTS: In total, 2,300 past-year drinkers participated: 58% female, 75% Caucasian, and mean age = 18.4. Regarding past 3-month blackouts, 72.7% reported none, 19.3% reported monthly or less, and 8% reported monthly or more. Multivariate cumulative logit regression indicated that blackout frequency was positively associated with: college involvement in Greek life, alcohol use severity, prescription drug misuse, marijuana, screening positive for depression, incapacitated sexual assault, and a gender by alcohol use severity interaction. CONCLUSION: With one-quarter of this clinical sample reporting recent blackouts, as well as the association between blackout frequency and health risk behaviors and other outcomes, findings underscore the need for programs focusing on substance use, depression, and preventing sexual assault. Interventions should also address poly-substance use and drinking motives. Although findings highlight how college students in Greek life may be at high risk for blackouts, many participants not in college also reported blackouts, suggesting that interventions in other settings are also needed.

Preventing and diagnosing dementia.

While dementia is an umbrella term for a range of degenerative brain disorders, many share similar presentations. Nurses are ideally placed to identify those at risk and empower them to access treatment and plan and prepare for their future needs--as such, they need up-to-date knowledge of the signs and symptoms of the different types of dementia to identify risk factors and make an informed diagnosis. This article, the third in a four-part series on dementia, examines the risk factors, signs, symptoms and diagnosis of dementia, as well as outlining lifestyle factors such as diet and exercise that may help to prevent the development of the condition.

Chronic alcohol consumption and its effect on nodes of frontocerebellar and limbic circuitry: comparison of effects in France and the United States.

Alcohol use disorders present a significant public health problem in France and the United States (U.S.), but whether the untoward effect of alcohol on the brain results in similar damage in both countries remains unknown. Accordingly, we conducted a retrospective collaborative investigation between two French sites (Caen and Orsay) and a U.S. laboratory (SRI/Stanford University) with T1-weighted, structural MRI data collected on a common imaging platform (1.5T, General Electric) on 288 normal controls (NC), 165 uncomplicated alcoholics (ALC), and 26 patients with alcoholic Korsakoff's syndrome (KS) diagnosed at all sites with a common interview instrument. Data from the two countries were pooled, then preprocessed and analyzed together at the U.S. site using atlas-based parcellation. National differences indicated that thalamic volumes were smaller in ALC in France than the U.S. despite similar alcohol consumption levels in both countries. By contrast, volumes of the hippocampus, amygdala, and cerebellar vermis were smaller in KS in the U.S. than France. Estimated amount of alcohol consumed over a lifetime, duration of alcoholism, and length of sobriety were significant predictors of selective regional brain volumes in France and in the U.S. The common analysis of MRI data enabled identification of discrepancies in brain volume deficits in France and the U.S. that may reflect fundamental differences in the consequences of alcoholism on brain structure between the two countries, possibly related to genetic or environmental differences.

Pellagra encephalopathy in the context of alcoholism: review and case report.

AIMS: The aim of the study was to review and describe the Alcoholic Pellagra Encephalopathy, a severe neuropsychiatric condition caused by a combination of niacin (vitamin B3) deficiency and alcohol abuse. METHODS: PsychInfo, Medline and Embase databases were searched for peer-reviewed studies addressing this illness. RESULTS: A historical and conceptual review of the psychopathological aspects of this condition is offered, followed by the report of a patient with a history of chronic alcohol consumption showing signs of pellagra, delusions and visual hallucinations, which was treated successfully with niacin. CONCLUSION: Pellagra encephalopathy should still be considered in the differential diagnosis of acute psychotic disorders seen in the context of chronic alcoholism.

Pellagra and alcoholism: a biochemical perspective.

Historical and clinical aspects of pellagra and its relationship to alcoholism are reviewed from a biochemical perspective. Pellagra is caused by deficiency of niacin (nicotinic acid) and/or its tryptophan (Trp) precursor and is compounded by B vitamin deficiencies. Existence on maize or sorghum diets and loss of or failure to isolate niacin from them led to pellagra incidence in India, South Africa, Southern Europe in the 18th century and the USA following the civil war. Pellagra is also induced by drugs inhibiting the conversion of Trp to niacin and by conditions of gastrointestinal dysfunction. Skin photosensitivity in pellagra may be due to decreased synthesis of the Trp metabolite picolinic acid → zinc deficiency → decreased skin levels of the histidine metabolite urocanic acid and possibly also increased levels of the haem precursor 5-aminolaevulinic acid (5-ALA) and photo-reactive porphyrins. Depression in pellagra may be due to a serotonin deficiency caused by decreased Trp availability to the brain. Anxiety and other neurological disturbances may be caused by 5-ALA and the Trp metabolite kynurenic acid. Pellagra symptoms are resolved by niacin, but aggravated mainly by vitamin B6. Alcohol dependence can induce or aggravate pellagra by inducing malnutrition, gastrointestinal disturbances and B vitamin deficiencies, inhibiting the conversion of Trp to niacin and promoting the accumulation of 5-ALA and porphyrins. Alcoholic pellagra encephalopathy should be managed with niacin, other B vitamins and adequate protein nutrition. Future studies should explore the potential role of 5-ALA and also KA in the skin and neurological disturbances in pellagra.

