The Experts below are selected from a list of 354 Experts worldwide ranked by ideXlab platform
Adolf Pfefferbaum - One of the best experts on this subject based on the ideXlab platform.
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concomitants of alcoholism differential effects of thiamine deficiency liver damage and food deprivation on the rat brain in vivo
Psychopharmacology, 2016Co-Authors: Natalie M Zahr, Amy M Collins, Richard Luong, Torsten Rohlfing, Adolf Pfefferbaum, Edith V Sullivan, Dirk MayerAbstract:Serious neurological concomitants of alcoholism include Wernicke’s encephalopathy (WE), Korsakoff’s syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by Pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.
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Interaction of Thiamine Deficiency and Voluntary Alcohol Consumption Disrupts Rat Corpus Callosum Ultrastructure
2014Co-Authors: Edith V Sullivan, Roger K Stankovic, Clive G Harper, Adolf PfefferbaumAbstract:The relative roles of alcohol and thiamine deficiency in causing brain damage remain controversial in alcoholics without the Wernicke– Korsakoff syndrome. Experimental control over alcohol consumption and diet are impossible in humans but can be accomplished in animal models. This experiment was designed to differentiate the separate and combined effects on the macro- and ultrastructure of the corpus callosum of thiamine deficiency and voluntary alcohol consumption. Adult male alcohol-preferring (P) rats (9 chronically alcohol-exposed and 9 water controls) received a thiamine-deficient diet for 2 weeks. There were four groups: five rats previously exposed to alcohol were treated with Pyrithiamine (a thiamine phosphorylation inhibitor); five rats never exposed to alcohol were treated with Pyrithiamine; four alcohol-exposed rats were treated with thiamine; and four rats never exposed to alcohol were treated with thiamine. On day 14, thiamine was restored in all 18 rats; 2 weeks later the 10 Pyrithiamine-treated rats received intraperitoneal thiamine. The rats were perfused 61 days post-Pyrithiamine treatment at age 598 days. Brains were dissected and weight and volumes were calculated. Sagittal sections were stained to measure white matter structures. The corpus callosum was examined using transmission electron microscopy to determine density of myelinated fibers, fiber diameter, and myelin thickness. The corpus callosum in the alcohol/ Pyrithiamine group was significantly thinner, had greater fiber density, higher percentage of small fibers, and myelin thinning than in the alcohol/thiamine and water/thiamine groups. Several measures showed a graded effect, where the alcohol/Pyrithiamine group had greater pathology than the water/Pyrithiamine group, which had greater pathology than the two thiamine-replete groups. Across all 1
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associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of wernicke s encephalopathy
Experimental Neurology, 2014Co-Authors: Natalie M Zahr, Richard Luong, Torsten Rohlfing, Edith V Sullivan, Dirk Mayer, Carsten Alt, Amy Manningbog, Adolf PfefferbaumAbstract:Abstract Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls + glucose, n = 6; Pyrithiamine + saline, n = 5; Pyrithiamine + glucose, n = 13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3 h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.
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ventricular expansion in wild type wistar rats after alcohol exposure by vapor chamber
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Adolf Pfefferbaum, Natalie M Zahr, Torsten Rohlfing, Dirk Mayer, Shara Vinco, Juan Orduna, Edith V SullivanAbstract:Magnetic resonance imaging (MRI) of the brains of chronically dependent alcoholic human adults commonly reveals a robust phenotype of widespread tissue damage and complementary ventriculomegaly (for review, Oscar-Berman and Marinkovic, 2007; Sullivan and Pfefferbaum, 2005). Specific brain regions affected by chronic alcohol exposure and described by structural MRI include cortical gray and white matter (Jernigan et al., 1991; Pfefferbaum et al., 1992), particularly prefrontal areas in older alcoholic individuals (Cardenas et al., 2007; Pfefferbaum et al., 1997), mammillary bodies (Davila et al., 1994; Shear et al., 1996; Sullivan et al., 2000b), anterior hippocampus (Agartz et al., 1999; Sullivan and Marsh, 2003; Sullivan et al., 1995), thalamus (Sullivan et al., 2003), pons (Pfefferbaum et al., 2002; Sullivan, 2003), and cerebellum (Sullivan et al., 2000a). These findings are typically documented in treatment-seeking alcoholics but may not necessarily characterize nontreatment seeking ones (Fein and Landman, 2005). A further source of variance stems from history and pattern of drinking over a lifetime, with some studies reporting dose effects of greater or more frequent drinking as resulting in greater evidence for brain damage (e.g., Pfefferbaum et al., 1998). Thus, the heterogeneity of effects possible with excessive alcohol drinking