Review
Alcohol-related amnesia and dementia: Animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment

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Abstract

Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol-related neurological disorders, alcohol-associated dementia and Wernicke-Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models—from repeated and chronic ethanol exposure to thiamine deficiency—is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone.

Research highlights

► Chronic alcohol ingestion is associated with alcohol-related dementia and Wernicke-Korsakoff Syndrome. ► Binge ethanol exposure disrupts cellular inhibition and increases neural excitation. ► Chronic ethanol exposure results in hippocampal and cortical cell loss. ► Thiamine deficiency produces diencephalic lesion and altered neurochemistry.

Introduction

Alcohol addiction is a severe disorder with many long-lasting health consequences—one of which can be impaired cognitive functioning. Numerous studies have reported that 50–75% of detoxified alcoholics have some type of cognitive or memory disturbance (for reviews, see Dufour, 1993, Parsons and Nixon, 1993, Smith and Atkinson, 1995). Furthermore, chronic alcohol consumption can lead to at least two long-lasting neurological disorders associated with severe cognitive dysfunction: alcohol-associated dementia (AAD) and Wernicke-Korsakoff syndrome (WKS). The neurotoxic effects of long-term heavy alcohol consumption are believed to produce AAD, whereas long-term heavy alcohol consumption in combination with dietary deficiencies—particularly thiamine—can lead to WKS. Although WKS is a nutrition deficiency disorder, it is most frequently reported in alcoholic patients (Kopelman, Thomson, Guerrini, & Marshall, 2009). Indeed, it has been estimated that greater than 10% of alcoholic patients have symptoms of either AAD or WKS (Harper and Kril, 1990, Parsons and Nixon, 1993).

To gain mechanistic insights to the consequences of ethanol neural toxicity and thiamine deficiency on learning and memory function, a number of animal models of alcohol-related disorders have been developed. Some models isolate the effects of long-term or repeated high levels of ethanol exposure whereas others assess the effects of thiamine deficiency. Other work has assessed the synergistic interactions between ethanol toxicity and thiamine deficiency. The amount of ethanol-induced neural and behavioral change seems to be dependent on length of ethanol exposure, volume of alcohol, and degree of withdrawal signs or number of binge bouts (Crews & Nixon, 2009). If animals are allowed to progress through a severe a bout of thiamine deficiency (Zhang et al., 1995), there are massive lesions in the anterior and midline thalamus as well as the mammillary bodies. Furthermore, recent evidence demonstrates that thiamine deficiency alters hippocampal- and frontal cortical-dependent behaviors and neurochemistry.

Section snippets

Human neurological disorders associated with chronic alcohol consumption

Autopsy evaluations and in vivo neuroimaging of the brains of diagnosed human alcoholics has revealed that 78% of this population exhibits some degree of brain pathology (Goldstein and Shelly, 1980, Harper, 1998). The clinical presentation of brain damage in alcoholics is heterogeneous and results in a range of cognitive abnormalities. This is likely due to that a multitude of factors present in the alcoholic lifestyle (head injury, liver disease, malnourishment) that can cause brain damage.

Animal models

Animal models serve a heuristic function by allowing for the precise manipulation of variables in an experimentally testable situation. It is not possible to control for duration or amount of alcohol exposure, malnutrition, or the age at which such exposure occurs in humans. Animal models provide a framework for the integration of these variables, which in turn allows for the direct testing of specific hypotheses about how gender, diet and ethanol exposure interact. Thus, animal models may

Summary

The neurological disorders of AAD and WKS are difficult to distinguish by their clinical or neuropathological features. There appears to be a continuum of brain and behavioral dysfunction in alcoholics with and without WKS. Numerous imaging studies have revealed the cortical and subcortical shrinkage, as well as ventricular enlargement, is greater in WKS alcoholics than uncomplicated alcoholics (Sullivan & Pfefferbaum, 2009). Despite relatively clear diagnostic criteria for WKS it is still

Acknowledgements

This research was funded by grant NINDS 054272 to LMS.

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