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

摘要 阿尔茨海默病和相关痴呆(ADRD)通常是神经退化过程的结果 开始于临床诊断前15-20年。尽管这一漫长的亚临床阶段和早期的进展 诊断技术包括脑脊液生物标记物、脑核磁共振成像和正电子发射 断层扫描(PET)意味着没有可扩展的生物标记物来识别患有临床前疾病的个人， 这可能为干预提供最佳时间窗口。具体来说，因为脑部核磁共振和正电子发射计算机断层扫描测试 资源密集型和脑脊液采样是侵入性的，迫切需要基于血液样本的生物标记物， 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)与稳定的核基因组不同，是动态的，积累体细胞。 在整个生命周期内发生突变。线粒体DNA的突变可以由氧化应激诱导并导致衰退 线粒体随着年龄的增长而发挥作用；反过来，功能较差的线粒体会产生更高水平的氧化应激， 导致包括大脑在内的特定器官的慢性炎症和组织损伤。然而，还没有研究表明 研究线粒体DNA突变对ADRD的早期预测作用。我们假设有更高水平的人 血液中mtDNA突变积累越快，认知能力下降越大，临床期ADRD脑 中年期间的影像变化，这些线粒体DNA生物标志物将预测老年人ADRD的诊断。 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(CARDIA)研究。CARDIA是一个多中心、以社区为基础的纵向队列，招募了5115人 黑人和白人青年(平均年龄25岁)，至少每五年跟踪他们一次，并正在准备 在2020/21年度(平均年龄60岁)进行35年(Y35)考试访问，参加人数超过3,000人 预计会回来。我们将使用最先进的深度测序技术来测量mtDNA突变 在第15年、第25年和第35年采集的CARDIA血样中。在目标1中，我们将确定较高水平的 线粒体DNA突变及其随时间的积累与中年认知能力下降有关。在……里面 目的2，我们将确定线粒体dna突变是否与结构、生理和功能有关。 临床前ADRD的MRI表型以及基于MRI的脑加速老化敏感标记物 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高危个体方面的临床应用价值。 未来ADRD在四个年龄较大的队列中进行，这些队列具有大量纵向识别的、临床诊断的 阿德勒。我们的重点是纵向测量血液mtDNA、认知功能和MRI在10年内的变化- 在中年期间，结合其在老年人群中的临床效用的特征，高度 创新。如果成功，我们的研究可能有助于在中年早期启动未来可能的干预并减少 阿尔茨海默病和痴呆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.