We have recently observed 35-75% decreases in cortical and hippocampal glutamate receptors in brains of people dying with senile dementia of the Alzheimer's type (SDAT). Other receptors (muscarinic cholinergic, GABA, benzodiazepine, dopamine and opiate) show little or no change in cortex of SDAT. However, the activity of the enzyme choline acetyltransferase (CAT) and levels of somatostatin are also reduced in SDAT. We propose to study three aspects of these deficiencies. First, we will study the relationship between glutamate receptors, the clinical degree of dementia and the pathological indices of disease (senile plaques and neurofibrillary tangles) in a series of patients dying of SDAT. Second, we will study the effects of cholinergic inputs to cortex on cortical glutamatergic function in rats. Third, we will study the effects of somatostatin depletion on cortical glutamate function in rats. The techniques we will use include quantitative autoradiography of receptors in human and rat brain, stereotaxic lesions using ibotenic acid, somatostatin depletion using cysteamine, glutamate release, levels and uptake, choline acetyltransferase activity and choline uptake. The investigators have experience in using all the proposed methodologies. The significance of the research is that the studies should yield important information about how the various neurochemical abnormalities demonstrated in SDAT relate to the pathogenesis of the disease.
