Blood mitochondrial DNA biomarkers of midlife cognitive decline and adverse brain imaging changes - A longitudinal investigation in the CARDIA population‐based cohort study

总结 阿尔茨海默病和相关痴呆症（ADRD）通常是神经退行性过程的结果 在临床诊断前开始15-20年。尽管这是一个漫长的亚临床阶段， 诊断技术，包括脑脊液（CSF）生物标志物、脑MRI和正电子发射 断层扫描（PET）测量没有可扩展的生物标志物来识别具有临床前疾病的个体， 这可能为干预提供最佳时间窗口。具体来说，因为大脑MRI和PET测试是 资源密集型和CSF采样是侵入性的，迫切需要基于血液样品的生物标志物， 即使在缺乏高度专业化技术的中心也可以非侵入性地收集。 线粒体基因组（mtDNA），不像稳定的核基因组，是动态的，积累体细胞 在生命周期中的突变。线粒体DNA的突变可由氧化应激诱导，并导致细胞凋亡率下降。 随着年龄的增长，线粒体功能下降;反过来，功能较弱的线粒体产生更高水平的氧化应激， 其在包括脑的特定器官中诱导慢性炎症和组织损伤。然而，没有研究表明， 研究了mtDNA突变作为ADRD的早期预测因子。我们假设高水平的个体 血液mtDNA突变的更快积累会导致更大的认知能力下降和临床前ADRD脑 这些线粒体DNA生物标志物将预测老年人的ADRD诊断。 我们将通过利用NHLBI资助的年轻人冠状动脉风险发展来检验我们的假设。 成人（心脏）研究。CARDIA是一项多中心、以社区为基础的纵向队列研究，招募了5，115名 黑人和白色年轻人（平均年龄25岁），至少每五年随访一次， 在2020/21学年（平均年龄60岁）进行35年级的考试，届时将有超过3，000名参加者 预计将返回。我们将使用最先进的深度测序技术来测量mtDNA突变 在Y15、Y25和Y35采集的CARDIA血液样本中。在目标1中，我们将确定 mtDNA突变及其随时间的积累与中年认知能力的下降有关。在 目的2，我们将确定mtDNA突变是否与结构，生理和功能相关， 临床前ADRD的MRI表型以及基于MRI的加速脑老化敏感标志物 和临床前ADRD由我们的团队使用现代机器学习技术构建。最后在 目的3，我们将测试这些mtDNA突变生物标志物在识别个体中的临床效用， 在四个年龄较大的队列中，有大量的纵向确定的，临床诊断的 ADRD。我们的重点是纵向测量血液mtDNA，认知功能和MRI变化超过10- 在中年期间，结合其在老年人群中的临床效用的特征， 新颖啊如果成功的话，我们的研究可能有助于在中年早期启动未来可能的干预措施， AD和痴呆症的公共卫生和医疗负担。

SUMMARY Alzheimer’s disease and related dementias (ADRDs) are typically the result of neurodegenerative processes that begin 15-20 years before clinical diagnosis. Despite this lengthy subclinical phase and advances in early diagnostic technologies including cerebrospinal fluid (CSF) biomarkers, brain MRIs, and positron emission tomography (PET) measures there are no scalable biomarkers to identify individuals with preclinical disease, which may offer the best time window for intervention. Specifically, because brain MRI and PET tests are resource-intensive and CSF sampling is invasive, there is urgent need for biomarkers based on blood samples, which can be non-invasively collected even in centers lacking highly specialized technology. The mitochondrial genome (mtDNA), unlike the stable nuclear genome, is dynamic and accumulates somatic mutations over the lifespan. Mutations in the mtDNA can be induced by oxidative stress and lead to declining mitochondrial function as we age; in turn, less functional mitochondria generate higher levels of oxidative stress, which induces chronic inflammation and tissue injury in specific organs including the brain. Yet, no study has investigated mtDNA mutations as early predictors of ADRD. We hypothesize that individuals with higher levels and faster accumulation of blood mtDNA mutations have greater cognitive decline and preclinical ADRD brain imaging changes during midlife, and that these mtDNA biomarkers will predict ADRD diagnosis in older adults. We will test our hypotheses by leveraging the NHLBI-funded Coronary Artery Risk Development In young Adults (CARDIA) study. CARDIA is a multicenter, community-based, longitudinal cohort that recruited 5,115 black and white young adults (mean age 25 years), followed them up at least every five years, and is preparing to conduct its examination Year 35 (Y35) visit in 2020/21 (mean age 60 years) when over 3,000 participants are expected to return. We will use state-of-the-art deep sequencing technology to measure mtDNA mutations in CARDIA blood samples collected at Y15, Y25, and Y35. In Aim 1, we will determine whether higher levels of mtDNA mutations and their accumulation over time are associated with greater cognitive decline in midlife. In Aim 2, we will determine whether mtDNA mutations are associated with structural, physiological, and functional MRI phenotypes of preclinical ADRD as well as with sensitive MRI-based markers of accelerated brain aging and preclinical ADRD constructed by our team using contemporary machine learning techniques. Finally, in Aim 3, we will test the clinical utility of these mtDNA mutation biomarkers in identifying individuals at risk of future ADRD in four older cohorts that have large numbers of longitudinally identified, clinically-diagnosed ADRD. Our focus on longitudinal measures of blood mtDNA, cognitive function, and MRI changes over a 10- year period during midlife, combined with characterization of their clinical utility in older populations, is highly innovative. If successful, our study may help initiate possible future interventions in early midlife and reduce the public health and medical burden of AD and dementia.