provides further justification for the desirability of developing an animal model to aid in identifying sources of heterogeneity in disruption of brain structure and function. A valid animal model of human alcoholism should exhibit signs of neuropathology in selective brain regions, circuits, and systems affected in human alcoholism. In response to alcohol exposure, focal changes to frontal cortex, corpus callosum (Savage et al., 2000), cerebellum (e.g., Dlugos and Pentney, 1997; Pentney and Dlugos, 2000; Pentney and Quackenbush, 1990; Rintala et al., 1997), and locus coeruleus (Lu et al., 1997) have been verified by cross-sectional, postmortem analysis of rodent brains. MRI, however, enables longitudinal whole-brain imaging, thereby permitting the testing of hypotheses about the specificity of regional abnormalities within the context of the entire brain. Animal models are essential in controlling factors, such as age of alcohol exposure onset, duration of dependence, nutrition, metabolism, and genetics, which will lead to identification of mechanisms and predictors of damage with alcohol exposure and recovery with alcohol cessation. The rich literature on human in vivo neuroimaging studies of alcoholism contrasts with the few such published neuroimaging studies in rodents. Initial MRI studies, conducted at 1.5T, used thiamine deficiency models of Wernicke's encephalopathy (Pentney et al., 1993) and reported increased volume of lateral ventricles followed by normalization with a thiamine-enriched diet (Acara et al., 1995). Glucose administration to rats previously made thiamine deficient with Pyrithiamine treatment produced impairment of the blood–brain barrier, observed qualitatively on T1-weighted images (Zelaya et al., 1995), and hyperintensities in the hippocampus as well as in the thalamus, hypothalamus, and collicular bodies, observed on T2-weighted images (Jordan et al., 1998). The selectively bred alcohol-preferring (P) rat has been extensively studied and satisfies many of the requirements for a suitable animal model of alcoholism (Rodd et al., 2004). In an attempt to validate in vivo MRI in the rat as a model of alcohol's effect on brain structure, our initial structural MR studies focused on the effects of high doses of alcohol, voluntarily consumed by P rats for about 1 year (Pfefferbaum et al., 2006a). The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. As observed in control animals (Sullivan et al., 2006), the brain structures of alcohol exposed adult P rats showed significant growth, attenuated in a few measures by alcohol exposure, with the greatest demonstrable effect on the corpus callosum (Pfefferbaum et al., 2006a). Indeed, only modest brain dysmorphology was revealed by structural MRI of the P rat voluntary consuming alcohol to BALs of ∼125 mg/dl. Given the subtle brain changes produced by high voluntary alcohol consumption in P rats, we have now repeated the MR experiment using the vapor chamber method of alcohol delivery. Exposure to alcohol by vapor is under experimental control, will reduce individual differences in drinking patterns (Carlson and Drew Stevens, 2006), and can accelerate and increase the timing and amount of alcohol exposure and thus better mimic the excessively high alcohol levels experienced by many human alcoholics (Kang et al., 2004; O'Dell et al., 2004). We expected that higher doses of alcohol would produce more dramatic changes in the brains of exposed rats than did voluntary exposure. Thus, controlled involuntary alcohol exposure would serve as a better model of alcoholism than did uncontrolled voluntary exposure in that these MRI findings would mimic those observed in the brain of human alcoholism, including widespread tissue shrinkage, notable in the corpus callosum, and complementary ventriculomegaly.
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development and resolution of brain lesions caused by Pyrithiamine and dietary induced thiamine deficiency and alcohol exposure in the alcohol preferring rat a longitudinal magnetic resonance imaging and spectroscopy study
Neuropsychopharmacology, 2007Co-Authors: Adolf Pfefferbaum, Elfar Adalsteinsson, Richard L Bell, Edith V SullivanAbstract:Development and Resolution of Brain Lesions Caused by Pyrithiamine- and Dietary-Induced Thiamine Deficiency and Alcohol Exposure in the Alcohol-Preferring Rat: A Longitudinal Magnetic Resonance Imaging and Spectroscopy Study
Edith V Sullivan - One of the best experts on this subject based on the ideXlab platform.
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concomitants of alcoholism differential effects of thiamine deficiency liver damage and food deprivation on the rat brain in vivo
Psychopharmacology, 2016Co-Authors: Natalie M Zahr, Amy M Collins, Richard Luong, Torsten Rohlfing, Adolf Pfefferbaum, Edith V Sullivan, Dirk MayerAbstract:Serious neurological concomitants of alcoholism include Wernicke’s encephalopathy (WE), Korsakoff’s syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by Pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.
