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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Neurology A Study Section (NEUA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Hopp, Sarah C; Bihlmeyer, Nathan A; Corradi, John P et al. (2018) Neuronal calcineurin transcriptional targets parallel changes observed in Alzheimer disease brain. J Neurochem 147:24-39
Farrar, Christian T; William, Christopher M; Hudry, Eloise et al. (2014) RNA aptamer probes as optical imaging agents for the detection of amyloid plaques. PLoS One 9:e89901
Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R et al. (2013) Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631-43
Serrano-Pozo, Alberto; Muzikansky, Alona; Gómez-Isla, Teresa et al. (2013) Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease. J Neuropathol Exp Neurol 72:462-71
Macklin, Eric A; Blacker, Deborah; Hyman, Bradley T et al. (2013) Improved design of prodromal Alzheimer's disease trials through cohort enrichment and surrogate endpoints. J Alzheimers Dis 36:475-86
Kopeikina, Katherine J; Polydoro, Manuela; Tai, Hwan-Ching et al. (2013) Synaptic alterations in the rTg4510 mouse model of tauopathy. J Comp Neurol 521:1334-53
Serrano-Pozo, Alberto; Gómez-Isla, Teresa; Growdon, John H et al. (2013) A phenotypic change but not proliferation underlies glial responses in Alzheimer disease. Am J Pathol 182:2332-44
Kopeikina, Katherine J; Wegmann, Susanne; Pitstick, Rose et al. (2013) Tau causes synapse loss without disrupting calcium homeostasis in the rTg4510 model of tauopathy. PLoS One 8:e80834
Kopeikina, Katherine J; Hyman, Bradley T; Spires-Jones, Tara L (2012) Soluble forms of tau are toxic in Alzheimer's disease. Transl Neurosci 3:223-233
Wu, Hai-Yan; Hudry, Eloise; Hashimoto, Tadafumi et al. (2012) Distinct dendritic spine and nuclear phases of calcineurin activation after exposure to amyloid-? revealed by a novel fluorescence resonance energy transfer assay. J Neurosci 32:5298-309

Showing the most recent 10 out of 49 publications