The Geriatric Dementia Research Clinic will focus on neurometabolic aspects of Alzheimer disease in the elderly. Glucose oxidation and neurotransmitter metabolism are known to decrease in the brains of demented subjects in vivo. This program project is an integrated group of investigations designed to elucidate the molecular bases of these abnormalities and to test their value in improving diagnoses, as well as their potential pathophysiologic and therapeutic significance. Meticulously diagnosed patients and controls from a Dementia Evaluation Clinic and another autopsy series will be studied. New signal analyses of 133Xenon washout curves and measurements of putative cholinergic and other neurotransmitter markers in blood and cerebrospinal fluid will be developed as aids to diagnosis. Recent observations in this unit and in two laboratories in England have demonstrated intrinsic abnormalities Alzheimer brainin two key enzymes of glucose utilization in--phosphofructokinase (PFK) and pyruvate dehydrogenase (PDHC). Activities of PFK, PDHC and other metabolic and neurotransmitter marker enzymes from physiologically relevant regions of autopsy Alzheimer and control brains will be compared; PFK will also be characterized in non-neural tissues, since recent data indicate that the abnormalities in it persist in Alzheimer fibroblasts. In addition, activities of PFK and PDHC and isozyme patterns of PFK will be studied in blood cells and fibroblasts from the clinic patients. These enzymes will be purified from autopsied tissues and studied kinetically and electrophoretically to test for structural abnormalities. Aluminum, a putative neurotoxin in Alzheimer disease, will be examined for its effects on glucose metabolism in rabbit brain. The selective vulnerability of certain neurones to impaired glucose catabolism will be explored with rat retina in vitro as a model system. Other investigations will study therapeutic agents, nutritional effects, and a possible relationship between altered immune function and intrinsic enzymatic abnormalities of Alzheimer lymphocytes. This program on the neurochemistry of Alzheimer's disease also aims to identify useful biochemical marker(s) for it or for a predisposition to it.
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