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Interaction of Thiamine Deficiency and Voluntary Alcohol Consumption Disrupts Rat Corpus Callosum Ultrastructure
2014Co-Authors: Edith V Sullivan, Roger K Stankovic, Clive G Harper, Adolf PfefferbaumAbstract:The relative roles of alcohol and thiamine deficiency in causing brain damage remain controversial in alcoholics without the Wernicke– Korsakoff syndrome. Experimental control over alcohol consumption and diet are impossible in humans but can be accomplished in animal models. This experiment was designed to differentiate the separate and combined effects on the macro- and ultrastructure of the corpus callosum of thiamine deficiency and voluntary alcohol consumption. Adult male alcohol-preferring (P) rats (9 chronically alcohol-exposed and 9 water controls) received a thiamine-deficient diet for 2 weeks. There were four groups: five rats previously exposed to alcohol were treated with Pyrithiamine (a thiamine phosphorylation inhibitor); five rats never exposed to alcohol were treated with Pyrithiamine; four alcohol-exposed rats were treated with thiamine; and four rats never exposed to alcohol were treated with thiamine. On day 14, thiamine was restored in all 18 rats; 2 weeks later the 10 Pyrithiamine-treated rats received intraperitoneal thiamine. The rats were perfused 61 days post-Pyrithiamine treatment at age 598 days. Brains were dissected and weight and volumes were calculated. Sagittal sections were stained to measure white matter structures. The corpus callosum was examined using transmission electron microscopy to determine density of myelinated fibers, fiber diameter, and myelin thickness. The corpus callosum in the alcohol/ Pyrithiamine group was significantly thinner, had greater fiber density, higher percentage of small fibers, and myelin thinning than in the alcohol/thiamine and water/thiamine groups. Several measures showed a graded effect, where the alcohol/Pyrithiamine group had greater pathology than the water/Pyrithiamine group, which had greater pathology than the two thiamine-replete groups. Across all 1
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associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of wernicke s encephalopathy
Experimental Neurology, 2014Co-Authors: Natalie M Zahr, Richard Luong, Torsten Rohlfing, Edith V Sullivan, Dirk Mayer, Carsten Alt, Amy Manningbog, Adolf PfefferbaumAbstract:Abstract Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls + glucose, n = 6; Pyrithiamine + saline, n = 5; Pyrithiamine + glucose, n = 13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3 h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.
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ventricular expansion in wild type wistar rats after alcohol exposure by vapor chamber
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Adolf Pfefferbaum, Natalie M Zahr, Torsten Rohlfing, Dirk Mayer, Shara Vinco, Juan Orduna, Edith V SullivanAbstract:Magnetic resonance imaging (MRI) of the brains of chronically dependent alcoholic human adults commonly reveals a robust phenotype of widespread tissue damage and complementary ventriculomegaly (for review, Oscar-Berman and Marinkovic, 2007; Sullivan and Pfefferbaum, 2005). Specific brain regions affected by chronic alcohol exposure and described by structural MRI include cortical gray and white matter (Jernigan et al., 1991; Pfefferbaum et al., 1992), particularly prefrontal areas in older alcoholic individuals (Cardenas et al., 2007; Pfefferbaum et al., 1997), mammillary bodies (Davila et al., 1994; Shear et al., 1996; Sullivan et al., 2000b), anterior hippocampus (Agartz et al., 1999; Sullivan and Marsh, 2003; Sullivan et al., 1995), thalamus (Sullivan et al., 2003), pons (Pfefferbaum et al., 2002; Sullivan, 2003), and cerebellum (Sullivan et al., 2000a). These findings are typically documented in treatment-seeking alcoholics but may not necessarily characterize nontreatment seeking ones (Fein and Landman, 2005). A further source of variance stems from history and pattern of drinking over a lifetime, with some studies reporting dose effects of greater or more frequent drinking as resulting in greater evidence for brain damage (e.g., Pfefferbaum et al., 1998). Thus, the heterogeneity of effects possible with excessive alcohol drinking provides further justification for the desirability of developing an animal model to aid in identifying sources of heterogeneity in disruption of brain structure and function. A valid animal model of human alcoholism should exhibit signs of neuropathology in selective brain regions, circuits, and systems affected in human alcoholism. In response to alcohol exposure, focal changes to frontal cortex, corpus callosum (Savage et al., 2000), cerebellum (e.g., Dlugos and Pentney, 1997; Pentney and Dlugos, 2000; Pentney and Quackenbush, 1990; Rintala et al., 1997), and locus coeruleus (Lu et al., 1997) have been verified by cross-sectional, postmortem