Alterations in cerebral function and levels of consciousness occur in certain metabolic diseases where changes in circulating substrates and hormones influence the synthesis and turnover of brain neurotransmitters. The pathophysiologic mechanisms responsible for cerebral dysfunction in these metabolic encephalopathies remain to be clarified. There have been several important technical advances in recent years which will permit further progress in the study of these diseases. Current hypotheses of the etiology of metabolic encephalopathy have tended to focus only on isolated facets of the disease. But the multifactorial nature of metabolic encephalopathy suggests that the most productive approach to elucidating its etiology will be to integrate the various abnormalities which have been described. Correlation of alterations in neurotransmitter metabolism and distribution, receptor density and distribution, protein synthesis, and cerebral function, at different stages of the disease may reveal crucial steps in the development of encephalopathy that might remain obscure in studies of single variables at isolated time points. Accordingly, the goals of this proposal will emphasize the following aspects: the identification of those biochemical, physiologic and structural changes which are important in causing alterations in consciousness in metabolic disease, followed by the determination of any etiologic factors common to various metabolic encephalopathies (e.g., hepatic, uremic and diabetic). Encephalopathy caused by portal-systemic shunting will be studied first. Regional localization of neurotransmitters and their metabolism will be related to the functional stages of metabolic encephalopathy. Regional glucose use will be measured by quantitative autoradiography and used as an index of cerebral function. Regional brain content of major neurotransmitters and their metabolites will be determined by high performance liquid chromatography. Distribution of their receptors will be evaluated by quantitative autoradiography. A method for measuring the regional rate of ammonia metabolism will be developed and validated. Amino acid profiles in blood and brain, which may effect neurotransmitter metabolism, will be measured concurrently. Subsequently studies will be extended to models of uremic and diabetic encephalopathy.
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