Biological Aging, the Proteome and Cognitive Resilience among Ischemic Stroke Survivors

项目总结/摘要 到目前为止，还没有有效的治疗认知障碍和痴呆症的方法。理解机制 促进认知恢复力和延迟血管性痴呆，特别是在高危人群中， 延长认知健康寿命的免费方法。缺血性中风幸存者代表了越来越多的 在美国的老年人中，老年痴呆症和相关疾病的风险非常高 痴呆症（ADRD）。除了脑梗死的潜在负担，生物因素和分子 引起认知恢复力和中风后痴呆发作时间差异的机制仍然存在， 不清楚生理层面的生物老化过程与年龄相关疾病的风险有关 包括认知、中风和痴呆。然而，人们对生物学上的差异仍然知之甚少， 衰老可以解释卒中后ADRD的变异性。在分子水平上，在公认的衰老生物学中 蛋白质组在蛋白质控制细胞功能中起着核心作用，可以帮助识别新的 治疗目标，并与衰老的认知轨迹相关。然而，这些协会 仅限于尸检评估，尚未在可触及组织（如外周）中进行评估 血液和脆弱人群，如缺血性中风幸存者。这件事的直接目标是 应用是评估生物老化和分子蛋白质组学机制在认知恢复中的作用 缺血性卒中幸存者中血管性痴呆的发病时间。我将测量生物老化 使用从心血管健康研究（CHS）的血液测试中收集的生理生物标志物数据， 鹿特丹研究（RS）。然后，我将把这些表型与最先进的临床确定相结合， 中风和认知超过15年的随访，以评估生物老化差异在认知功能中的作用。 中风后的恢复力我将利用基于适体的蛋白质组学平台来识别分子网络， 卒中幸存者中生物老化、认知恢复力和血管性痴呆的细胞水平途径 健康的对照。我将评估结合生物老化、蛋白质组学和临床中风数据的算法 使用监督机器预测认知弹性和特定领域的认知结果 学习我很适合进行这项研究的基础上，1）我以前的流行病学研究经验， 中风和衰老，2）优秀的指导团队，以确保这项研究是最高质量的;和3） 优秀的研究环境，以支持我的职业发展。拟议的培训和研究将 帮助我获得分子流行病学，高维数据和机器学习方面的实质性新技能 在分子流行病学和ADRD的交叉点建立一个独立的职业生涯， 弱势群体。该项目将使生物学和分子生物学领域的前景前所未有。 认知弹性机制，以发现新的生物标志物和治疗靶点，以保护认知能力 缺血性中风幸存者中老年人的健康状况。

Project Summary/Abstract To date, there is no effective treatment for cognitive impairment and dementia. Understanding mechanisms that promote cognitive resilience and delay vascular dementia, particularly in high-risk populations, is a complimentary approach to extend cognitive health span. Ischemic stroke survivors represent a growing population among older adults in the U.S. and a very high-risk group for Alzheimer’s disease and related dementias (ADRD). Beyond the underlying burden of brain infarction, biological factors and molecular mechanisms that elicit differences in cognitive resilience and timing of dementia onset after stroke, remain unclear. Biological aging processes at the physiological level are associated with risk of age-related diseases including cognition, stroke and dementia. However, it remains poorly understood if differences in biological aging explain variabilities in post-stroke ADRD. At the molecular level, among recognized aging biology mechanisms, the proteome plays a central role as proteins control cell functions, can help identify novel therapeutic targets and are associated with cognitive trajectories in aging. However, these associations were restricted to post-mortem assessments and have not been assessed in accessible tissue such as peripheral blood and in vulnerable populations such as ischemic stroke survivors. The immediate objective of this application is to assess the role of biological aging and molecular proteomic mechanisms in cognitive resilience and timing of onset of vascular dementia among ischemic stroke survivors. I will measure biological aging using physiological biomarkers data collected from blood tests in the Cardiovascular Health Study (CHS) and the Rotterdam Study (RS). I will then integrate these phenotypes with state-of-the art clinical ascertainment of stroke and cognition over >15 years of follow-up to assess the role of biological aging differences in cognitive resilience after stroke. I will leverage an Aptamer-based proteomic platform to identify molecular networks and cellular-level pathways of biological aging, cognitive resilience and vascular dementia among stroke survivors and healthy controls. I will evaluate algorithms of combined biological aging, proteomic and clinical stroke data for prognosis of cognitive resilience and domain-specific cognitive outcomes using supervised machine learning. I am well suited to perform this research based on 1) my prior research experience in epidemiology of stroke and aging, 2) the outstanding mentoring team to ensure this research is of highest quality; and 3) the exceptional research environment to support my career development. The proposed training and research will help me acquire substantive new skills in molecular epidemiology, high-dimensional data and machine learning to establish an independent career as a researcher at the intersection of molecular epidemiology and ADRD in vulnerable populations. This project will enable unprecedented perspectives on biological and molecular mechanisms of cognitive resilience to uncover novel biomarkers and therapeutic targets to protect cognitive health in old age among ischemic stroke survivors.