analysis of rodent brains. MRI, however, enables longitudinal whole-brain imaging, thereby permitting the testing of hypotheses about the specificity of regional abnormalities within the context of the entire brain. Animal models are essential in controlling factors, such as age of alcohol exposure onset, duration of dependence, nutrition, metabolism, and genetics, which will lead to identification of mechanisms and predictors of damage with alcohol exposure and recovery with alcohol cessation. The rich literature on human in vivo neuroimaging studies of alcoholism contrasts with the few such published neuroimaging studies in rodents. Initial MRI studies, conducted at 1.5T, used thiamine deficiency models of Wernicke's encephalopathy (Pentney et al., 1993) and reported increased volume of lateral ventricles followed by normalization with a thiamine-enriched diet (Acara et al., 1995). Glucose administration to rats previously made thiamine deficient with Pyrithiamine treatment produced impairment of the blood–brain barrier, observed qualitatively on T1-weighted images (Zelaya et al., 1995), and hyperintensities in the hippocampus as well as in the thalamus, hypothalamus, and collicular bodies, observed on T2-weighted images (Jordan et al., 1998). The selectively bred alcohol-preferring (P) rat has been extensively studied and satisfies many of the requirements for a suitable animal model of alcoholism (Rodd et al., 2004). In an attempt to validate in vivo MRI in the rat as a model of alcohol's effect on brain structure, our initial structural MR studies focused on the effects of high doses of alcohol, voluntarily consumed by P rats for about 1 year (Pfefferbaum et al., 2006a). The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. As observed in control animals (Sullivan et al., 2006), the brain structures of alcohol exposed adult P rats showed significant growth, attenuated in a few measures by alcohol exposure, with the greatest demonstrable effect on the corpus callosum (Pfefferbaum et al., 2006a). Indeed, only modest brain dysmorphology was revealed by structural MRI of the P rat voluntary consuming alcohol to BALs of ∼125 mg/dl. Given the subtle brain changes produced by high voluntary alcohol consumption in P rats, we have now repeated the MR experiment using the vapor chamber method of alcohol delivery. Exposure to alcohol by vapor is under experimental control, will reduce individual differences in drinking patterns (Carlson and Drew Stevens, 2006), and can accelerate and increase the timing and amount of alcohol exposure and thus better mimic the excessively high alcohol levels experienced by many human alcoholics (Kang et al., 2004; O'Dell et al., 2004). We expected that higher doses of alcohol would produce more dramatic changes in the brains of exposed rats than did voluntary exposure. Thus, controlled involuntary alcohol exposure would serve as a better model of alcoholism than did uncontrolled voluntary exposure in that these MRI findings would mimic those observed in the brain of human alcoholism, including widespread tissue shrinkage, notable in the corpus callosum, and complementary ventriculomegaly.
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development and resolution of brain lesions caused by Pyrithiamine and dietary induced thiamine deficiency and alcohol exposure in the alcohol preferring rat a longitudinal magnetic resonance imaging and spectroscopy study
Neuropsychopharmacology, 2007Co-Authors: Adolf Pfefferbaum, Elfar Adalsteinsson, Richard L Bell, Edith V SullivanAbstract:Development and Resolution of Brain Lesions Caused by Pyrithiamine- and Dietary-Induced Thiamine Deficiency and Alcohol Exposure in the Alcohol-Preferring Rat: A Longitudinal Magnetic Resonance Imaging and Spectroscopy Study
Natalie M Zahr - One of the best experts on this subject based on the ideXlab platform.
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concomitants of alcoholism differential effects of thiamine deficiency liver damage and food deprivation on the rat brain in vivo
Psychopharmacology, 2016Co-Authors: Natalie M Zahr, Amy M Collins, Richard Luong, Torsten Rohlfing, Adolf Pfefferbaum, Edith V Sullivan, Dirk MayerAbstract:Serious neurological concomitants of alcoholism include Wernicke’s encephalopathy (WE), Korsakoff’s syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by Pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.
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associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of wernicke s encephalopathy
Experimental Neurology, 2014Co-Authors: Natalie M Zahr, Richard Luong, Torsten Rohlfing, Edith V Sullivan, Dirk Mayer, Carsten Alt, Amy Manningbog, Adolf PfefferbaumAbstract:Abstract Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls + glucose, n = 6; Pyrithiamine + saline, n = 5; Pyrithiamine + glucose, n = 13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3 h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.
