Mitochondrial health, cardiovascular risk, and blood pressure targets in hypertensive adults

项目摘要 阿尔茨海默病和阿尔茨海默病相关性痴呆（AD/ADRD）越来越常见 由于缺乏有效的治疗，神经退行性疾病是致命的和渐进的。 线粒体是细胞内的细胞器，对能量代谢和应激适应至关重要。 实验模型表明，线粒体功能障碍发生在AD/ADRD发病机制的早期， 在AD/ADRD患者的脑组织中观察到线粒体受损。最近 流行病学研究已经将线粒体DNA（mtDNA）数量和质量的畸变与几种 年龄相关的结果，包括心血管疾病，肾脏疾病和死亡的风险，但他们的 与认知功能和痴呆症风险的关联尚未得到很好的确立。 该AD/ADRD补充将利用现有的母公司R 01来研究基于血液的 mtDNA的数量和质量对大脑健康的影响在四个临床实验室的16,000多名参与者中进行了测量。 研究：健康，衰老和身体成分研究（健康ABC，N= 3，075）;生活方式干预和 老年人独立研究（LIFE，N= 1，755）;收缩压干预试验（SPRINT， N= 9，361）和糖尿病心血管风险控制措施试验（雅阁，N= 2，488）。我们的首要目标 将确定通过血液mtDNA拷贝数评估的mtDNA数量是否与以下风险相关： 认知能力下降和痴呆，独立于传统的临床风险因素。我们的第二个目标将评估 通过遗传和获得性mtDNA突变评估的mtDNA质量与认知障碍风险的关系 使用创新方法整合突变负担， 线粒体基因组的区域。这些项目将：1）产生新的假设的关系 线粒体功能障碍与脑健康之间的关系; 2）提高线粒体DNA的数量和质量作为候选人 对促进线粒体健康的AD/ADRD的未来干预措施的反应的生物标志物;以及3）告知 丰富参与者，以用于治疗或预防的靶向治疗的未来临床试验 AD/ADRD。

PROJECT SUMMARY Alzheimer’s disease and Alzheimer’s disease related dementias (AD/ADRD) are increasingly common neurodegenerative conditions that are fatal and progressive due to the lack of effective treatments. Mitochondria are intracellular organelles that are essential for energy metabolism and stress adaptation. Experimental models suggest that mitochondrial dysfunction occurs early in the pathogenesis of AD/ADRD, and damaged mitochondria have been observed in brain tissue of persons with AD/ADRD. Recent epidemiologic studies have linked aberrations in mitochondrial DNA (mtDNA) quantity and quality with several age-related outcomes, including risk of cardiovascular disease, kidney disease, and death, but their associations with cognitive function and dementia risk are not well-established. This AD/ADRD supplement will capitalize on an existing parent R01 to investigate the impact of blood-based measures of mtDNA quantity and quality on brain health among over 16,000 participants of four clinical studies: the Health, Aging and Body Composition Study (Health ABC, N=3,075); the Lifestyle Interventions and Independence for Elders Study (LIFE, N=1,755); the Systolic Blood Pressure Intervention Trial (SPRINT, N=9,361) and the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD, N=2,488). Our first Aim will determine whether mtDNA quantity, assessed by blood mtDNA copy number, is associated with risk of cognitive decline and dementia, independent of traditional clinical risk factors. Our second Aim will evaluate associations of mtDNA quality, assessed by inherited and acquired mtDNA mutations, with risk of cognitive decline and dementia using an innovative approach for integration of mutation burden across functional regions of the mitochondrial genome. These projects will: 1) generate novel hypotheses into the relationships between mitochondrial dysfunction and brain health; 2) advance mtDNA quantity and quality as candidate biomarkers of response to future interventions for AD/ADRD that promote mitochondrial health; and 3) inform enrichment of participants for future clinical trials of mitochondria-targeted therapies for treatment or prevention of AD/ADRD.