Impact of Genetic Risk for Increased Oxidative Stress on Brain Integrity

 描述(申请人提供)：正常衰老涉及生理过程的逐渐崩溃，导致认知功能和大脑完整性的下降，1-5然而，衰退的开始和进展在老年人中是不同的。6虽然许多生物变化可能导致这种程度的变异性，但氧化应激是衰老过程的关键机制，可能会对大脑内的细胞结构造成直接损害。7-8少突胶质细胞由于其在髓鞘维持和产生以及有限的修复机制中的作用，处于氧化损伤的高风险中。9-10大脑中的抗氧化防御酶，如超氧化物歧化酶、过氧化氢酶和谷胱甘肽-S转移酶，对分解氧化磷酸化的有害最终产物至关重要，并已显示出随着年龄的增长额叶和颞叶的氧化损伤减少。11此外，三个基因多态性(SOD2，CAT-262，GSTM1)的等位基因变异与超氧化物歧化酶、过氧化氢酶和谷胱甘肽转移酶活性的功能异常有关，12表明具有这些基因突变的个体的氧化损伤增加的风险。尽管衰老和氧化应激之间的关系已经得到了很好的证实，但很少有研究将遗传风险增加的氧化损伤作为年龄相关认知能力下降的机制，也没有研究使用扩散张量成像(DTI)和神经心理学指数来检查这些风险因素对老年人的影响。本研究将使用DTI标量测量和神经心理学评估来比较107名具有和不具有SOD2、CAT-262和GSTM1遗传风险因素的个体在微结构白质完整性和认知表现方面的差异。这将是第一次将神经成像和神经心理学指标相结合的研究，以调查抗氧化防御基因对原本健康的老年人大脑完整性的影响。

 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.