Procoagulant platelets as biomarkers for post-COVID-19 cognitive decline

无论是急性疾病，SARS-CoV-2感染后认知障碍都很常见 严肃性。机制知之甚少，限制了我们防止认知能力下降的能力 退伍军人人数。识别新冠肺炎后综合征认知功能下降的风险标记物对 有效的防治策略。无症状性脑梗塞(SBI)，隐匿性脑血管事件 与认知功能障碍的风险相关，在新冠肺炎幸存者中普遍存在。尽管机械装置是 尚不清楚，有可能是新冠肺炎中血小板高反应性的缺血性表现。涂覆的- 血小板，与胶原和凝血酶共激活后产生的一种强促凝血的亚群， 与缺血性卒中风险以及患者脑成像上SBI的存在和数量有关 有血管危险因素。退伍军人管理局资助的新冠肺炎退伍军人研究的初步工作显示 包被血小板水平升高可预测90天内死亡。在幸存者中，SARS-CoV-2感染显著 改变了血小板促凝血潜能，并注意到包被的血小板水平急剧和持续增加 在疗养期。在急性感染期间获得的血小板的RNA测序证实了一种关联 在膜联蛋白和包被的血小板水平之间。在同一队列中，39.4%的人报告一年有脑雾症状 感染后，58.6%的人在蒙特利尔认知评估中筛查出认知障碍 (MOCA)在14个月时。重要的是，在急性感染期间测得的平均包被血小板水平是 与未来的MoCA评分呈显著负相关。最后，在另一组患有轻度疾病的退伍军人中 认知障碍、SARS-CoV-2感染和年龄是进展为痴呆的重要预测因素 18个月。SARS-CoV-2感染前后的脑成像对比显示新的 进展者在感染后发生SBIs。我们的核心假设，得到了我们初步的支持 研究结果是，患有后新冠肺炎综合征的退伍军人的认知功能障碍是由积累介导的 在SARS期间和之后被包裹的血小板水平升高的人中，SBIs的速度会加快- 冠状病毒2型感染。我们的长期目标是开发预防认知能力下降的策略 从新冠肺炎中恢复过来。目前应用的目的是确定包被的血小板作为 新冠肺炎康复后认知功能障碍和SBI的预测因素。三个具体目标将考验我们的 假设。目标1将确认并扩展我们的初步发现，表明涂层- 新冠肺炎康复后血小板水平与认知功能障碍的关系包被的血小板水平将被检测 有SARS-CoV-2感染史的退伍军人，以及1)认知障碍与 正式的神经心理测试和2)MRI上是否存在SBI。目标2将描述 在目标1注册后每6个月测量一次的包被血小板水平之间的纵向关系， 1)重复神经心理测试中认知功能减退的比率；2)重复测试中认知功能障碍的发生率 18个月时行核磁共振检查。AIM 3将验证血小板膜联蛋白与包被血小板相关的假设 具有后新冠肺炎综合征认知表现的退伍军人的水平。血小板膜联蛋白-1和 将使用RT-qPCR和ELISA法检测受试者血液中PAnnexin-2的mRNA和蛋白水平 登记入AIM 1，并与包被血小板水平进行比较。并发非感染控制和历史记录 (大流行前)控制措施将用于比较目的。考虑到高龄和血管风险 退伍军人的负担，以及SARS冠状病毒之后认知损害率飙升的实质性影响- 2大流行、风险分层和预防COVID后认知下降的干预策略具有 潜在的巨大利益。该项目利用血栓形成前血小板反应性的新范例 开发一种创新的血液生物标记物方法，如果成功，还将产生新的治疗目标。

Post-COVID cognitive impairment is common after SARS-CoV-2 infection regardless of acute disease severity. Mechanisms are poorly understood, limiting our ability to prevent cognitive decline for a growing number of veterans. Identifying markers of risk for cognitive decline in post-COVID-19 syndrome is crucial for effective prevention and treatment strategies. Silent brain infarctions (SBIs), covert cerebrovascular events associated with risk of cognitive impairment, are prevalent in COVID-19 survivors. Although mechanisms are unclear, it is plausible that they are ischemic manifestations of platelet hyperreactivity in COVID-19. Coated- platelets, a strongly procoagulant subset of platelets produced after co-activation with collagen and thrombin, are associated with ischemic stroke risk and the presence and number of SBIs on brain imaging from patients with vascular risk factors. Preliminary work from VA funded research in veterans with COVID-19 showed that increased coated-platelet levels predicted death at 90 days. In survivors, SARS-CoV-2 infection significantly altered platelet procoagulant potential, with a sharp and sustained increase in coated-platelet levels noted during convalescence. RNA sequencing in platelets obtained during acute infection identified an association between pannexins and coated-platelet levels. In the same cohort, 39.4% reported brain fog symptoms a year after infection, and 58.6% screened positive for cognitive impairment on the Montreal Cognitive Assessment (MoCA) at 14 months. Importantly, mean coated-platelet levels measured during acute infection were significantly inversely associated with future MoCA score. Lastly, in a separate cohort of veterans with mild cognitive impairment, SARS-CoV-2 infection and age were significant predictors of progression to dementia at 18 months. Comparison of brain imaging before and after SARS-CoV-2 infection showed accumulation of new SBIs following infection in those who progressed. Our central hypothesis, supported by our preliminary findings, is that cognitive dysfunction in veterans with post-COVID-19 syndrome is mediated by accumulation of SBIs, which is accelerated among those whose coated-platelet levels are elevated during and after SARS- CoV-2 infection. Our long-range objective is to develop strategies for preventing cognitive decline after recovery from COVID-19. The objective of the current application is to determine the role of coated-platelets as predictors of cognitive dysfunction and SBI after recovery from COVID-19. Three specific aims will test our hypotheses. Aim 1 will confirm and extend our preliminary findings showing an association between coated- platelet levels and cognitive dysfunction after recovery from COVID-19. Coated-platelet levels will be assayed in veterans with a history of SARS-CoV-2 infection, and the association between 1) cognitive impairment on formal neuropsychological testing and 2) the presence of SBI on MRI determined. Aim 2 will characterize the longitudinal relationship between coated-platelet levels measured every 6 months after enrollment in Aim 1, and 1) the rate of cognitive decline on repeat neuropsychological testing and 2) the incidence of SBI on repeat MRI at 18 months. Aim 3 will test the hypothesis that platelet pannexins are associated with coated-platelet levels in veterans with cognitive manifestations of post-COVID-19 syndrome. Platelet pannexin-1 and pannexin-2 mRNA and protein levels will be measured using RT-qPCR and ELISA in blood from subjects enrolled in Aim 1 and compared with coated-platelet levels. Concurrent non-infected controls and historical (pre-pandemic) controls will be used for comparison purposes. Considering the older age and vascular risk burden among veterans, and the substantial impact of soaring cognitive impairment rates after the SARS-CoV- 2 pandemic, risk stratification and intervention strategies to prevent post-COVID cognitive decline have the potential for enormous benefit. This project utilizes a new paradigm of prothrombotic platelet reactivity to develop an innovative blood biomarker approach that will also yield novel treatment targets if successful.