This is a continuing renewal of our R01 previously titled """"""""Functional MRl for Early Diagnosis of Alzheimer's Disease"""""""" (5 R01 AG013308-10). The proposed third grant cycle builds on recent findings from this project and new technologies we have developed for imaging hippocampal structure and function. Our data support the utility of combining genetic risk, structural and functional MRl to identify early manifestations of Alzheimer's disease (AD), and further suggest that brain changes may occur much earlier than previously thought in Apolipoprotein epsilon-4 (APOE-4) carriers. Recently, our group has developed new techniques in high-resolution functional MRl acquisition and analysis, and in mathematical modeling algorithms that identify structural MRl change in Alzheimer's disease subjects over very short time periods. In addition, our group has recently worked with positron emission tomography (PET) using [18F]MPPF imaging, a ligand that measures pyramidal cell density in the hippocampus (HC), entorhinal cortex and amygdala;our preliminary data show that [18F]MPPF binding is decreased in MCI and AD, and correlates with memory in healthy controls, suggesting its potential as an independent assessment of risk for AD. This grant proposes using a combination of four new imaging techniques, two structural (HC cortical thickness and HC radial atrophy), and two functional (FMRI and [18F]MPPF) in control subjects in the 40-80 range at-risk for AD and MCI patients, to determine if there are subtle longitudinal changes in HC structure and function similar to those seen in AD, in cognitively intact at-risk subjects in the late middle age to elderly range. We will recruit 60 younger (40-60) and 36 older (60+) controls, (50% of each with APOE-4), and 35 mild MCI subjects, and follow them for 21/2 years using these novel imaging measures and clinical assessments. Analyses will focus on modeling the rate of change of each measure alone and in combination, with the goal of identifying subjects at highest risk for developing AD. Diagnostic and neuropsychological evaluations will provide clinical corroboration that genotype, family history, and short-term brain changes predict cognitive decline. By combining these different measures of hippocampal structure and function, our primary goal is to develop an approach to identifying those at-risk who are more likely to develop AD, and to determine which of these novel imaging techniques provide the most optimal and independent predictors of future decline.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hsiao, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
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
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
Harrison, Theresa M; Bookheimer, Susan Y (2016) Neuroimaging genetic risk for Alzheimer's disease in preclinical individuals: From candidate genes to polygenic approaches. Biol Psychiatry Cogn Neurosci Neuroimaging 1:14-23
Yushkevich, Paul A; Amaral, Robert S C; Augustinack, Jean C et al. (2015) Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: towards a harmonized segmentation protocol. Neuroimage 111:526-41
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
Chen, Stephen T; Siddarth, Prabha; Saito, Nathan Y et al. (2014) Psychological well-being and regional brain amyloid and tau in mild cognitive impairment. Am J Geriatr Psychiatry 22:362-9
Wagshal, Dana; Knowlton, Barbara Jean; Cohen, Jessica Rachel et al. (2014) Impaired automatization of a cognitive skill in first-degree relatives of patients with schizophrenia. Psychiatry Res 215:294-9
Burggren, Alison; Brown, Jesse (2014) Imaging markers of structural and functional brain changes that precede cognitive symptoms in risk for Alzheimer's disease. Brain Imaging Behav 8:251-61
Donix, Markus; Burggren, Alison C; Scharf, Maria et al. (2013) APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer's disease. Psychiatry Res 214:212-20

Showing the most recent 10 out of 77 publications