Our memory changes as we age. Age-related memory decline in and of itself represents a significant public health impact, but cognitive decline - and in particular memory decline - has been shown to be an important risk factor for Alzheimer's Disease (AD). Examining neurocognitive aging will help us better characterize pathological and non-pathological changes in the brain throughout the lifespan and identify preclinical markers for cognitive decline. The goal of this proposal is to test key predictions of neurocognitive model of aging and amnestic Mild Cognitive Impairment (aMCI) that suggests changes in connectivity and activity within structures in the MTL underlie behavioral deficits in memory. In particular, in both rodent and human studies, the hippocampus exhibits hyperactivity - a potentially dysfunctional state that has been tied to behavioral shifts away from successful mnemonic discrimination (derived from pattern separation and leading to accurate memory for details) and towards over-generalization (derived from pattern completion). To this end, reduction of this hyperactivity in aMCI using a low-dose antiepileptic s associated with improved performance in a mnemonic discrimination task that we have used many times to index hippocampal function and age- and aMCI-related changes. Without the direct recording of hyperactivity possible in rodents, human studies have often relied on the indirect and relative measures provided by BOLD fMRI. Here, we propose a directed, novel, metabolic investigation into the neuronal pathways responsible for this hyperactivity to determine the applicability of the rodent model. Using magnetic resonance imaging spectroscopy (MRS) and metabolite imaging methods, we aim to measure the metabolic signatures for excitatory and inhibitory activity (e.g. GABA, glutamate, choline, etc.), testing th hypothesis that hippocampal hyperactivity arises from the release of inhibition on the CA3 recurrent collaterals within the hippocampus, leading to an increase in excitatory activity and a decrease in inhibitory activity when the hippocampus is actively processing new information. We propose utilizing two MRS scans, 1H-MRS and 31P-MRS to determine which scan is more sensitive to this hyperactivity. Finally, we will evaluate if these MRS measures of hyperactivity have an inverse relationship with performance on several hippocampal-dependent memory tasks, known to be sensitive to aging and MCI.
The percentage of the world's population aged 65 and older is expected to be triple what it was several decades ago and double the current proportion, representing a huge demographic shift. The incidence of dementia (e.g., Alzheimer's Disease, Vascular Dementia, etc.) increases dramatically with age. Outside of dementia, there are also clear cognitive effects of age, particularly in the domain of memory. Understanding the neural mechanisms that underlie these age-related deficits is crucial for understanding the effects of aging and dementia, and paving the way to improve treatments for both normal and pathological changes in memory and for early prevention.
| Nikolova, Simona; Stark, Shauna M; Stark, Craig E L (2017) 3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging. Neurobiol Aging 54:103-111 |
