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

卒中是美国成人残疾流行病的主要原因，卒中后认知障碍和痴呆（PSCID）是主要原因，其发病率在健康差异人群中非常高。尽管PSCID对公共卫生产生了压倒性的影响，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，存在知识差距。了解与指数卒中事件相关的调节PSCID风险的因素对于制定PSCID的个性化诊断、预防PSCID的靶向干预措施以及为未来的临床试验设计提供信息至关重要。为了应对这一关键挑战，我们提出了卒中认知结局和血管对恢复影响的决定因素（DISCOVERY），这是一个由临床站点组成的协作网络，可接触急性卒中人群，并具有系统评估PSCID的专业知识和能力，由VCID，AD，急性卒中，健康差异和多中心研究方面的公认专家团队领导。本提案的总体目标是确定卒中事件的哪些特定子集导致（或不导致）PSCID，以及哪些其他人口统计学（性别、人种、种族）、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阐明不同美国人群中PSCID的脑弹性/易感性机制，其基于多种血管风险因素的生命过程暴露、微血管和神经退行性病理学的既存负担、战略性急性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。我们将通过实施由30家临床研究中心组成的DISCOVERY网络来实现这一目标，该网络将在行政核心的领导下，在招募和保留、统计和储存库核心所描述的研究策略的指导下，对8家临床研究中心进行前瞻性、多中心、观察性、嵌套队列研究，000例症状发作后72小时内发生的非痴呆性缺血性和出血性卒中患者，将对这些患者进行至少2年的随访，并进行系列认知评价和功能结局评估，亚组接受研究MRI和PET以及全面的遗传/基因组和流体生物标志物测试。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、预先存在的疾病负担和脑弹性的基线标志物对PSCID的独立和联合作用; 2）检查急性卒中作为加速AD/ADRD和VCID病理导致PSCID的关键因素的作用;以及3）开发两种不同的可推广的个性化医学模型，用于个体患者结果预测和用于临床试验的患者选择。DISCOVERY将成为一项具有里程碑意义的研究，以揭示中风后认知障碍，早期中风恢复的机制，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.