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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

中风是美国成年残疾流行病的主要原因，在势力后认知障碍和痴呆症（PSCID）中，中风的贡献很大，其率在健康差异人群中的速度不成比例。尽管PSCID对公共卫生产生了压倒性的影响，但知识差距仍然存在与急性中风事件与高度普遍的与脑血管（VCID）和阿尔茨海默氏病有关的高度普遍存在的脑病理学，或相关痴呆症（AD/ADRD）。了解调节PSCID风险与索引中风事件有关的因素对于开发PSCID的个性化预测，有针对性的干预措施以防止PSCID并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，我们提出了事件中风认知结果的决定因素和对恢复的血管影响（发现），这是一个临床站点的协作网络，该网站可以访问急性中风人群，以及由PSCID领导的PSCID领导的专业知识和能力，由VCID，AD，AD AD，AD，NEACTOKE，健康分布，多人研究和Mutie Contractions和Multi Centressions和Multi-Centeress和Multi-Centeres和Centerser的PSCID团队领导。该提案的总体目标是确定PSCID的中风事件的特定子集原因（或不引起）PSCID以及哪些其他人口统计学（性别，种族，种族），临床因素和合并症，这些因素和合并症与急性中风协同导致或预防PSCID。这项研究的总体科学目标是基于生命过程中的复杂相互作用，暴露于多种血管危险因素，预先存在微血管和神经退行性病理学的伯嫩，策略性急性疾病变异的效果以及基因分类效应的效果。 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 2年，通过序列认知评估和功能结果评估，子集接受了研究MRI和PET，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）确定急性中风病变的独立和综合作用，疾病预先存在的燃烧以及脑弹性在PSCID上的基线标记； 2）研究急性中风作为加速AD/ADRD和VCID病理学的关键因素，导致PSCID； 3）开发两个不同的可推广性个性化医学模型，用于单个患者预测和临床试验的患者选择。发现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，早期恢复的机制以及个性化预防，干预和康复的潜在目标。