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ventricular expansion in wild type wistar rats after alcohol exposure by vapor chamber
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Adolf Pfefferbaum, Natalie M Zahr, Torsten Rohlfing, Dirk Mayer, Shara Vinco, Juan Orduna, Edith V SullivanAbstract:Magnetic resonance imaging (MRI) of the brains of chronically dependent alcoholic human adults commonly reveals a robust phenotype of widespread tissue damage and complementary ventriculomegaly (for review, Oscar-Berman and Marinkovic, 2007; Sullivan and Pfefferbaum, 2005). Specific brain regions affected by chronic alcohol exposure and described by structural MRI include cortical gray and white matter (Jernigan et al., 1991; Pfefferbaum et al., 1992), particularly prefrontal areas in older alcoholic individuals (Cardenas et al., 2007; Pfefferbaum et al., 1997), mammillary bodies (Davila et al., 1994; Shear et al., 1996; Sullivan et al., 2000b), anterior hippocampus (Agartz et al., 1999; Sullivan and Marsh, 2003; Sullivan et al., 1995), thalamus (Sullivan et al., 2003), pons (Pfefferbaum et al., 2002; Sullivan, 2003), and cerebellum (Sullivan et al., 2000a). These findings are typically documented in treatment-seeking alcoholics but may not necessarily characterize nontreatment seeking ones (Fein and Landman, 2005). A further source of variance stems from history and pattern of drinking over a lifetime, with some studies reporting dose effects of greater or more frequent drinking as resulting in greater evidence for brain damage (e.g., Pfefferbaum et al., 1998). Thus, the heterogeneity of effects possible with excessive alcohol drinking provides further justification for the desirability of developing an animal model to aid in identifying sources of heterogeneity in disruption of brain structure and function. A valid animal model of human alcoholism should exhibit signs of neuropathology in selective brain regions, circuits, and systems affected in human alcoholism. In response to alcohol exposure, focal changes to frontal cortex, corpus callosum (Savage et al., 2000), cerebellum (e.g., Dlugos and Pentney, 1997; Pentney and Dlugos, 2000; Pentney and Quackenbush, 1990; Rintala et al., 1997), and locus coeruleus (Lu et al., 1997) have been verified by cross-sectional, postmortem analysis of rodent brains. MRI, however, enables longitudinal whole-brain imaging, thereby permitting the testing of hypotheses about the specificity of regional abnormalities within the context of the entire brain. Animal models are essential in controlling factors, such as age of alcohol exposure onset, duration of dependence, nutrition, metabolism, and genetics, which will lead to identification of mechanisms and predictors of damage with alcohol exposure and recovery with alcohol cessation. The rich literature on human in vivo neuroimaging studies of alcoholism contrasts with the few such published neuroimaging studies in rodents. Initial MRI studies, conducted at 1.5T, used thiamine deficiency models of Wernicke's encephalopathy (Pentney et al., 1993) and reported increased volume of lateral ventricles followed by normalization with a thiamine-enriched diet (Acara et al., 1995). Glucose administration to rats previously made thiamine deficient with Pyrithiamine treatment produced impairment of the blood–brain barrier, observed qualitatively on T1-weighted images (Zelaya et al., 1995), and hyperintensities in the hippocampus as well as in the thalamus, hypothalamus, and collicular bodies, observed on T2-weighted images (Jordan et al., 1998). The selectively bred alcohol-preferring (P) rat has been extensively studied and satisfies many of the requirements for a suitable animal model of alcoholism (Rodd et al., 2004). In an attempt to validate in vivo MRI in the rat as a model of alcohol's effect on brain structure, our initial structural MR studies focused on the effects of high doses of alcohol, voluntarily consumed by P rats for about 1 year (Pfefferbaum et al., 2006a). The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. As observed in control animals (Sullivan et al., 2006), the brain structures of alcohol exposed adult P rats showed significant growth, attenuated in a few measures by alcohol exposure, with the greatest demonstrable effect on the corpus callosum (Pfefferbaum et al., 2006a). Indeed, only modest brain dysmorphology was revealed by structural MRI of the P rat voluntary consuming alcohol to BALs of ∼125 mg/dl. Given the subtle brain changes produced by high voluntary alcohol consumption in P rats, we have now repeated the MR experiment using the vapor chamber method of alcohol delivery. Exposure to alcohol by vapor is under experimental control, will reduce individual differences in drinking patterns (Carlson and Drew Stevens, 2006), and can accelerate and increase the timing and amount of alcohol exposure and thus better mimic the excessively high alcohol levels experienced by many human alcoholics (Kang et al., 2004; O'Dell et al., 2004). We expected that higher doses of alcohol would produce more dramatic changes in the brains of exposed rats than did voluntary exposure. Thus, controlled involuntary alcohol exposure would serve as a better model of alcoholism than did uncontrolled voluntary exposure in that these MRI findings would mimic those observed in the brain of human alcoholism, including widespread tissue shrinkage, notable in the corpus callosum, and complementary ventriculomegaly.
Roger F. Butterworth - One of the best experts on this subject based on the ideXlab platform.
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brain lactate synthesis in thiamine deficiency a re evaluation using 1h 13c nuclear magnetic resonance spectroscopy
Journal of Neuroscience Research, 2005Co-Authors: Darren Navarro, Alan S Hazell, Claudia Zwingmann, Roger F. ButterworthAbstract:Region-selective accumulation of brain lactate occurs in TD; however, the mechanisms responsible have not been elucidated fully. 1H and 13C nuclear magnetic resonance (NMR) spectroscopy were therefore used to investigate de novo lactate synthesis from [1-13C]glucose in vulnerable (medial thalamus) and nonvulnerable (frontal cortex) brain regions of rats made thiamine deficient by administration of the central thiamine antagonist Pyrithiamine. De novo synthesis of lactate was increased in the medial thalamus to 148% and 226% of pair-fed control values at presymptomatic and symptomatic stages of thiamine deficiency, respectively, whereas no such changes were observed in the frontal cortex. Administration of a glucose load selectively worsened the changes in medial thalamus. Pyruvate recycling and peripherally derived lactate did not contribute significantly to the lactate increase within the thiamine-deficient brain. Increases in immunolabeling of the lactate dehydrogenase isoenzymes (LDH1 and LDH5) were observed in the medial thalamus of thiamine-deficient animals. Metabolic impairment due to thiamine deficiency thus results in increased glycolysis, increased LDH immunolabeling of neurons and astrocytes and increased de novo synthesis of lactate in brain regions vulnerable to thiamine deficiency. These results are consistent with the notion that focal lactate accumulation participates in the worsening of neurologic symptoms in thiamine-deficient patients. © 2004 Wiley-Liss, Inc.
