Treatment with cholinesterase inhibitors is now routine for patients with very mild-to-mild dementia of the Alzheimer type (DAT). While the cholinesterase inhibitors have been shown to ameliorate cognitive deficits in DAT patients, there is little evidence that such drugs have the capacity to slow progression of the diseases. In the fall of 2003, the first drug treatment for DAT other than a cholinesterase inhibitor was approved for use in the U.S. Memantine, a voltage dependent, uncompetitive NMDA antagonist, ameliorates the cognitive deficits associated with Alzheimer's Disease (AD), and combined treatment with memantine and donepezil has been shown to be superior to donepezil alone. Because the mechanism of action of memantine involves modulation of the excitotoxic neurotransmitter, glutamate, it has been hypothesized to slow progression of the disease process. However, direct evidence of memantine's capacity to slow neurodegeneration associated with AD has not yet been obtained. During the initial funding period, we tested the hypothesis that assessments of hippocampal volume and shape could predict the outcome of donepezil treatment in DAT patients. We also conducted studies in mouse models of AD to investigate the capacity of cholinesterase inhibitors to reverse experimentally induced behavioral deficits analogous to those found in DAT patients. We now propose to extend our investigation of the relationships between neuroanatomical structure and the treatment of AD by determining what neuroanatomical changes are most strongly correlated with the progression of cognitive deficits in patients with DAT and whether treatment with cholinesterase inhibitors and/or memantine can slow progression of such neuroanatomical changes. As during the initial funding period, we will pursue these objectives in subjects with DAT that are undergoing treatment and in an experimental mouse model of AD. We propose to use high resolution magnetic resonance imaging and the tools of computational anatomy to assess changes in the structure of the hippocampus, parahippocampal gyrus and cingulate gyrus in subjects with very mild-to-mild DAT that are untreated, treated with donepezil alone, or treated with the combination of donepezil and memantine. Parallel studies of progressive amyloid plaque deposition and neuronal degeneration will be performed in transgenic mice (Tg2576) that express a mutant form of the APP gene.
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