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: 9071280
• 负责人: Lauren E. Salminen
• 金额: $ 1.29万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9071280
• 关键词: Age; Age-associated memory impairment; Aging; Aging-Related Process; Alleles; Alzheimer' s Disease; Anisotropy; Antioxidants; Architecture; Area; Biological; 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; 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; brain health; catalase; cerebrovascular health; 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（适用提供）：正常衰老涉及物理过程的分解，导致认知功能和大脑完整性的下降，但1-5然而，较老的个体的开始和下降进展是可变的。6虽然许多生物学变化可能会导致这种变异性，但氧化压力可能会导致氧化型的重要机制。氧化损伤因其在髓磷脂维持和生产中的作用以及有限的维修机制而造成的氧化损伤风险，这表明白质可能特别容易受到氧化活性的影响。9-10大脑内的抗氧化剂防御酶，例如超氧化物蒸发酶（SOD），催化酶（Catalase（Catalase）（CAT）和粘液性凝聚力（Glutathione-s-s-Transiative），并且是偏向于偏移型的氧化物（Glutathione normitation）是损坏的，并且是破碎的原始杂物。 11此外，三种多态性（SOD2，CAT -262，GSTM1）的等位基因变化与SOD，CAT和GST活动的功能异常相关，这表明对这些遗传突变增强氧化损害的风险。尽管已经建立了衰老与氧化应激之间的关系，但很少有研究检查遗传风险增加氧化损伤作为与年龄相关的认知下降机制的影响，并且任何研究都没有使用距离张力张量成像（DTI）和神经心理学指数的差异来检查这些危险因素对这些老年人的影响。本研究将使用DTI标量指标和神经心理学评估来比较107名具有和没有SOD2遗传危险因素的人的微结构白质完整性和认知性能的差异。这将是第一项结合神经影像学和神经心理学指数的研究，以研究抗氧化剂防御基因对其他健康老年人样本中脑完整性的影响。