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thiamine deficiency results in metabolic acidosis and energy failure in cerebellar granule cells an in vitro model for the study of cell death mechanisms in wernicke s encephalopathy
Journal of Neuroscience Research, 2000Co-Authors: Pierre Pannunzio, Alan S Hazell, Marc Pannunzio, Roger F. ButterworthAbstract:Thiamine deficiency (TD) in both humans and experimental animals results in severe compromise of mitochondrial function and leads to selective neuronal cell death in diencephalic and cerebellar structures. To examine further the influence of TD on neuronal survival in relation to metabolic changes, primary cultures of rat cerebellar granule cells were exposed to thiamine-deficient medium for up to 7 days in the absence or presence of the central thiamine antagonist Pyrithiamine (Py). Exposure of cells for 7 days to thiamine-deficient medium alone resulted in no detectable cell death. On the other hand, 50 μM Py treatment led to reductions of thiamine phosphate esters, decreased activities of the thiamine-dependent enzymes α-ketoglutarate dehydrogenase and transketolase, a twofold increase in lactate release (P < 0.001), a lowering of pH, and significant (58%, P < 0.001) cell death. DNA fragmentation studies did not reveal evidence of apoptotic cell death. Addition of 50 μM α-tocopherol (vitamin E) or 100 μM of butylated hydroxyanisole (BHA) to Py-treated cells resulted in significant neuroprotection. On the other hand, addition of 10 μM MK-801, an NMDA receptor antagonist, was not neuroprotective. These results suggest that reactive oxygen species (ROS) play a major role in thiamine deficiency-induced neuronal cell death. Insofar as this experimental model recapitulates the metabolic and mitochondrial changes characteristic of thiamine deficiency in the intact animal, it might be useful in the elucidation of mechanisms involved in the neuronal cell death cascade resulting from thiamine deficiency. J. Neurosci. Res. 62:286–292, 2000. © 2000 Wiley-Liss, Inc.
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Mechanisms of Neuronal Cell Death in Wernicke's Encephalopathy
Metabolic Brain Disease, 1998Co-Authors: Alan S Hazell, Kathryn G. Todd, Roger F. ButterworthAbstract:Wernicke's Encephalopathy (WE) is a serious neurological disorder resulting from thiamine deficiency, encountered in chronic alcoholics and in patients with grossly impaired nutritional status. Neuropathologic studies as well as Magnetic Resonance Imaging reveal selective diencephalic and brainstem lesions in patients with WE. The last decade has witnessed major advances in the understanding of pathophysiologic mechanisms linking thiamine deficiency to the selective brain lesions characteristic of WE. Activities of the thiamine-dependent enzyme α-ketoglutarate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme are significantly reduced in autopsied brain tissue from patients with WE and from rats treated with the central thiamine antagonist, Pyrithiamine. In the animal studies, evidence suggests that such enzyme deficits result in focal lactic acidosis, cerebral energy impairment and depolarization resulting from increased release of glutamate in vulnerable brain structures. It has been proposed that this depolarization may result in N-Methyl-D-Aspartate receptor-mediated excitotoxicity as well as increased expression of immediate early genes such as c-fos and c-jun resulting in apoptotic cell death. Other mechanisms involved in thiamine deficiency-induced cell loss may involve free radicals and alterations of the blood-brain barrier. Additional studies are still required to identify the site of the initial cellular insult and to explain the predilection of diencephalic and brainstem structures due to thiamine deficiency.
