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

中风是美国成年人残疾流行的主要原因，中风后认知障碍和痴呆（PSCID）是主要原因，在健康差异较大的人群中，其发病率高得不成比例。尽管PSCID对公共卫生产生了巨大的影响，但关于急性卒中事件与高度流行的与脑血管（VCID）和阿尔茨海默病或相关痴呆（AD/ADRD）相关的预先存在的脑病理之间的复杂相互作用，存在知识空白。了解与指数脑卒中事件相关的PSCID风险调节因素对于PSCID的个性化预测、有针对性的干预措施预防PSCID以及为未来的临床试验设计提供信息至关重要。为了应对这一关键挑战，我们提出了卒中认知结果决定因素和血管对恢复的影响（DISCOVERY），这是一个由VCID， AD，急性卒中，健康差异和多中心研究领域公认的专家团队领导的临床站点协作网络，可以访问急性卒中人群和PSCID系统评估的专业知识和能力。该提案的总体目标是确定哪些特定的卒中事件引起（或不引起）PSCID，以及哪些额外的人口统计学（性别、种族、民族）、临床因素和合并症与急性卒中协同导致或预防PSCID。本研究的总体科学目标是阐明基于生命过程中多种血管危险因素暴露、微血管和神经退行性病理的预先负担、战略性急性脑卒中病变的影响以及基因组/表观基因组变异的介导作用之间的复杂相互作用，不同美国人群对PSCID的脑恢复力/易感性机制。我们将通过实施由30个临床站点组成的DISCOVERY网络来实现这一目标，该网络在行政核心的领导下，在招募和保留、统计和存储库核心所描述的研究策略的指导下，将对8,000名症状出现72小时内的非痴呆性缺血性和出血性卒中患者进行前瞻性、多中心、观察性、巢式队列研究，这些患者将被随访至少2年。进行一系列的认知评估和功能结果评估，并对亚组进行MRI和PET研究以及全面的遗传/基因组和液体生物标志物测试。在一系列系统的、假设驱动的实验中，我们将：1)确定急性卒中病变、既往疾病负担和脑恢复力基线标志物对PSCID的独立和联合影响；2)研究急性卒中作为加速AD/ADRD和VCID病理导致PSCID的关键因素的作用；3)开发两种不同的可推广的个性化药物模型，用于个体患者预后预测和临床试验患者选择。DISCOVERY将成为一项里程碑式的研究，揭示脑卒中后认知障碍、早期脑卒中恢复的机制，以及个性化预防、干预和康复的潜在目标。

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.