Cerebellar Vermis Proteome of Chronic Alcoholic Individuals (original) (raw)
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Neuroscience, 1999
This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiaminedeficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways.
Alcohol-Related Brain Damage in Humans
PLoS ONE, 2014
Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin b II, and aand b-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in a-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in b-spectrin protein levels, and a significant increase in transmembranous a3 (catalytic) subunit of the Na + ,K + -ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of a-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic aand b-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.
Alcohol-Related Brain Damage in Humans Editor
Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin b II, and aand b-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in a-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in b-spectrin protein levels, and a significant increase in transmembranous a3 (catalytic) subunit of the Na + ,K + -ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of a-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic aand b-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.
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 T1weighted, 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 Additional Supporting Information may be found in the online version of this article.
Disruption of Frontocerebellar Circuitry and Function in Alcoholism
Alcoholism: Clinical & Experimental Research, 2003
This article represents a symposium of the 2002 joint meeting of RSA and ISBRA held in San Francisco. Presentations were Neuropathology of alcohol-related cerebellar damage in humans, by Antony J. Harding; Neuropathological evidence of cerebellar damage in an animal model of alcoholism, by Roberta Pentney and Cynthia Dlugos; Understanding cortical-cerebellar circuits through neuroimaging study of chronic alcoholics, by
CNS Drug Reviews, 2006
Studies of alcohol-induced brain damage have clearly indicated that alcohol is neurotoxic. Alcoholics are at increased risk for brain damage from a variety of causes, including poor nutrition, liver disease, and head trauma. Further, alcoholic dementia is the second leading cause of adult dementia in the United States, accounting for approximately 10% of the cases (Alzheimer's disease is the leading cause, accounting for 40 to 60% of cases). A variety of studies report that 50 to 75% of sober, detoxified, long-term alcohol-dependent individuals suffer from some degree of detectable cognitive impairment with approximately 10% suffering from serious dementia. Although more research is required to precisely delineate the effects of alcohol on various types of brain function, there appears to be a continuum of moderate deficits in the majority of long-term alcoholics, progressing to much more severe deficits of Wernicke's disease and Wernicke's encephalopathy with Korsakoff's amnestic syndrome (12,79). A variety of lifestyle factors, including nutrition, are implicated in the more severe cases. However, all of these on the continuum appear to be related to alcohol consumption and to the amount of alcohol consumed. That is, the more severe cases are associated with more severe and chronic longterm alcoholism (12,79). Alcohol-induced changes in the structure of the adult brain have been studied in both humans and rodents. A variety of postmortem histological analyses, as well as supporting imaging analysis, suggest that chronic alcohol changes brain structure. Computed tomography (CT) and magnetic resonance imaging (MRI) studies of human brain have repeatedly shown enlargement of the cerebral ventricles and sulci in most alcoholics. The enlargement of the ventricles and sulci essentially reflects a shrinking of the brain mass. This is consistent with studies on postmortem brain tissue, where alcoholics have a reduction in total brain weight. Particularly severe alcoholics have reductions in the global cerebral hemisphere and cerebellar brain weights that are significantly reduced compared
Journal of Neurology, 2005
Chronic alcohol consumption is frequently accompanied by cerebellar degeneration. The exact aetiology of alcoholic cerebellar degeneration is still a matter of debate. The aim of the present study was to investigate whether patients with chronic alcohol consumption exhibit a decrease in dentate nuclei intensity as measured by MRI, and if so, whether this decrease correlates with cerebellar atrophy as revealed by MR imaging or with clinical signs of cerebellar ataxia. A decrease in dentate nuclei intensity would indirectly indicate that iron accumulation, and therefore, oxidative stress may play a role in alcoholic cerebellar degeneration. MRI of 45 alcoholics and 44 ageand sex–matched healthy control subjects was performed using a 3D–T1–weighted fast low angle shot (FLASH) echo sequence. Signal intensities of the dentate nuclei and cerebellar white matter were bilaterally measured. Planimetric measurements of cerebellar size were performed using a 3D–T1–weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) sequence. Results demonstrated that dentate nuclei intensity was not significantly decreased in patients with chronic alcohol consumption (mean ± SD signal intensity 65.36 ± 13.0) if compared with control subjects (mean ± SD signal intensity 68.95 ± 9.4) (p = 0.15). Dentate nuclei intensity did not correlate with cerebellar size neither in control subjects nor in alcoholics. In contrast, vitamin B1 level correlated with cerebellar size in alcoholics even if the vitamin B1 concentration was within normal values (r = 0.344, p = 0.028). These results support the view that thiamine deficiency rather than direct neurotoxic effects of alcohol is the main causative factor for the development of alcoholic cerebellar degeneration.
Contributions of Studies on Alcohol Use Disorders to Understanding Cerebellar Function
Neuropsychology Review, 2010
Neuropathological, neuropsychological, and neuroimaging studies of human alcoholism provide evidence for degradation of frontal, pontine, thalamic, and cerebellar brain sites and disturbed associated functions. Current studies using neuroimaging combined with examination of executive functions, traditionally considered the sole purview of the frontal lobes, have identified a role for the cerebellum serving as a compensatory processing adjunct to enable normal performance