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Regional alterations of thiamine phosphate esters and of thiamine diphosphate-dependent enzymes in relation to function in experimental Wernicke's encephalopathy
Neurochemical Research, 1995Co-Authors: Maryse Héroux, Roger F. ButterworthAbstract:Thiamine phosphate esters (thiamine monophosphate-TMP; thiamine diphosphate-TDP and thiamine triphosphate-TTP) were measured as their thiochrome derivatives by High Performance Liquid Chromatography in the brains of Pyrithiamine-treated rats at various stages during the development of thiamine deficiency encephalopathy. Severe encephalopathy was accompanied by significant reductions of all three thiamine phosphate esters in brain. Neurological symptoms of thiamine deficiency appeared when brain levels of TMP and TDP fell below 15% of normal values. Activities of the TDP-dependent enzyme α-ketoglutarate dehydrogenase were more severely reduced in thalamus compared to cerebral cortex, a less vulnerable brain structure. On the other hand, reductions of TTP, the non-cofactor form of thiamine, occurred to a greater extent in cerebral cortex than thalamus. Early reductions of TDP-dependent enzymes and the ensuing metabolic pertubations such as lactic acidosis impaired brain energy metabolism, and NMDA-receptor mediated excitotoxicity offer rational explanations for the selective vulnerability of brain structures such as thalamus to the deleterious effects of thiamine deficiency.
Dirk Mayer - One of the best experts on this subject based on the ideXlab platform.
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concomitants of alcoholism differential effects of thiamine deficiency liver damage and food deprivation on the rat brain in vivo
Psychopharmacology, 2016Co-Authors: Natalie M Zahr, Amy M Collins, Richard Luong, Torsten Rohlfing, Adolf Pfefferbaum, Edith V Sullivan, Dirk MayerAbstract:Serious neurological concomitants of alcoholism include Wernicke’s encephalopathy (WE), Korsakoff’s syndrome (KS), and hepatic encephalopathy (HE). This study was conducted in animal models to determine neuroradiological signatures associated with liver damage caused by carbon tetrachloride (CCl4), thiamine deficiency caused by Pyrithiamine treatment, and nonspecific nutritional deficiency caused by food deprivation. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) were used to evaluate brains of wild-type Wistar rats at baseline and following treatment. Similar to observations in ethanol (EtOH) exposure models, thiamine deficiency caused enlargement of the lateral ventricles. Liver damage was not associated with effects on cerebrospinal fluid volumes, whereas food deprivation caused modest enlargement of the cisterns. In contrast to what has repeatedly been shown in EtOH exposure models, in which levels of choline-containing compounds (Cho) measured by MRS are elevated, Cho levels in treated animals in all three experiments (i.e., liver damage, thiamine deficiency, and food deprivation) were lower than those in baseline or controls. These results add to the growing body of literature suggesting that MRS-detectable Cho is labile and can depend on a number of variables that are not often considered in human experiments. These results also suggest that reductions in Cho observed in humans with alcohol use disorder (AUD) may well be due to mild manifestations of concomitants of AUD such as liver damage or nutritional deficiencies and not necessarily to alcohol consumption per se.
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associations between in vivo neuroimaging and postmortem brain cytokine markers in a rodent model of wernicke s encephalopathy
Experimental Neurology, 2014Co-Authors: Natalie M Zahr, Richard Luong, Torsten Rohlfing, Edith V Sullivan, Dirk Mayer, Carsten Alt, Amy Manningbog, Adolf PfefferbaumAbstract:Abstract Thiamine (vitamin B1) deficiency, associated with a variety of conditions, including chronic alcoholism and bariatric surgery for morbid obesity, can result in the neurological disorder Wernicke's encephalopathy (WE). Recent work building upon early observations in animal models of thiamine deficiency has demonstrated an inflammatory component to the neuropathology observed in thiamine deficiency. The present, multilevel study including in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) and postmortem quantification of chemokine and cytokine proteins sought to determine whether a combination of these in vivo neuroimaging tools could be used to characterize an in vivo MR signature for neuroinflammation. Thiamine deficiency for 12 days was used to model neuroinflammation; glucose loading in thiamine deficiency was used to accelerate neurodegeneration. Among 38 animals with regional brain tissue assayed postmortem for cytokine/chemokine protein levels, three groups of rats (controls + glucose, n = 6; Pyrithiamine + saline, n = 5; Pyrithiamine + glucose, n = 13) underwent MRI/MRS at baseline (time 1), after 12 days of treatment (time 2), and 3 h after challenge (glucose or saline, time 3). In the thalamus of glucose-challenged, thiamine deficient animals, correlations between in vivo measures of pathology (lower levels of N-acetyle aspartate and higher levels of lactate) and postmortem levels of monocyte chemotactic protein-1 (MCP-1, also known as chemokine ligand 2, CCL2) support a role for this chemokine in thiamine deficiency-related neurodegeneration, but do not provide a unique in vivo signature for neuroinflammation.