[Alcohol induced cognitive deficits]. / Alkohol induzierte kognitive Dysfunktion.

Previous studies could show a complex relationship between alcohol consumption and cognition but also with processes of ageing both social and biological. Acute effects of alcohol during intoxication include clinical signs such as excitation and reduced inhibition, slurred speech, and increased reaction time but also cognitive dysfunction, especially deficits in memory functions. However, these cognitive deficits during alcohol intoxication are reversible while patients with alcohol addiction and chronic alcohol intake show severe impairments of cognitive functions especially deficits in executive functions. Frontal executive impairments in these patients include deficits in problem solving, abstraction, planning, organizing, and working memory.Additionally, gender specific deficits are relevant for the course of the disease and its concomitant health problems with female alcoholics showing a higher vulnerability for cognitive dysfunction and brain atrophy at earlier stages of alcoholism history.

Dynamics of the cognitive procedural learning in alcoholics with Korsakoff's syndrome.

BACKGROUND: While procedures acquired before the development of amnesia are likely to be preserved in alcoholic patients with Korsakoff's syndrome, the ability of Korsakoff patients (KS) to learn new cognitive procedures is called in question. According to the Adaptive Control of Thoughts model, learning a new cognitive procedure requires highly controlled processes in the initial cognitive phase, which may be difficult for KS with episodic and working memory deficits. The goals of the present study were to examine the learning dynamics of KS compared with uncomplicated alcoholic patients (AL) and control subjects (CS) and to determine the contribution of episodic and working memory abilities in cognitive procedural learning performance. METHODS: Fourteen KS, 15 AL, and 15 CS were submitted to 40 trials (4 daily learning sessions) of the Tower of Toronto task (disk-transfer task similar to the tower of Hanoi task) as well as episodic and working memory tasks. RESULTS: The 10 KS who were able to perform the cognitive procedural learning task obtained lower results than both CS and AL. The cognitive phase was longer in the Korsakoff's syndrome group than in the other 2 groups but did not differ between the 3 groups any more when episodic memory abilities were controlled. CONCLUSIONS: Our results indicate that KS have impaired cognitive procedural learning abilities compared with both AL and CS. Episodic memory deficits observed in KS result in a delayed transition from the cognitive learning phase to more advanced learning phases and, as a consequence, in an absence of automation of the procedure within 40 trials.

Function and dysfunction of prefrontal brain circuitry in alcoholic Korsakoff's syndrome.

The signature symptom of alcohol-induced persisting amnestic disorder, more commonly referred to as alcoholic Korsakoff's syndrome (KS), is anterograde amnesia, or memory loss for recent events, and until the mid 20th Century, the putative brain damage was considered to be in diencephalic and medial temporal lobe structures. Overall intelligence, as measured by standardized IQ tests, usually remains intact. Preservation of IQ occurs because memories formed before the onset of prolonged heavy drinking--the types of information and abilities tapped by intelligence tests--remain relatively well preserved compared with memories recently acquired. However, clinical and experimental evidence has shown that neurobehavioral dysfunction in alcoholic patients with KS does include nonmnemonic abilities, and further brain damage involves extensive frontal and limbic circuitries. Among the abnormalities are confabulation, disruption of elements of executive functioning and cognitive control, and emotional impairments. Here, we discuss the relationship between neurobehavioral impairments in KS and alcoholism-related brain damage. More specifically, we examine the role of damage to prefrontal brain systems in the neuropsychological profile of alcoholic KS.

[Clinical application of neuroimaging to alcohol-related dementia].

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.

NMDA receptors in frontal cortex and hippocampus of alcohol consumers.

Specific binding of [³H]MK801 to N-methyl-D-aspartate (NMDA) receptors in the frontal cortex and hippocampus (CA1 and gyrus dentatus) was measured by receptor autoradiography in 16 Caucasian chronic alcohol consumers free of clinical manifestations of alcoholism, and compared with 16 Caucasian control subjects. Binding densities were not significantly different between heavy and moderate drinkers, neither between alcohol consumers that were abstinent or non-abstinent before death, nor between ethanol drinkers and controls. Continued alcohol consumption, in the absence of hepatic, neurologic or psychiatric disorders related to alcoholism, does not alter the binding properties of NMDA receptors in the brain areas studied.

Alcohol-related cognitive impairment in New South Wales hospital patients aged 50 years and over.

