Although deficits in episodic memory and coinciding brain atrophy within the hippocampus and medial temporal lobe (MTL) are well-documented in patients diagnosed with Alzheimer?s disease (AD), the behavioral and brain changes in earlier preclinical stages of AD are subtle and poorly understood, especially for still cognitively normal individuals. Identifying and validating markers of these early changes in preclinical AD? especially within the MTL?is necessary to inform the discovery and validation of novel approaches to prevent or retard disease progression, long before the onset of dementia. Within the scope of the parent grant, this post-doctoral supplement to promote diversity in health-related research will incorporate an episodic memory task referred to as ?mnemonic discrimination? (not to be confused with Gluck and colleagues? ?mnemonic flexibility? as a measure of generalization and already implemented in the parent grant). In the mnemonic discrimination task (a.k.a., ?Behavioral Pattern Separation?), participants are first shown everyday objects during an encoding phase and then are given a retrieval test where participants identify repeated objects (targets), novel objects (foils), and similar but not identical objects (lures). Mnemonic discrimination performance is quantified as the ratio of similar responses given to lures minus similar responses given to foils. Older African American participants (N=120) in our study will perform this task while undergoing functional magnetic resonance imaging (fMRI) during their regularly scheduled brain imaging sessions (hence, no additional brain imaging sessions will need to be scheduled). This will allow us to better understand the neural systems involved in encoding, how the neural activity during encoding relates to behavioral performance during retrieval, and how this relationship is influenced by other measures that are already being collected on these participants (i.e., genetic assays of AD risk factors). In particular, we will (1) relate observable dynamic network connectivity of the MTL network during encoding to behavioral differences in mnemonic discrimination during retrieval and (2) examine whether the relationship between MTL network dynamics and behavioral performance on mnemonic discrimination is modulated by APOE and ABCA7 high-risk variants for AD. This two-year supplement will extend the parent grant methods by incorporating a new generation episodic memory task, novel dynamic network neuroscience techniques, and task-based fMRI while providing the post-doctoral trainee an intensive training experience in cognitive, neural, and genetic markers of AD.
Existing ways to accurately predict future cognitive decline and Alzheimer?s disease (AD) lack sensitivity to subtle neural and cognitive changes in preclinical AD. The proposed research will allow us to better understand neural function involved in encoding new memories, how this neural function during encoding relates to behavioral performance in retrieving memories, and whether this neural?behavior relationship is influenced by genetic factors associated with increased risk for AD. The results will provide insights toward identifying and validating markers of early changes in AD ? a necessary step to inform the discovery of novel approaches to prevent or slow disease progression, long before the onset of dementia.
|Sinha, Neha; Reagh, Zachariah M; Tustison, Nicholas J et al. (2018) ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training. Hippocampus :|