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

中风是美国成人残疾流行的主要原因，中风后认知障碍和痴呆症(PSCID)是主要原因，在健康差距人群中，这一比例高得不成比例。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高度流行的与脑血管疾病(VCID)和阿尔茨海默病(AD/ADRD)或相关痴呆(AD/ADRD)相关的先前存在的脑病理之间的复杂相互作用，仍存在着知识差距。了解与指标性卒中事件相关的调节PSCID风险的因素对于发展PSCID的个性化预测、预防PSCID的有针对性的干预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，我们提出了突发事件卒中认知结果的决定因素和血管对康复的影响(DISCOVERS)，这是一个由临床站点组成的协作网络，可以接触到急性卒中人群，并由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，系统评估PSCID的专业知识和能力。这项建议的首要目标是确定哪些特定的卒中事件亚组导致(或不引起)PSCID，以及哪些额外的人口统计(性别、种族、民族)、临床因素和与急性卒中协同作用而导致或预防PSCID。这项研究的总体科学目标是基于生命过程中暴露于多种血管危险因素、先前存在的微血管和神经退行性病变负担、战略性急性中风损害的影响以及基因组/表观遗传变异的中介作用之间的复杂相互作用，阐明不同美国人群中脑对PSCID的复原力/易感性的机制。我们将通过实施由30个临床站点组成的发现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、统计和资料库核心所描绘的研究战略的指导下，将在症状出现72小时内对8,000名非痴呆缺血性和出血性中风患者进行前瞻性、多中心、观察性、嵌套队列研究，这些患者将被跟踪至少2年，进行一系列认知评估和功能结果评估，亚组接受研究MRI和PET以及全面的基因/基因组和液体生物标记物测试。在一系列系统的、假设驱动的实验中，我们将：1)确定急性中风损伤、既有疾病负担和大脑韧性基线标记物对PSCID的独立和综合影响；2)检验急性中风作为加速AD/ADRD和VCID病理导致PSCID的关键因素的作用；以及3)为临床试验的个别患者结果预测和患者选择开发两种不同的、可推广的个性化医学模型。Discovery将成为一项里程碑式的研究，旨在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.