Success requires focus and the ability to screen out distractions. This is especially important in arousing situations: When avoiding imminent danger, tackling a cognitive challenge or trying to achieve a desired goal, focusing on what has highest priority or is most salient is often helpful. We plan to test the hypothesis that when arousing or challenging situations activate the locus coeruleus (LC) in healthy younger adults, it enhances processing high priority or highly salient items but impairs processing of less active competing representations. The framework behind this hypothesis is the first to explain how arousal both enhances and impairs attention and memory and this project will be the first to systematically examine the relationship between LC structural decline and cognitive function in normal aging and in Alzheimer's disease. We predict that, in older adults, the LC has a less targeted effect than it does in younger adults, meaning that arousal still has a significant impact on older adults' cognitive processing but that it is less likely to increase the selectivity of their attention or the specificity of their memories. Furthermore, we predict that in Alzheimer's disease, declines in structural connectivity will be extensive enough to impair both the excitatory and inhibitory effects of LC activity. This work to understand the role of the LC in cognitive function becomes particularly urgent in light of recent striking findings indicating that the LC is the first place in the brain that sporadic (or late-onset) Alzheimer's related tau pathology emerges, and that by young adulthood, most people have at least some tau pathology in the LC. Here we use neuromelanin-weighted structural MRI images and diffusion tensor imaging structural connectivity measures to examine how LC integrity relates to function on a variety of tasks that assess cognitive selectivity. We will test healthy older adults, older adults with late-onset Alzheimer's and younger and middle-aged adults with genetic subtypes of Alzheimer's disease (due to mutations in the PSEN1 and APP genes) that lead to early onset of the disease.

Public Health Relevance

Recent findings indicate that the locus coeruleus is the first place in the brain that Alzheimer?s disease pathology is found and that nearly all adults have at least some disease-related pathology there by age 40. Post-mortem neuron density in the locus coeruleus is also one of the strongest brain predictors of cognitive decline, yet little is known about how function in this region changes with age and disease. In this project, we examine relationships between the locus coeruleus and attention and memory processes in aging and in Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025340-12
Application #
9440315
Study Section
Social Psychology, Personality and Interpersonal Processes Study Section (SPIP)
Program Officer
Nielsen, Lisbeth
Project Start
2004-09-01
Project End
2022-02-28
Budget Start
2018-03-15
Budget End
2019-02-28
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Other Specialized Schools
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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