Cognitive decline with aging, especially in the memory domain, has been documented as an important risk factor for Alzheimer's disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. It will also help us pinpoint cognitive processes and mechanisms that can be altered to delay onset or reverse pathology altogether. With the population over 60 rising rapidly, discoveries in this domain will likely have dramatic impact on public health and substantially reduce the burden on families as well as government and social programs. There is a clear need for targeted investigations of memory and the brain that cover the entire spectrum of aging throughout the adult lifespan. The goal of this proposal is to collect a comprehensive set of behavioral and high-resolution neuroimaging data to test several key predictions of a neurocognitive model of age-related memory impairment. This work is based on converging insights from computational models as well as behavioral, electrophysiological, and neuroanatomical findings in rodent models of aging. The approach is based on the premise that the hippocampal dentate gyrus is critically involved in episodic memory by virtue of its exceptional capacity for performing pattern separation, or the ability to isolate similar memories from each other. Pattern separation is a key computational component of many forms of memory often attributed to the hippocampus (e.g., episodic memory, recollection, etc). The model posits that degraded input to the dentate gyrus and CA3 region from layer II entorhinal cortex neurons with aging leaves the system with an impaired ability to perform pattern separation. We propose to test predictions of this model using behavioral experiments and a combination of cutting-edge neuroimaging techniques (functional and structural MRI, DTI, and PIB PET). We predict that aging will result in behavioral impairments consistent with a reduction in pattern separation abilities, and that there will be neural changes in CA3/DG activity consistent with this reduction. We also predict that aging will result in changes in the connectivity within the hippocampus and between the hippocampus and surrounding cortices (e.g. entorhinal cortex). Finally, we predict that individual differences in memory performance, imaging data, and ApoE4 genetic susceptibility will differentiate healthy from pathological aging and that these differences will be key to predicting subsequent decline. Critically, this rich dataset will have uses beyond our questions and hypotheses. We will provide and share all components of this extensive dataset for other researchers to study using the robust Biomedical Informatics Research Network (BIRN) infrastructure.

Public Health Relevance

The population over 65 is projected to increase to 86.7 million by 2050 (U.S. Census Bureau, Population Estimates and Projections, 2004) and the impact of aging and aging-related disorders e.g. Alzheimer's disease (AD) on the health care system will rise dramatically as the rate of AD doubles for every five year period beyond the age of 65. Even outside of AD, one of the primary complaints and deficits observed with aging is a decline in learning and memory function, leading to decreased quality of life and a greater burden on families and social services. Understanding the neural mechanisms that underlie these age-related deficits is crucial to understanding the effect of aging on dementia, and paving the way to improving treatments for both normal and pathological changes in memory and for early prevention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG034613-05
Application #
8531812
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (M2))
Program Officer
Wagster, Molly V
Project Start
2009-09-15
Project End
2014-08-31
Budget Start
2013-09-15
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$391,561
Indirect Cost
$135,639
Name
University of California Irvine
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Bennett, Ilana J; Huffman, Derek J; Stark, Craig E L (2015) Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan. Cereb Cortex 25:2988-99
Reagh, Zachariah M; Yassa, Michael A (2014) Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans. Proc Natl Acad Sci U S A 111:E4264-73
Leal, Stephanie L; Tighe, Sarah K; Yassa, Michael A (2014) Asymmetric effects of emotion on mnemonic interference. Neurobiol Learn Mem 111:41-8
Huffman, Derek J; Stark, Craig E L (2014) Multivariate pattern analysis of the human medial temporal lobe revealed representationally categorical cortex and representationally agnostic hippocampus. Hippocampus 24:1394-403
Azab, Marwa; Stark, Shauna M; Stark, Craig E L (2014) Contributions of human hippocampal subfields to spatial and temporal pattern separation. Hippocampus 24:293-302
Borota, Daniel; Murray, Elizabeth; Keceli, Gizem et al. (2014) Post-study caffeine administration enhances memory consolidation in humans. Nat Neurosci 17:201-3
Reagh, Zachariah M; Roberts, Jared M; Ly, Maria et al. (2014) Spatial discrimination deficits as a function of mnemonic interference in aged adults with and without memory impairment. Hippocampus 24:303-14
Leal, Stephanie L; Tighe, Sarah K; Jones, Craig K et al. (2014) Pattern separation of emotional information in hippocampal dentate and CA3. Hippocampus 24:1146-55
Roberts, Jared M; Ly, Maria; Murray, Elizabeth et al. (2014) Temporal discrimination deficits as a function of lag interference in older adults. Hippocampus 24:1189-96
Reagh, Zachariah M; Yassa, Michael A (2014) Repetition strengthens target recognition but impairs similar lure discrimination: evidence for trace competition. Learn Mem 21:342-6

Showing the most recent 10 out of 17 publications