This competing continuation application proposes to build upon our studies of the anatomic specificity of neurofibrillary tangles (NFT) and senile plaques (SP) to ask the next generation of questions regarding the disruption of the complex topography of human brain architecture by Alzheimer's disease (AD). We have found that the neuropathological changes of AD seemingly obey anatomical principles by selectively and specifically destroying projection neurons within limbic and association areas, leading to loss of feed forward and feedback projections and of neural systems that underlie aspects of normal memory and cognition. We now propose to move beyond anatomical descriptions to quantitative analyses in order to generate and test new hypotheses about AD pathophysiology. We have merged newly developed stereological anatomical techniques with computerized image analysis systems to create quantitative maps of cytoarchitecture and of AD related lesions.A major new thrust is a collaboration with Dr. Gene Stanley, an international leader in applying the mathematical techniques of complex systems analysis to biological systems. Together we will ask how the pathological alterations of AD deform the neural landscape. Quantitation will allow the comparison of individuals with different clinical duration or severity of illness, and different risk factors such as ApoE genotype or Down syndrome.
Four specific aims will examine SP deposition, NFT formation, neuronal loss and neuronal cellular integrity. Already our preliminary results suggest that the approach of combining state of the art quantitative anatomical techniques with powerful mathematical analyses will yield new clues about the pathophysiology of AD. For example, we have discovered that the distribution of SP sizes fits a log-normal plot quite well, which argues in favor of some, and against other, hypotheses about SP formation. The SP size distribution plot has led us to generate a new hypothesis about AD deposition in AD (aim 1). Quantitative assessment shows that neuronal loss and NFT, but not SP, correlate strongly with duration of dementia. Moreover, neuronal loss parallels but outstrips NFT formation by an order of magnitude. We will map the locations of NFT and neuronal loss to determine whether they occur in register, to test.specific hypotheses about the relationship of NFTs and neural death. Surprisingly we find that there are long range correlations of the locations of NFT, and we have generated testable hypotheses to explain this observation (aim 2). We have devised methods to quantitate the features that classical anatomists use to distinguish cytoarchitectural fields - lamination, packing density, and topographic patterns - and found that these quantitative analyses reveal specific alterations in AD (aim 3). We will study the structural and metabolic integrity of individual neurons in relationship to NFT and SP (aim 4). In sum, we will develop and use quantitative techniques and analyses in order to test new hypotheses about the structure organization of the normal human cerebral cortex and the specific alterations that occur in AD.
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