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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013308-14
Application #
7841734
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Hsiao, John
Project Start
1995-08-10
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$562,890
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
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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

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