Episodic memory involves being able to accurately distinguish new from old events and is highly dependent on the hippocampus. With advancing age, episodic memory declines and is often the first cognitive domain impaired in Alzheimer's disease (AD). A computational model of hippocampal function, referred to as pattern separation, suggests that alterations in hippocampal circuitry are likely responsible for the observed cognitive changes. Recent studies have sought to use functional magnetic resonance imaging (fMRI) to understand why deficits in episodic memory arise and commonly report that hyperactivity in the hippocampus is associated with poorer performance in older adults. However, a significant proportion of cognitively normal older individuals harbor beta-amyloid (A?) pathology, suggesting that it is important to differentiate age-related from pathology- related influences on cognition. This proposal employs a multimodal neuroimaging approach to investigate the influence of A? (via PIB-PET imaging) on hippocampal function and episodic memory (via task-related fMRI). Fifty cognitively normal older and 20 young subjects will be recruited from the Berkeley Aging Cohort to participate in an fMRI pattern separation paradigm. Subjects will be shown pictures of everyday objects and asked to determine whether the object is new, old or similar but not identical to a previous object. Hippocampal activation will be assessed for all conditions involving similar objects as these stress pattern separation and memory encoding processes. A? burden will be quantified as the mean cortical PIB uptake in areas of traditionally high A? accumulation in AD, and used to dichotomize older subjects into A?+ and A?-groups. In addition, high-resolution structural MRI will be used to calculate medial temporal lobe and hippocampal subfield volumes, as there is reason to believe A? influences local atrophy that impacts episodic memory function. Lastly, hippocampal glucose metabolism will be quantified using FDG-PET to assess the integrity of the structure at rest. We hypothesize that older subjects will perform worse and have greater activity in the hippocampus, specifically the dentate gyrus (DG) and CA3 subfield, for objects correctly identified as similar relative to young subjects. A?- subjects will perform worse and have greater activity in the DG/CA3 relative to A?- subjects. A?+ subjects will have smaller subfield volumes than A?- subjects, most notably in areas closely related to AD, the entorhinal cortex and CA1 subfield. Finally, A?+ subjects will demonstrate higher resting hippocampal glucose metabolism, suggesting a more pronounced dysfunction beyond task-related activity. As a whole, this proposal will help to shed light on our understanding of episodic memory, aging and preclinical AD. Furthermore, upon completion of the proposed research, the applicant will have developed the skills necessary to process and analyze neuroimaging data, including PET, structural MRI and functional MRI, and assess changes in cognition and episodic memory. These skills will bolster career development and help advance the applicant to a postdoctoral research appointment.
The accumulation of beta-amyloid pathology is a common occurrence in cognitively normal older individuals, but the relationship between this pathology and changes observed during aging remain unclear. This proposal employs a multimodal neuroimaging approach to investigate the influence of beta-amyloid pathology on hippocampal function and episodic memory, which will improve our understanding of the mechanisms of disease-related memory dysfunction. Distinguishing disease-related from age-related dysfunction will be important for developing treatments of memory impairment that occurs with age.
| Marks, Shawn M; Lockhart, Samuel N; Baker, Suzanne L et al. (2017) Tau and ?-Amyloid Are Associated with Medial Temporal Lobe Structure, Function, and Memory Encoding in Normal Aging. J Neurosci 37:3192-3201 |
