ReviewAlcohol-related amnesia and dementia: Animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment
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.
References (177)
- et al.
Cholinergic system and memory in the rat: Effects of chronic ethanol, embryonic basal forebrain brain transplants and excitotoxic lesions of cholinergic basal forebrain projection system
Neuroscience
(1989) - et al.
Effects of alcoholization on the rat hippocampus
Neuroscience Letters
(1991) - et al.
Effects of chronic alcohol intake and withdrawal on the prefrontal neurons and synapses
Alcohol
(1990) - et al.
Chronic intermittent ethanol (CIE) administration in rats decreases levels of neurosteroids in hippocampus, accompanied by altered behavioral responses to neurosteroids and memory function
Neuropharmacology
(2004) - et al.
Dietary restriction attenuates the neuronal loss, induction of hemeoxygenase-1 and blood barrier breakdown induced by impaired oxidative metabolism
Brain Research
(2000) - et al.
Long-term ethanol consumption by rats: Effect on acetylcholine release in vivo, choline acetyltransferase activity, and behavior
Neuroscience
(1993) Ethanol-BDNF interactions: Still more questions than answers
Pharmacology & Therapeutics
(2008)- et al.
Memory and the Korsakoff syndrome: Not remembering what is remembered
Neuropsychologia
(2007) - et al.
A requirement for the mitogen-activated protein kinase cascade in hippocampal long-term potentiation
The Journal of Biological Chemistry
(1997) - et al.
Chronic ingestion produces cholinergic hypofunction in rat brain
Alcohol
(1997)
The reaction of astrocytes and neurons in the hippocampus of adult rats during chronic ethanol treatment and correlations to behavioral impairments
Alcohol
Effect of age on behavioural and enzymatic changes during thiamine deficiency
Neurobiology of Aging
Hippocampal AgNOR activity after chronic alcohol consumption and alcohol deprivation in rats
Physiology & Behavior
Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration
Neurochemistry International
Acetylcholine modulation of neural systems involved in learning and memory
Neurobiology of Learning and Memory
Loss of vasopressin-immunoreactive neurons in alcoholics is dose-related and time-dependent
Neuroscience
The yin and yang of NMDA receptor signaling
Trends in Neuroscience
Ethanol and brain damage
Current Opinion in Pharmacology
The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats
Behavioural Brain Research
Persistent reduction of GABA(A) receptor-mediated inhibition in rat hippocampus after chronic intermittent ethanol treatment
Brain Research
Functional significance of adult neurogenesis
Current Opinion in Neurobiology
Remote and autobiographical memory, temporal context memory and frontal atrophy in Korsakoff and Alzheimer patients
Neuropsychologia
Diencephalic lesions, learning impairments, and intact retrograde memory following acute thiamine deficiency in the rat
Behavioural Brain Research
Thiamine deficiency in rats produces cognitive and memory deficits on spatial tasks that correlate with tissue loss in diencephalon, cortex and white matter
Behavioural Brain Research
Alcoholic dementia: A hypothesis
The Lancet
Arrested neuronal proliferation and impaired hippocampal function following fractionated brain irradiation in the adult rat
Neuroscience
Behavioral impairments, brain lesions, and monoaminergic activity in the rat following recovery from a bout of thiamine deficiency
Behavioural Brain Research
Diencephalic amnesia: A reorientation towards tracts?
Brain Research Reviews
The neuropathology of amnesia
Progress in Neurobiology
Location of lesions in Korsakoff’s syndrome: Neuropsychological and neuropathological data on two patients
Cortex
Patterns of brain acetylcholine release predict individual differences in preferred learning strategies in rats
Neurobiology of Learning and Memory
Chronic ethanol consumption in rats: Correlation between memory performance and hippocampal acetylcholine release in vivo
Neuroscience
Repeated episodic exposure to ethanol affects neurotrophin content in the forebrain of the mature rat
Experimental Neurology
Neuropsychological deficits in alcoholics: the relative contributions of gender and drinking history
British Journal of Addiction
Cerebellar vermis proteome of chronic alcoholic individuals
Alcoholism: Clinical and Experimental Research
Cortical cholinergic abnormalities contribute to the amnesia state induced by pyrithiamine-induced thiamine deficiency in the rat
European Journal of Neuroscience
Cholinergic-rich brain transplant reverse alcohol-induced memory deficits
Nature
Repeated ethanol withdrawal experience selectively alters sensitivity to different chemoconvulsant drugs in mice
Psychopharmacology
Long-lasting potentiation of synaptic transmisstion in the dentate area of the anesthetized rabbit following stimulation of the perforant path
Journal of Physiology
Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path
Journal of Physiology
Separating cognitive impairment in neurologically asymptomatic alcoholism from Wernicke-Korsakoff syndrome: Is the neuropsychological distinction justified?
Psychological Bulletin
Alcoholic Korsakoff’s syndrome: Some unresolved issues concerning etiology, neuropathology, and cognitive deficits
Journal of Clinical and Experimental Neuropsychology
The continuity hypothesis: The relationship of long-term alcoholism to the Wernicke-Korsakoff syndrome
Recent Developments in Alcohol
Episodic and semantic memory: A comparison of amnesic and demented patients
Journal of Clinical and Experimental Neuropsychology
Effect of pyrithiamine treatment and subsequent thiamine rehabilitation on regional cerebral amino acids and thiamine-dependent enzymes
Journal of Neurochemistry
Withdrawal from chronic intermittent ethanol treatment changes subunit composition, reduces synaptic function, and decreases behavioral responses to positive allosteric modulators of GABAA receptors
Molecular Pharmacology
Trophic factors: An evolutionary cul-de-sac or door into higher neuronal function?
Journal of Neuroscience Research
Reduced frontal lobe activity in subjects with high impulsivity and alcoholism
Alcoholism: Clinical and Experimental Research
Regulation of hippocampal progenitor cell survival, proliferation and dendritic development by BDNF
Molecular Degeneration
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