Amyloid senile plaques (SPs) and neurofibrillary tangles (NFTs) are neuropathological hallmarks of Alzheimer's disease (AD) that also accumulate in key brain regions in association with normal aging. Our group has synthesized a small molecule probe, 2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([18F]FDDNP), which provides excellent visualizations of NFTs, SPs, and diffuse amyloid in AD brain specimens using fluorescent microscopy, and in vivo human positron emission tomography (PET) studies show that [18F]FDDNP labels medial temporal cortex in AD patients. This program project grant is designed to determine whether this method of plaque and tangle PET imaging (1) correlates with the expected accumulation of neuropathological changes associated with aging and dementia (AD and frontotemporal dementia [FTD]); (2) predicts future decline in people at risk for AD and in patients with dementia; and (3) augments other informative imaging (e.g., structural and functional magnetic resonance imaging [MRI], FDG-PET measures of glucose metabolism, [18FJMPPF-PET measures of serotonin receptor density), neuropsychological, and genetic risk (apolipoprotein E-4 [APOE-4], H1 haplotype of the tau gene) measures in diagnosis and differential diagnosis of normal aging and dementia. An Administrative and Clinical Core, a Chemistry and PET Imaging Core, and an Image Analysis Core will support three proposed projects: (1) Visualizing brain A-beta, tau and serotonin receptor densities; (2) Clinical plaque and tangle imaging in aging and dementia; and (3) Multi-modal brain imaging in aging and dementia. This infrastructure will provide an opportunity to study transgenic animal models, neuropathological correlations, binding characteristics, and longitudinal PET, MRI, neuropsychological and genetic risk data in patients with AD and frontotemporal dementia, people with MCI, and younger and older adult controls. This project will expand an established program in early detection and prevention of AD, designed (1) to identify presymptomatic persons most likely to benefit from early intervention and (2) to provide an objective, noninvasive means to monitor therapeutic trials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG025831-04
Application #
7434502
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4 (J2))
Program Officer
Buckholtz, Neil
Project Start
2005-09-30
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$1,364,255
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Roussotte, Florence F; Siddarth, Prabha; Merrill, David A et al. (2018) In Vivo Brain Plaque and Tangle Burden Mediates the Association Between Diastolic Blood Pressure and Cognitive Functioning in Nondemented Adults. Am J Geriatr Psychiatry 26:13-22
Burggren, Alison C; Mahmood, Zanjbeel; Harrison, Theresa M et al. (2017) Hippocampal thinning linked to longer TOMM40 poly-T variant lengths in the absence of the APOE ?4 variant. Alzheimers Dement 13:739-748
Ghezzi, Chiara; Yu, Amy S; Hirayama, Bruce A et al. (2017) Dapagliflozin Binds Specifically to Sodium-Glucose Cotransporter 2 in the Proximal Renal Tubule. J Am Soc Nephrol 28:802-810
Harrison, Theresa M; Burggren, Alison C; Small, Gary W et al. (2016) Altered memory-related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease. Hum Brain Mapp 37:366-80
Merrill, David A; Siddarth, Prabha; Raji, Cyrus A et al. (2016) Modifiable Risk Factors and Brain Positron Emission Tomography Measures of Amyloid and Tau in Nondemented Adults with Memory Complaints. Am J Geriatr Psychiatry 24:729-37
Wong, Koon-Pong; Bergsneider, Marvin; Glenn, Thomas C et al. (2016) A semi-automated workflow solution for multimodal neuroimaging: application to patients with traumatic brain injury. Brain Inform 3:1-15
Baerresen, Kimberly M; Miller, Karen J; Hanson, Eric R et al. (2015) Neuropsychological tests for predicting cognitive decline in older adults. Neurodegener Dis Manag 5:191-201
Barrio, Jorge R; Small, Gary W; Wong, Koon-Pong et al. (2015) In vivo characterization of chronic traumatic encephalopathy using [F-18]FDDNP PET brain imaging. Proc Natl Acad Sci U S A 112:E2039-47
Ye, Hu; Wong, Koon-Pong; Wardak, Mirwais et al. (2014) Automated movement correction for dynamic PET/CT images: evaluation with phantom and patient data. PLoS One 9:e103745
Dubal, Dena B; Yokoyama, Jennifer S; Zhu, Lei et al. (2014) Life extension factor klotho enhances cognition. Cell Rep 7:1065-76

Showing the most recent 10 out of 52 publications