Validation of Early Prognostic Data for Recovery Outcomes after Stroke for Future, Higher Yield Trials (VERIFY)

目前，美国有700万中风幸存者患有严重残疾，其中一半以上患有残余运动缺陷。运动功能，特别是上肢(UE)的运动功能，对于中风后恢复独立性至关重要。UE的功能在很大程度上依赖于运动皮质及其下行纤维的完整性，统称为皮质运动系统(CMS)。尤其是对于经常受到影响和功能重要的CMS，迫切需要经过验证的、与临床相关的生物标记物来识别生物学上不同的患者亚群。他们的缺席是开发和个性化新的康复疗法的主要障碍，特别是在中风后的早期。运动诱发电位(MEP)对TMS的反应的存在或不存在，以及MRI测量的涉及皮质脊髓束(CST)的急性病变负荷的范围都准备好进行正式验证。此外，预测恢复潜力(PREP)-2预测工具，顺序结合急性临床信息和MEP状态，为多点验证做好准备。我们目前的目标，与StrokeNet的很好地一致，是在第一个大规模、前瞻性、急性的临床、经颅磁刺激(TMS)和MRI测量的数据集中，验证与缺血性中风后90天UE运动结果最生物学相关和最基本的生物标记物。中心假设是，根据TMS测量的CMS功能和MRI测量的CST损伤，患者的UE结局不同。这项名为“未来卒中后早期预后数据的验证，更高收益试验”(VERIFY)的研究将从美国30个地点的657名患者那里收集数据，以解决以下具体目标。目的1：外部验证卒中后7天获得的CMS完整性的TMS和MRI生物标志物与缺血性卒中后90天的UE运动损害结局之间的关系。目的2：外部验证卒中后7天使用的PREP2预测工具，以预测单个缺血性卒中患者90天的UE功能结果。我们对UE运动结果的多维方法是对以前生物标记物研究的创新进步，后者通常仅限于预测一个或两个领域的结果。我们将在世界卫生组织国际功能、残疾和健康分类中确定的三个运动表现领域--损害、功能和使用--全面衡量中风后90天的UE结果。我们的跨学科团队在多中心急性试验、神经生理学、神经成像以及中风恢复和康复方面拥有专业知识。这些结果预计将产生积极影响，因为在急性卒中期间使用生物标记物来识别具有不同90天结果的患者亚组，可以帮助中风恢复试验并为康复决策提供信息。

Currently, 7 million US stroke survivors have significant disability, more than half with residual motor deficits. Motor function, particularly of the upper extremity (UE), is critical for regaining independence after stroke. UE function largely depends on integrity of motor cortex and its descending fibers, collectively termed the corticomotor system (CMS). Validated, clinically relevant biomarkers that identify biologically distinct patient subgroups are critically needed, particularly for the often affected and functionally important CMS. Their absence is a major obstacle to developing and personalizing new recovery therapies, especially in the early days post- stroke. Presence or absence of motor evoked potential (MEP) responses to TMS and extent of MRI-measured acute lesion load involving corticospinal tract (CST) are ready for formal validation. Also, the Predict Recovery Potential (PREP)-2 prediction tool, which sequentially combines acute clinical information and MEP status, is primed for multi-site validation. Our current objective, well-aligned with StrokeNet’s, is to validate the most biologically relevant and primed biomarkers of 90-day UE motor outcomes after ischemic stroke in the first large- scale, prospective, acute dataset of clinical, transcranial magnetic stimulation (TMS), and MRI measures. The central hypothesis is that patients have different UE outcomes depending on CMS function measured with TMS, and on CST injury measured with MRI. The proposed study, “Validation of Early Prognostic Data for Recovery Outcomes after Stroke for Future, Higher Yield Trials” (VERIFY), will collect data from 657 patients at 30 US sites to address the following specific aims. Aim 1: To externally validate the relationships that TMS and MRI biomarkers of CMS integrity acquired < 7 days after stroke have with UE motor impairment outcome at 90 days after ischemic stroke. Aim 2: To externally validate the PREP2 prediction tool used < 7 days after stroke to predict 90-day UE functional outcome for individual patients with ischemic stroke. Our multi-dimensional approach to UE motor outcomes is an innovative advance on previous biomarker studies, which were typically limited to predicting outcomes in one or two domains. We will comprehensively measure UE outcomes 90 days post-stroke in three domains of motor performance —impairment, function, and use — identified by the World Health Organization International Classification of Functioning, Disability and Health. Our cross-disciplinary team has established expertise in multicenter acute trials, neurophysiology, neuroimaging, and stroke recovery and rehabilitation. The results are expected to have a positive impact because biomarkers used in the acute stroke period to identify patient subgroups with distinct day-90 outcomes can aid stroke recovery trials and inform rehabilitation decision-making.