Despite extensive efforts focused on preventing and treating age related cognitive decline, this debilitating condition continues to plague the American population, and is projected to increase dramatically in prevalence unless appropriate interventions are discovered. Due to the irreversible nature of neurodegeneration, prevention, early diagnosis and treatment are imperative. Although oxidative stress is known to be involved early in the etiologies of both normal aging and neurodegenerative disease, lack of a noninvasive assay for brain oxidative status has limited development of antioxidant based interventions. The goal of this proposal is to provide a noninvasive assay for human brain antioxidant concentrations that can be used to: identify influences responsible for compromised antioxidant levels, diagnose reduced antioxidant capacity prior to appearance of symptoms or structural damage, and monitor antioxidant capacity throughout therapeutic intervention.
In specific aim 1, a novel noninvasive magnetic resonance spectroscopy (MRS) assay will be used to quantify levels of the two most concentrated non-enzymatic antioxidants in the central nervous system, reduced glutathione (GSH) and vitamin C (Asc) in two homogenous human populations.
In specific aim 2, this antioxidant profile will be measured under the respective endogenous and exogenous influences of aging and diet. The research design will start with measuring inter- and intra- individual variation of the antioxidant profile under constant experimental conditions. Next, this noninvasive assay will be used to determine whether previous post mortem findings of a 25% decrease in human brain Asc concentration with increasing age will be replicated in vivo. Finally, antioxidant concentrations will be measured in the elder group both before and after administration of vitamin C supplementation. Double edited H MRS will be used to 1 measure antioxidant profiles from anatomically matched cortical volumes of interest in vivo. Editing is a specialized form of MRS routinely used to resolve one signal of interest from overlapping signals in vivo. Double editing is a novel application that will be used to resolve two signals, i.e. Asc and GSH resonances in the same amount of time previously required to measure one. Seven additional neurochemical concentrations will be co-measured with but resolved from Asc and GSH, and will be evaluated for dependence upon age and diet, as will serum Asc levels. Public health relevance: Oxidative stress is involved in the process that leads to age related cognitive decline, which is expected to afflict an increasing number of Americans unless effective interventions are discovered. The goal of this project is to develop a noninvasive means to measure human brain antioxidant capacity and to explore the extent to which this novel assay can be used to design experiments aimed at discovering new interventions. This work could lead to improved cognitive health of the aging American population. Public health relevance: Oxidative stress is involved in the process that leads to age related cognitive decline, which is expected to afflict an increasing number of Americans unless effective interventions are discovered. The goal of this project is to develop a noninvasive means to measure human brain antioxidant capacity and to explore the extent to which this novel assay can be used to design experiments aimed at discovering new interventions. This work could lead to improved cognitive health of the aging American population. ? ? ?