OBJECTIVES: The aim of this study was to describe the principal reasons for admission, medical comorbidities, interventions and outcomes of patients admitted to New South Wales hospitals with alcohol-related cognitive impairment. METHODS: We extracted data from the NSW Admitted Patient Care Database for nearly 410 000 multi-day hospital admissions from 222 public hospitals ending between July 2006 and June 2007 for people aged 50 and over. Data linkage using a unique patient identifier, derived by the Centre for Health Record Linkage identified hospital transfers and readmissions for individual patients. Using ICD10-AM codes, we identified patients with alcohol-related dementia, amnesic syndrome due to alcohol, and Wernicke's encephalopathy, their principal reasons for admission and medical comorbidities, and procedures undertaken. Outcomes were length of stay, mortality, discharge destination, and readmission. RESULTS: A total of 462 patients diagnosed with alcohol-related dementia (n = 300; 82% male, mean age 63.9 years), Wernicke's encephalopathy (n = 77) or amnesic syndrome due to alcohol (n = 126) were identified with overlap between diagnoses. Alcohol-related dementia occurred in 1.4% of dementia patients, and was more likely to occur in younger age groups and men than other types of dementia. Alcohol-related mental disorder was recorded in 70% of alcohol-related dementia multi-day admissions: dependence (52%), 'harmful use' (11%) and withdrawal (12%). Principal reasons for admission for multi-day stays included alcohol-related mental disorder (18%), liver disease (11%) and injuries/poisonings (10%). Medical comorbidity was common. Like other dementia patients, alcohol-related dementia patients had longer length of stay (mean of 15 days) than non-dementia patients and more transfers to residential care (7%). However, mortality was similar to non-dementia patients (5%). Discharge at own risk was high (3.7%). CONCLUSIONS: Alcohol-related dementia is a preventable and potentially reversible condition. Investigation of intervention strategies initiated during hospitalization are warranted.

The specificity of thalamic alterations in Korsakoff's syndrome: Implications for the study of amnesia.

The pathophysiological mechanisms behind amnesia are still unknown. Recent literature, through the study of patients with Alcohol Use Disorder with and without Korsakoff's syndrome, increasingly shows that physiological alterations to the thalamus have an important role in the development of amnesia. This review gives an overview of neuropsychological, neuropathological and neuroimaging contributions to the understanding of Korsakoff's syndrome, highlighting the central role of the thalamus in this amnesia. The thalamus being a multi-nucleus structure, the limitations regarding the loci, nature and alterations to specific nuclei are discussed, along with potential solutions. Finally, future directions for clinical research are laid out to unravel the intricacies inherent to amnesia. They consider the need to evaluate the physiological role of the thalamus, not only as an entity but also as part of a brain circuit through a more integrative approach.

Categorization abilities for emotional and nonemotional stimuli in patients with alcohol-related Korsakoff syndrome.

OBJECTIVE: To investigate whether patients with alcohol-related Korsakoff syndrome (KR) have emotion-specific or general deficits in multicategoric classification performance. BACKGROUND: Earlier studies have shown reduced performance in classifying stimuli according to their emotional valence in patients with KS. However, it is unclear whether such classification deficits are of emotion-specific nature or whether they can also occur when nonemotional classifications are demanded. METHOD: In this study, we examined 35 patients with alcoholic KS and 35 healthy participants with the Emotional Picture Task (EPT) to assess valence classification performance, the Semantic Classification Task (SCT) to assess nonemotional categorizations, and an extensive neuropsychologic test battery. RESULTS: KS patients exhibited lower classification performance in both tasks compared with the healthy participants. EPT and SCT performance were related to each other. EPT and SCT performance correlated with general knowledge and EPT performance in addition with executive functions. CONCLUSIONS: Our results indicate a common underlying mechanism of the patients' reductions in emotional and nonemotional classification performance. These deficits are most probably based on problems in retrieving object and category knowledge and, partially, on executive functioning.

Subjective ratings of prospective memory deficits in chronic alcohol users.

Previous research showing everyday memory is impaired by heavy alcohol use may have underestimated the cognitive impairment of heavy users because drinkers consuming over the recommended limits for safe drinking have often been treated as a homogeneous group, often with a low threshold for inclusion. The current study investigated whether the reported linear relationship applies to participants consuming alcohol significantly above recommended limits. The everyday memory of 80 participants (43 men; modal age, 31-35 years) was investigated using the Prospective Memory Questionnaire. Participants also detailed their average weekly intake of alcohol and other substances. Current heavy users of alcohol (who consumed on average over 25 units per week) reported more memory problems than low (1-9 units per week) or medium users (10-25 units per week). Participants undergoing counselling for alcohol use reported more deficits than low or medium drinkers, but fewer than current heavy drinkers. Possible reasons for this were discussed. Strengths and limitations of subjective approaches to memory assessment were discussed as well as suggestions for future research.

Memory impairment in Korsakoff's psychosis: a correlation with brain noradrenergic activity.

The concentration of the primary brain metabolite of norepinephrine is diminished in the lumbar spinal fluid of patients with Korsakoff's syndrome. The extent of its reduction is significantly correlated with measures of memory impairment for individual patients. These data suggest that the memory disorder of Korsakoff's syndrome may result from damage to ascending noradrenergic pathways by the diencephalic and brainstem lesions associated with this disease.

Preserved learning and retention of pattern-analyzing skill in amnesia: dissociation of knowing how and knowing that.

Amnesic patients acquired a mirror-reading skill at a rate equivalent to that of matched control subjects and retained it for at least 3 months. The results indicate that the class of preserved learning skills in amnesia is broader than previously reported. Amnesia seems to spare information that is based on rules or procedures, as contrasted with information that is data-based or declarative--"knowing how rather than "knowing that." The results support the hypothesis that such a distinction is honored by the nervous system.