DISCOVERY: Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY

发现：中风事件认知结果的决定因素和血管对恢复的影响

• 批准号: 10241401
• 负责人: Steven M Greenberg
• 金额: $ 1405.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10241401
• 关键词: Acute; Address; Adult; Alzheimer' s Disease; Amyloid beta-Protein; Aneurysmal Subarachnoid Hemorrhages; Biological; Biological Markers; Blood; Blood Vessels; Brain; Brain Injuries; Brain Pathology; Caring; Cerebral hemisphere hemorrhage; Characteristics; Classification Scheme; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Cohort Studies; Complex; Dementia; Environmental Risk Factor; Epidemic; Ethnic Origin; Evaluation; Event; Exposure to; Future; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Hemorrhage; Hospitals; Hour; Impaired cognition; Incidence; Individual; Inflammation; Intervention; Intervention Trial; Ischemic Stroke; Knowledge; Leadership; Lesion; Life Cycle Stages; Liquid substance; Location; Magnetic Resonance Imaging; Measurable; Mediating; Methylation; Microvascular Dysfunction; Modeling; Nerve Degeneration; Outcome; Participant; Pathologic; Pathology; Patient Selection; Patients; Perfusion; Population; Population Heterogeneity; Positron-Emission Tomography; Predisposition; Prevention trial; Process; Prospective Studies; Public Health; Race; Recovery; Rehabilitation therapy; Research; Research Priority; Risk; Risk Factors; Role; Series; Serum; Stroke; Structure; Subgroup; Symptoms; Testing; Time; Translations; United States; Variant; acute stroke; base; burden of illness; cerebrovascular; clinical application; clinical research site; cognitive disability; cognitive load; cohort; comorbidity; deep learning; dementia risk; disability; epigenomics; exome sequencing; experience; experimental study; functional outcomes; genome wide association study; health care delivery; health disparity; health disparity populations; imaging biomarker; improved; indexing; individual patient; individualized prevention; morphometry; multiple omics; neuroimaging; non-demented; outcome prediction; patient stratification; personalized medicine; population based; post stroke; post stroke cognitive impairment; prevent; prognostic; prospective; recruit; repository; resilience; response; sex; statistics; stroke event; stroke patient; stroke recovery; tau Proteins; vascular injury; vascular risk factor

Stroke is the major cause of an adult disability epidemic in the US, with a major contribution from post-stroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID’s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent pre-existing brain pathology related to cerebrovascular (VCID) and Alzheimer’s disease, or related dementia (AD/ADRD). Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent PSCID, and informing future clinical trial design. In response to this critical challenge, we propose Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on RecoverY (DISCOVERY), a collaborative network of clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID led by a team of recognized experts in VCID, AD, acute stroke, health disparities, and multi-center research. The overarching goal of this proposal is to determine which specific subsets of stroke events cause (or do not cause) PSCID and which additional demographic (sex, race, ethnicity), clinical factors and comorbidities that synergize with acute stroke to result in or prevent PSCID. The overall scientific objective of this study is to elucidate mechanisms of brain resilience/susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, pre-existing burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic/epigenomic variation. We will achieve this goal by implementing the DISCOVERY Network of 30 clinical sites, which under the leadership of the Administrative Core and guided by the research strategy delineated by the Recruitment and Retention, Statistics, and Repository Cores, will conduct a prospective, multi- center, observational, nested-cohort study of 8,000 nondemented ischemic and hemorrhagic incident stroke patients within 72 hours of symptom onset, who will be followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research MRI and PET and comprehensive genetic/genomic and fluid biomarker testing. In a series of systematic, hypothesis driven experiments we will: 1) identify the independent and combined effect of the acute stroke lesion, pre-existing burden of disease, and baseline markers of brain resilience on PSCID; 2) examine the role of acute stroke as a critical factor in accelerating AD/ADRD and VCID pathology leading to PSCID; and 3) develop two distinct generalizable personalized-medicine models for individual patient outcome prediction and patient selection for clinical trials. DISCOVERY will become a landmark study to unravel the mechanisms of post-stroke cognitive disability, early stroke recovery, and potential targets for personalized prevention, intervention, and rehabilitation.

中风是美国成人残疾流行的主要原因，其中一个主要原因是中风后认知障碍和痴呆（PSCID），在健康差异人群中，其发病率异常高。尽管 PSCID 对公众健康产生了压倒性的影响，但对于急性中风事件与与脑血管 (VCID) 和阿尔茨海默氏病或​​相关痴呆 (AD/ADRD) 相关的高度普遍的既存脑病理学之间的复杂相互作用，仍存在知识差距。了解调节与指数卒中事件相关的 PSCID 风险的因素对于制定 PSCID 的个性化预测、预防 PSCID 的有针对性的干预措施以及为未来的临床试验设计提供信息至关重要。为了应对这一严峻挑战，我们提出了“中风事件认知结果和血管对恢复影响的决定因素”(DISCOVERY)，这是一个临床中心协作网络，可接触急性中风人群，并具有系统评估 PSCID 的专业知识和能力，由 VCID、AD、急性中风、健康差异和多中心研究方面的知名专家团队领导。该提案的总体目标是确定哪些特定的卒​​中事件子集导致（或不引起）PSCID，以及哪些额外的人口统计（性别、种族、民族）、临床因素和合并症与急性卒中协同作用导致或预防 PSCID。本研究的总体科学目标是基于生命过程中多种血管危险因素的暴露、预先存在的微血管和神经退行性病理负担、战略性急性中风病变的影响以及基因组/表观基因组变异的中介作用之间复杂的相互作用，阐明美国不同人群的大脑弹性/对 PSCID 的易感性机制。我们将通过实施由 30 个临床中心组成的 DISCOVERY 网络来实现这一目标，该网络在行政核心的领导下，并以招募和保留、统计和存储核心制定的研究策略为指导，将对 8,000 名非痴呆缺血性和出血性中风患者在症状出现后 72 小时内进行一项前瞻性、多中心、观察性、嵌套队列研究，并对这些患者进行至少2 数年，进行了一系列认知评估和功能结果评估，并对子集进行了研究性 MRI 和 PET 以及全面的遗传/基因组和体液生物标志物测试。在一系列系统的、假设驱动的实验中，我们将：1）确定急性中风病变、预先存在的疾病负担和大脑恢复能力基线标记对 PSCID 的独立和综合影响； 2) 研究急性中风作为加速 AD/ADRD 和 VCID 病理导致 PSCID 的关键因素的作用； 3）开发两种不同的通用个性化医疗模型，用于个体患者结果预测和临床试验患者选择。 DISCOVERY 将成为一项里程碑式的研究，旨在揭示中风后认知障碍、中风早期恢复的机制以及个性化预防、干预和康复的潜在目标。