A range of studies suggests that Alzheimer's disease (AD) begins by impairing synaptic function in select subregions of the hippocampal formation. Detecting synaptic dysfunction with anatomical precision has emerged as an important goal, both to improve our diagnostic abilities and for the purposes of drug development. Synaptic dysfunction typically affects basal brain metabolism. Among the hemodynamic correlates of brain metabolism that can be assessed with magnetic resonance imaging (MRI), cerebral blood volume (CBV) is the one that can most readily visualize individual hippocampal subregions. The first goal of this proposal is to determine whether high-resolution measures of CBV do in fact reflect underlying physiology and metabolism, and whether it can detect AD-related and age-related neuronal dysfunction. The second goal is to confirm that AD-related and age-related hippocampal dysfunction target separate hippocampal subregions. The third goal is to demonstrate that CBV measures can reliably detect the effect of a pharmacological intervention, thereby testing whether this approach can be used for drug development. Independent validation of neuronal dysfunction requires invasive techniques--such as ex vivo slice electrophysiology and in vitro histochemistry-- and therefore these goals can only be achieved in experimental animals. Here we focus on mice because they are the only species that provide both a model of AD and a model of normal aging. Furthermore, because of their relatively short life span, we can follow mice longitudinally, thereby mapping the temporal as well as spatial pattern of dysfunction. With these advantages in mind, we have constructed an MRI laboratory tailored exclusively to mouse MRI, and have optimized CBV approaches for subregional analysis of the hippocampus.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025161-02
Application #
7009921
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Snyder, Stephen D
Project Start
2005-02-01
Project End
2009-01-31
Budget Start
2006-02-15
Budget End
2007-01-31
Support Year
2
Fiscal Year
2006
Total Cost
$305,937
Indirect Cost
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Small, Scott A; Petsko, Gregory A (2015) Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci 16:126-32
Brickman, Adam M; Khan, Usman A; Provenzano, Frank A et al. (2014) Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci 17:1798-803
Khan, Usman A; Liu, Li; Provenzano, Frank A et al. (2014) Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci 17:304-11
Mecozzi, Vincent J; Berman, Diego E; Simoes, Sabrina et al. (2014) Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol 10:443-9
Small, Scott A (2014) Isolating pathogenic mechanisms embedded within the hippocampal circuit through regional vulnerability. Neuron 84:32-39
Morabito, Michael V; Berman, Diego E; Schneider, Remy T et al. (2014) Hyperleucinemia causes hippocampal retromer deficiency linking diabetes to Alzheimer's disease. Neurobiol Dis 65:188-92
Pavlopoulos, Elias; Jones, Sidonie; Kosmidis, Stylianos et al. (2013) Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48. Sci Transl Med 5:200ra115
Schobel, Scott A; Chaudhury, Nashid H; Khan, Usman A et al. (2013) Imaging patients with psychosis and a mouse model establishes a spreading pattern of hippocampal dysfunction and implicates glutamate as a driver. Neuron 78:81-93
Morel, Etienne; Chamoun, Zeina; Lasiecka, Zofia M et al. (2013) Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system. Nat Commun 4:2250
Lewandowski, Nicole M; Bordelon, Yvette; Brickman, Adam M et al. (2013) Regional vulnerability in Huntington's disease: fMRI-guided molecular analysis in patients and a mouse model of disease. Neurobiol Dis 52:84-93

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