Thiamine Deficiency and Alcoholic Brain Disease : Part 5

by National Institute of Health

(Page 5 of 5)

Other investigators, however, have found no differences in the ability of transketolase from Korsakoff's patients and healthy subjects to bind ThDP. Several reasons may explain these differences in findings. For example, if a study includes active alcoholics, toxic substances formed during alcohol degradation in the body (acetaldehyde or oxygen radicals) could conceivably damage the transketolase, leading to impaired transketolase activity even if the person does not have a genetic predisposition. Moreover, processing of the samples being studied could have modified and deactivated the transketolase. Overall, researchers to date have found no consistent correlation between genetically determined transketolase variants and a person's sensitivity to thiamine deficiency. To determine whether a genetic predisposition to thiamine deficiency and resulting brain damage does indeed exist, more detailed molecular genetic studies are required.

Another possible explanation for the differences among people in their sensitivity to thiamine deficiency has focused on the assembly of functional transketolase. To yield a functional enzyme, two transketolase molecules - each of which is bound to ThDP and to magnesium - must come together. This assembly step is aided by an as yet unidentified "assembly factor," which is probably also involved in the assembly of other thiamine-using enzymes. If this factor were defective, the final enzyme complex would be formed at a lower rate and would be unstable. Researchers have identified at least one person with WKS whose cells showed enhanced sensitivity to thiamine deficiency and in whom the assembly factor was defective. Other mechanisms that could contribute to individual differences in the sensitivity to alcoholism could involve variability in the capacity for thiamine uptake into the cells or in the overall sensitivity to cell damage induced by oxidative stress.

Differential Sensitivity of Various Brain Regions

Various brain regions and even different cell types within one brain region may differ in their sensitivity to alcohol-induced damage as well as in their susceptibility to associated problems, including alcohol-related malnutrition (thiamine deficiency). For example, as mentioned earlier, the cerebellum appears to be particularly sensitive to thiamine deficiency, as indicated by the high frequency of cerebellar degeneration in alcoholics. Autopsy studies have found that a region of the cerebellum known as the anterior superior cerebellar vermis most frequently exhibits alcohol-induced damage. Additional studies have found that the cerebellar vermis is particularly sensitive to the deleterious effects of thiamine deficiency. For example, thiamine deficiency contributes to a reduction in the number and size of a certain cerebellar cell type called Purkinje cells in parts of the cerebellar vermis.

The sensitivity of the cerebellum to alcohol-related damage was confirmed in a recent study in which investigators used an imaging technique called proton magnetic resonance spectroscopy to determine the levels of certain molecules (metabolites) that reflect the functionality of the cells in various brain regions of alcoholics and nonalcoholics. For example, one metabolite reflects nerve cell activity, another metabolite reflects the degradation and formation (turnover) of cell membrane components, and a third metabolite reflects cellular energy levels. The results of the analyses indicated that these metabolites are significantly reduced in the cerebellum of alcoholics, more so than in another brain region commonly affected by alcohol, the frontal white-matter cortex. Moreover, only some of these reductions in metabolite levels were reversed when the subjects were tested again after 3 weeks and then 3 months of abstinence. These findings suggest that the cerebellum, in particular the cerebellar vermis, is uniquely sensitive to alcohol's effects, including alcohol-related thiamine deficiency, and therefore may be the initial target of alcohol-related damage.

This hypothesis is consistent with the clinical course of the neurocognitive deficits observed in alcoholics. Networks of nerve cells (neural pathways) extend from the cerebellum through brain regions called the basal ganglia and thalamus to the frontal lobe. These pathways mediate not only traditional cerebellar functions, such as motor control, but also perceptual- motor tasks, executive functions, and learning and memory, all of which are impaired in alcoholics. Accordingly, alcohol-induced damage to the cerebellar vermis could indirectly affect neurocognitive functions attributed to the frontal lobe, even early in the disease process when no cortical damage is detectable, by disrupting the neural pathways connecting the two brain regions. As the alcoholism progresses and alcohol exposure persists, damage to the frontal lobe is also likely to occur, further interfering with the functions of that brain region.

In addition to the cerebellum, numerous other brain regions and structures are damaged in people with WKS. Although animal studies have suggested that thiamine deficiency may contribute to damage to these structures, the exact role of thiamine deficiency and the level of sensitivity of these structures to thiamine deficiency have not yet been determined. Further studies are certainly needed in this area.

Summary

Thiamine deficiency, which is found in a large number of alcoholics, is an important contributor to alcohol-related brain damage of all kinds, not only WKS, as was commonly thought in the past. Thiamine is an essential cofactor for several enzymes involved in brain cell metabolism that are required for the production of precursors for several important cell components as well as for the generation of the energy-supplying molecule ATP. Thiamine deficiency leads to significant reductions in the activities of these enzymes, and to deleterious effects on the viability of brain cells.

Chronic alcohol consumption can cause thiamine deficiency and thus reduced enzyme activity through several mechanisms, including inadequate dietary intake, malabsorption of thiamine from the gastrointestinal tract, and impaired utilization of thiamine in the cells. Accordingly, thiamine deficiency can potentiate a number of processes associated with chronic alcohol consumption that are toxic to brain cells, as discussed in other articles in this journal issue. It is important to note that these adverse effects of alcohol-induced thiamine deficiency, particularly the reduction of transketolase activity, can occur even in alcoholics who do not show evidence of WE or WKS.

The extent to which alcohol exerts its detrimental effects on the brain and various other tissues may be genetically determined via individual differences in predisposition to thiamine deficiency disorders. For example, some studies have suggested that there may be different variants of the genes encoding transketolase, which differ in their ability to bind the active form of thiamine, particularly at low thiamine concentrations. Such a genetic variation could be one explanation for why only a subset of alcoholics who experience thiamine deficiency develop the pathological consequences of that condition, such as WKS. Additional genetic studies are necessary, however, to clarify the roles of different genetic variants and determine whether a genetically determined susceptibility does indeed exist.

Various brain regions also differ in their sensitivity to alcohol's effects, including alcohol-induced thiamine deficiency. The cerebellum appears to be particularly sensitive to the effects of thiamine deficiency and is the region most frequently damaged in association with chronic alcohol consumption. This heightened susceptibility is consistent with the cognitive deficits typically associated with alcoholism. These deficits are indicative either of cerebellar damage or of damage to the frontal lobes, which are connected to the cerebellum through neural pathways. Accordingly, reversal of thiamine deficiency - for example, by administering thiamine at pharmacological levels - may not only ameliorate the consequences of cerebellar damage but improve some brain functions typically associated with the frontal lobe.

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