DESCRIPTION (provided by applicant): Normal aging involves a gradual breakdown of physiological processes that leads to a decline in cognitive functions and brain integrity,1-5 yet the onset and progression of decline is variable among older individuals.6 While many biological changes may contribute to this degree of variability, oxidative stress is a key mechanism of the aging process that can cause direct damage to cellular architecture within the brain.7-8 Oligodendrocytes are at a high risk for oxidative damage due to their role in myelin maintenance and production and limited repair mechanisms, suggesting that white matter may be particularly vulnerable to oxidative activity.9-10 Antioxidant defense enzymes within the brain such as superoxide dismutase (SOD), catalase (CAT), and glutathione-S-transferase (GST) are crucial for breaking down harmful end products of oxidative phosphorylation, and have shown to decrease with age in the frontal and temporal lobes.11 Additionally, allele variations of three polymorphisms (SOD2, CAT -262, GSTM1) have been associated with functional abnormalities in SOD, CAT, and GST activity,12 suggesting a risk for enhanced oxidative damage among individuals with these genetic mutations. Although the relationship between aging and oxidative stress has been well established, few studies have examined the impact of genetic risk for increased oxidative damage as a mechanism of age-related cognitive decline, and no studies have used diffusion tensor imaging (DTI) and neuropsychological indices to examine the impact of these risk factors in older individuals. The present study will use DTI scalar metrics and neuropsychological assessment to compare differences in microstructural white matter integrity and cognitive performance among 107 individuals with and without genetic risk factors of SOD2, CAT -262, and GSTM1. This will be the first study to combine neuroimaging and neuropsychological indices to investigate the impact of antioxidant defense genes on brain integrity among a sample of otherwise healthy older adults.

PUBLIC HEALTH RELEVANCE: Aging is associated with decreased brain integrity and cognitive performance, yet the onset and rate of decline is variable among older individuals. Oxidative stress has been identified as a key mechanism of age-related decline and genetic risk factors for increased oxidative damage may contribute to age-related brain variability. To date, no study has examined the impact of these risk factors on microstructural white matter integrity and cognition among older individuals. The proposed study will be the first to integrate metrics of diffusion tensor imaging (DTI) with neuropsychological evaluation to examine the impact of genetic risk for increased oxidative damage among otherwise healthy older adults.