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ventricular expansion in wild type wistar rats after alcohol exposure by vapor chamber
Alcoholism: Clinical and Experimental Research, 2008Co-Authors: Adolf Pfefferbaum, Natalie M Zahr, Torsten Rohlfing, Dirk Mayer, Shara Vinco, Juan Orduna, Edith V SullivanAbstract:Magnetic resonance imaging (MRI) of the brains of chronically dependent alcoholic human adults commonly reveals a robust phenotype of widespread tissue damage and complementary ventriculomegaly (for review, Oscar-Berman and Marinkovic, 2007; Sullivan and Pfefferbaum, 2005). Specific brain regions affected by chronic alcohol exposure and described by structural MRI include cortical gray and white matter (Jernigan et al., 1991; Pfefferbaum et al., 1992), particularly prefrontal areas in older alcoholic individuals (Cardenas et al., 2007; Pfefferbaum et al., 1997), mammillary bodies (Davila et al., 1994; Shear et al., 1996; Sullivan et al., 2000b), anterior hippocampus (Agartz et al., 1999; Sullivan and Marsh, 2003; Sullivan et al., 1995), thalamus (Sullivan et al., 2003), pons (Pfefferbaum et al., 2002; Sullivan, 2003), and cerebellum (Sullivan et al., 2000a). These findings are typically documented in treatment-seeking alcoholics but may not necessarily characterize nontreatment seeking ones (Fein and Landman, 2005). A further source of variance stems from history and pattern of drinking over a lifetime, with some studies reporting dose effects of greater or more frequent drinking as resulting in greater evidence for brain damage (e.g., Pfefferbaum et al., 1998). Thus, the heterogeneity of effects possible with excessive alcohol drinking provides further justification for the desirability of developing an animal model to aid in identifying sources of heterogeneity in disruption of brain structure and function. A valid animal model of human alcoholism should exhibit signs of neuropathology in selective brain regions, circuits, and systems affected in human alcoholism. In response to alcohol exposure, focal changes to frontal cortex, corpus callosum (Savage et al., 2000), cerebellum (e.g., Dlugos and Pentney, 1997; Pentney and Dlugos, 2000; Pentney and Quackenbush, 1990; Rintala et al., 1997), and locus coeruleus (Lu et al., 1997) have been verified by cross-sectional, postmortem analysis of rodent brains. MRI, however, enables longitudinal whole-brain imaging, thereby permitting the testing of hypotheses about the specificity of regional abnormalities within the context of the entire brain. Animal models are essential in controlling factors, such as age of alcohol exposure onset, duration of dependence, nutrition, metabolism, and genetics, which will lead to identification of mechanisms and predictors of damage with alcohol exposure and recovery with alcohol cessation. The rich literature on human in vivo neuroimaging studies of alcoholism contrasts with the few such published neuroimaging studies in rodents. Initial MRI studies, conducted at 1.5T, used thiamine deficiency models of Wernicke's encephalopathy (Pentney et al., 1993) and reported increased volume of lateral ventricles followed by normalization with a thiamine-enriched diet (Acara et al., 1995). Glucose administration to rats previously made thiamine deficient with Pyrithiamine treatment produced impairment of the blood–brain barrier, observed qualitatively on T1-weighted images (Zelaya et al., 1995), and hyperintensities in the hippocampus as well as in the thalamus, hypothalamus, and collicular bodies, observed on T2-weighted images (Jordan et al., 1998). The selectively bred alcohol-preferring (P) rat has been extensively studied and satisfies many of the requirements for a suitable animal model of alcoholism (Rodd et al., 2004). In an attempt to validate in vivo MRI in the rat as a model of alcohol's effect on brain structure, our initial structural MR studies focused on the effects of high doses of alcohol, voluntarily consumed by P rats for about 1 year (Pfefferbaum et al., 2006a). The paradigm involved a 3-bottle choice with 0, 15 (or 20%), and 30% (or 40%) alcohol available in several different exposure schemes: continuous exposure, cycles of 2 weeks on followed by 2 weeks off alcohol, and binge drinking in the dark. As observed in control animals (Sullivan et al., 2006), the brain structures of alcohol exposed adult P rats showed significant growth, attenuated in a few measures by alcohol exposure, with the greatest demonstrable effect on the corpus callosum (Pfefferbaum et al., 2006a). Indeed, only modest brain dysmorphology was revealed by structural MRI of the P rat voluntary consuming alcohol to BALs of ∼125 mg/dl. Given the subtle brain changes produced by high voluntary alcohol consumption in P rats, we have now repeated the MR experiment using the vapor chamber method of alcohol delivery. Exposure to alcohol by vapor is under experimental control, will reduce individual differences in drinking patterns (Carlson and Drew Stevens, 2006), and can accelerate and increase the timing and amount of alcohol exposure and thus better mimic the excessively high alcohol levels experienced by many human alcoholics (Kang et al., 2004; O'Dell et al., 2004). We expected that higher doses of alcohol would produce more dramatic changes in the brains of exposed rats than did voluntary exposure. Thus, controlled involuntary alcohol exposure would serve as a better model of alcoholism than did uncontrolled voluntary exposure in that these MRI findings would mimic those observed in the brain of human alcoholism, including widespread tissue shrinkage, notable in the corpus callosum, and complementary ventriculomegaly.
