Impact of Genetic Risk for Increased Oxidative Stress on Brain Integrity

氧化应激增加的遗传风险对大脑完整性的影响

• 批准号: 8908833
• 负责人: Lauren E. Salminen
• 金额: $ 3.18万
• 依托单位: UNIVERSITY OF MISSOURI-ST. LOUIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908833
• 关键词: Age; Age-associated memory impairment; Aging; Aging-Related Process; Alleles; Alzheimer' s Disease; Anisotropy; Antioxidants; Architecture; Area; Biological; Blood Vessels; Brain; Brain region; Cell Respiration; Cognition; DNA Sequence Alteration; Data; Dementia; Diffusion Magnetic Resonance Imaging; Drug Metabolic Detoxication; Elderly; Enzymes; Evaluation; Exhibits; Funding; Future Generations; GSTM1 gene; Genes; Genetic; Genetic Markers; Genetic Polymorphism; Genetic Risk; Genetic Variation; Genomic DNA; Glutathione S-Transferase; Goals; Health; Individual; Intervention; Investigation; Language; Life Expectancy; Link; Lipids; Maintenance; Mediating; Memory; Methodology; Minor; Motor; Myelin; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Oligodendroglia; Oxidative Phosphorylation; Oxidative Stress; Parents; Participant; Performance; Phase; Physiological Processes; Production; Proteins; Reactive Oxygen Species; Recruitment Activity; Research Infrastructure; Risk; Risk Factors; Role; SOD2 gene; Saliva; Sampling; Source; Superoxide Dismutase; Temporal Lobe; Testing; Training; United States National Institutes of Health; Variant; Visuospatial; age related; aging brain; antioxidant enzyme; catalase; cognitive function; cognitive performance; executive function; frontal lobe; genetic risk factor; genetic variant; high risk; indexing; mild cognitive impairment; neuroimaging; neuropsychological; normal aging; oxidation; oxidative damage; parent grant; public health relevance; repaired; risk variant; white matter; white matter change

 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.

 描述（由申请人提供）：正常衰老涉及生理过程的逐渐崩溃，从而导致认知功能和大脑完整性下降1-5，但老年人中衰退的发生和进展是可变的。6 虽然许多生物变化可能会导致认知功能和大脑完整性下降。导致这种程度的变异性的是，氧化应激是衰老过程的一个关键机制，可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磷脂维持和维持中的作用而面临氧化损伤的高风险。产生和有限的修复机制，表明白质可能特别容易受到氧化活性的影响。9-10 大脑内的抗氧化防御酶，如超氧化物歧化酶 (SOD)、过氧化氢酶 (CAT) 和谷胱甘肽-S-转移酶 (GST)对于分解氧化磷酸化的有害终产物至关重要，并且在额叶和颞叶中已显示出随着年龄的增长而减少。 11 此外，三种多态性的等位基因变异（SOD2、CAT -262、GSTM1）与 SOD、CAT 和 GST 活性的功能异常有关，12 这表明尽管衰老和氧化应激之间存在良好的关系，但具有这些基因突变的个体存在氧化损伤增强的风险。尽管已经确定，但很少有研究探讨遗传风险对氧化损伤增加作为与年龄相关的认知能力下降的机制的影响，也没有研究使用弥散张量成像（DTI）和神经心理学指标来检查氧化损伤的遗传风险。本研究将使用 DTI 标量指标和神经心理学评估来比较 107 名有或没有 SOD2、CAT -262 和 GSTM1 遗传风险因素的个体的微结构白质完整性和认知能力的差异。这将是第一项将神经影像学和神经心理学指标结合起来的研究，以调查抗氧化防御基因对健康老年人样本中大脑完整性的影响。