The goal of the proposed study is to investigate the influence of tau pathology on medial temporal lobe (MTL) function in normal aging. More specifically, we plan to examine how tau in the MTL influences hippocampal pattern separation, the process of disambiguating overlapping inputs into distinct outputs and how this process changes over time after consolidation and forgetting have occurred. Hippocampal pattern separation and its underlying behavioral phenotype mnemonic discrimination have been shown in both rodents and humans to be impaired in aging. Pattern separation provides a robust empirical framework for testing hippocampal function by manipulating mnemonic discrimination. To achieve these goals, we will use powerful high-resolution fMRI (1.8 mm isotropic) methods that are capable of dissociating subfield-specific signals, coupled with a parametric design manipulating interference of dynamic video stimuli rather than static, objects, words, or scenes, which are less ecologically valid. We will use this design to examine hippocampal pattern separation immediately and 24 hours later, once consolidation has occurred, in a group of cognitively normal older adults who have been studied with tau PET imaging. This is a highly innovative experiment that has never been previously accomplished. Successful completion of the project will shed light on the neural basis of memory consolidation in aging and the influence of tau pathology on hippocampal subfield activity, providing a better understanding of the network changes in cognitively normal aging and paving the way to improving dissociation of normal and pathological aging.
The proposed project investigates the role of tau pathology on memory consolidation in normal aging. It is vital to understand cognitive and neurobiological changes in normal aging, as 1) treatments may be developed to alleviate memory impairment in normal aging and 2) we may be able to better differentiate normal aging from pathological aging. The findings of the proposed research will also speak to the neural mechanisms underlying age-related memory impairment by investigating tau deposition in the medial temporal lobe (MTL), its influence on hippocampal subfield activity, and their relationship with cortical regions involved in memory consolidation in humans using state-of-the-art high-resolution neuroimaging techniques and novel tau imaging techniques. Establishing the locus of age-related network changes and how activity is changing with age in these regions of the MTL will aid in the production of therapeutic drugs and interventions by which to prevent further decline.
| Leal, Stephanie L; Yassa, Michael A (2018) Integrating new findings and examining clinical applications of pattern separation. Nat Neurosci 21:163-173 |
| Leal, Stephanie L; Lockhart, Samuel N; Maass, Anne et al. (2018) Subthreshold Amyloid Predicts Tau Deposition in Aging. J Neurosci 38:4482-4489 |
| Leal, Stephanie L; Noche, Jessica A; Murray, Elizabeth A et al. (2017) Disruption of amygdala-entorhinal-hippocampal network in late-life depression. Hippocampus 27:464-476 |
| Leal, Stephanie L; Landau, Susan M; Bell, Rachel K et al. (2017) Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline. Elife 6: |
| Leal, Stephanie L; Yassa, Michael A (2015) Neurocognitive Aging and the Hippocampus across Species. Trends Neurosci 38:800-812 |
