Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type


Degree Name



Psychiatry and Behavioral Neurosciences

First Advisor

Naftali Raz

Second Advisor

Jeffrey A. Stanley


Episodic and associative memory decline is one of the earliest cognitive impairments in normal aging and among the defining cognitive features of Alzheimer’s disease (AD). Since, age-related cognitive decline gradually devolves into AD, with neuropathology preceding cognitive changes by many years, the identification of biomarkers of early disease progression is crucial. Reduction in glutamate, the main excitatory neurotransmitter involved in associative memory, in key brain regions such as the hippocampus, has been theorized as one of the cellular mechanisms underlying cognitive decline in aging and AD. A few neuroimaging studies that demonstrated a link between older adults’ weaker cognitive performance and lower hippocampal glutamate levels, correlated static levels of glutamate with out-of-scanner performance. The current study is the first to investigate age effects on temporal modulation of hippocampal glutamate during associative memory performance. Proton functional magnetic resonance spectroscopy (1H fMRS) was used to examine hippocampal glutamate modulation in healthy young and old adults during associative memory performance. Proton spectra from unilateral hippocampi were acquired during task performance and during a preceding non-task-active control condition. Young adults demonstrated better associative memory performance than the old. Despite no age differences in glutamate levels during the control condition, significant age differences were detected in the temporal modulation of glutamate during the associative memory task that were specific to memory encoding. Young adults evinced higher glutamate levels earlier during encoding, that later reduced when the capacity to encode had presumably approached saturation. Conversely, old adults failed to demonstrate significant glutamate modulation in either memory stage. However, within the older group, associative memory performance seemed to depend on the timing of glutamate elevation during encoding. Specifically, old adults who displayed earlier glutamate elevation demonstrated a trend towards a later inflection point and a slower rate of learning. These results indicate that early glutamatergic response during memory encoding reflects early engagement of the hippocampus leading to better associative memory performance. This study provides the first in vivo demonstration of age differences in hippocampal glutamate modulation during associative memory performance and is the first step towards better elucidation of glutamatergic contribution to age-related cognitive differences.

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