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

中年认知能力下降和不良脑成像变化的血液线粒体 DNA 生物标志物 - 基于 CARDIA 人群的队列研究的纵向调查

• 批准号: 10619552
• 负责人: Andrea Baccarelli
• 金额: $ 76.33万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619552
• 关键词: Acceleration; Address; Age; Aging; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Biological Markers; Blood; Blood specimen; Brain; Brain imaging; Cerebrospinal Fluid; Chronic; Clinical; Cognitive; Cohort Studies; Communities; Coronary Artery Risk Development in Young Adults Study; Data; Dementia; Development; Diagnosis; Disease; Elderly; Environmental Risk Factor; Framingham Heart Study; Functional Magnetic Resonance Imaging; Funding; Future; Genome; Goals; Health; Impaired cognition; Individual; Inflammation; Intervention; Investigation; Link; Longevity; Longitudinal cohort; Machine Learning; Magnetic Resonance Imaging; Measures; Medical; Mitochondria; Mitochondrial DNA; Mutation; National Heart, Lung, and Blood Institute; Nerve Degeneration; Nuclear; Older Population; Organ; Oxidative Stress; Oxidative Stress Induction; Participant; Patients; Pattern; Phase; Phenotype; Physiological; Positron-Emission Tomography; Process; Public Health; Research; Research Design; Research Personnel; Resources; Risk; Role; Sampling; Solid; Somatic Mutation; Techniques; Technology; Testing; Time; Trans-Omics for Precision Medicine; United States National Institutes of Health; Visit; Work; age related; aged; aging brain; biomarker identification; blood-based biomarker; brain magnetic resonance imaging; cerebral atrophy; clinical diagnosis; clinical predictors; clinical risk; cognitive function; cognitive testing; cohort; critical period; deep sequencing; dementia risk; design; diagnostic technologies; epigenome; experience; follow-up; genome sequencing; innovation; insight; middle age; mitochondrial DNA mutation; mitochondrial genome; novel; personalized intervention; population based; pre-clinical; pre-clinical assessment; predictive marker; prevent; programs; prospective; recruit; tissue injury; tool; whole genome; young adult

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.

概括 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 临床诊断前 15-20 年开始。尽管有漫长的亚临床阶段和早期进展 诊断技术，包括脑脊液 (CSF) 生物标志物、脑部 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患有临床前疾病的个体， 这可能提供最佳的干预时间窗口。具体来说，因为脑部 MRI 和 PET 测试 资源密集型且脑脊液采样具有侵入性，迫切需要基于血液样本的生物标志物， 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这些数据。 线粒体基因组（mtDNA）与稳定的核基因组不同，是动态的并积累体细胞 生命周期中的突变。氧化应激可诱发线粒体 DNA 突变，导致细胞衰老 随着年龄的增长线粒体功能；反过来，功能较少的线粒体会产生更高水平的氧化应激， 它会引起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 研究 mtDNA 突变作为 ADRD 的早期预测因子。我们假设具有较高水平的个体 血液 mtDNA 突变积累速度更快，导致认知能力下降更大，并且出现临床前 ADRD 脑损伤 中年时期的影像学变化，这些 mtDNA 生物标志物将预测老年人 ADRD 的诊断。 我们将利用 NHLBI 资助的年轻人冠状动脉风险开发项目来检验我们的假设 成人（CARDIA）研究。 CARDIA 是一个多中心、基于社区的纵向队列，招募了 5,115 名患者 黑人和白人年轻人（平均年龄 25 岁），至少每五年对他们进行一次随访，并正在准备 在 2020/21 年（平均年龄 60 岁）进行 35 年级（Y35）访问检查，届时参与者超过 3,000 人 预计将返回。我们将使用最先进的深度测序技术来测量线粒体DNA突变 在第 15 年、第 25 年和第 35 年收集的 CARDIA 血液样本中。在目标 1 中，我们将确定更高水平的 线粒体 DNA 突变及其随时间的积累与中年认知能力的严重下降有关。在 目标 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 的敏感大脑加速老化标志物 以及我们团队使用当代机器学习技术构建的临床前 ADRD。最后，在 目标 3，我们将测试这些 mtDNA 突变生物标志物在识别有风险的个体方面的临床效用 四个较老的队列中未来 ADRD 的情况有大量纵向识别、临床诊断 ADRD。我们专注于血液 mtDNA、认知功能和 MRI 变化的纵向测量 10 年来的变化 中年期间的一年，结合其在老年人群中的临床效用特征，是高度 创新的。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措施，并减少 AD 和痴呆症的公共卫生和医疗负担。

项目成果

Marijuana use and DNA methylation-based biological age in young adults.

• DOI: 10.1186/s13148-022-01359-8
• 发表时间: 2022-10-26
• 期刊: Clinical epigenetics
• 影响因子: 5.7

Associations between GrimAge acceleration and pulmonary function in the Coronary Artery Risk Development in Young Adults (CARDIA) study.

• DOI: 10.2217/epi-2023-0164
• 发表时间: 2023-09
• 期刊: Epigenomics
• 影响因子: 3.8
• 作者: B. Joyce;Xuefen Chen;Tao Gao;Yinan Zheng;D. Nannini;Lei Liu;B. Henkle;Ravi Kalhan;G. Washko-G.-Was

Epigenetic Aging Is Associated With Measures of Midlife Muscle Volume and Attenuation in CARDIA Study.

CARDIA 研究中表观遗传衰老与中年肌肉体积和衰减的测量相关。

• DOI: 10.1093/gerona/glad261
• 发表时间: 2024
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Gao,Tao;Zheng,Yinan;Joyce,BrianT;Kho,Minjung;Terry,JamesG;Wang,Jun;Nannini,Drew;Carr,JohnJeffrey;Nair,Sangeeta;Zhang,Kai;Zhao,Wei;JacobsJr,DavidR;Schreiner,PamelaJ;Greenland,Philip;Lloyd-Jones,Donald;Smith,JenniferA

Genome-wide DNA methylation association study of recent and cumulative marijuana use in middle aged adults.

• DOI: 10.1038/s41380-023-02106-y
• 发表时间: 2023-06
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Nannini, Drew R. R.;Zheng, Yinan;Joyce, Brian T.;Kim, Kyeezu;Gao, Tao;Wang, Jun;Jacobs, David R. R.;Schreiner, Pamela J. J.;Yaffe, Kristine;Greenland, Philip;Lloyd-Jones, Donald M. M.;Hou, Lifang
• 通讯作者: Hou, Lifang

Inequalities in urban greenness and epigenetic aging: Different associations by race and neighborhood socioeconomic status.

• DOI: 10.1126/sciadv.adf8140
• 发表时间: 2023-06-28
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Kim, Kyeezu;Joyce, Brian T. T.;Nannini, Drew R. R.;Zheng, Yinan;Gordon-Larsen, Penny;Shikany, James M. M.;Lloyd-Jones, Donald M. M.;Hu, Ming;Nieuwenhuijsen, Mark J. J.;Vaughan, Douglas E. E.;Zhang, Kai;Hou, Lifang
• 通讯作者: Hou, Lifang