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

无论急性疾病如何，SARS-CoV-2感染后COVID后认知障碍都很常见 严重性。机制知之甚少，限制了我们防止认知能力下降的能力， 一些退伍军人。识别COVID-19后综合征认知能力下降的风险标志物对于 有效的预防和治疗策略。无症状脑梗死（SBI），隐性脑血管事件 与认知障碍风险相关，在COVID-19幸存者中普遍存在。虽然机制是 尚不清楚，但它们似乎是COVID-19中血小板高反应性的缺血性表现。涂层- 血小板是在与胶原蛋白和凝血酶共活化后产生的血小板的强促凝血亚类， 与缺血性卒中风险以及患者脑成像中SBI的存在和数量相关 有血管危险因素的人退伍军人事务部资助的对患有COVID-19的退伍军人的研究的初步工作表明， 增加的包被血小板水平预测90天时的死亡。在幸存者中，SARS-CoV-2感染显著 血小板促凝血功能改变，包被血小板水平急剧持续升高 在康复期。在急性感染期间获得的血小板RNA测序确定了一种相关性 和包被血小板水平之间的关系在同一队列中，39.4%的人每年报告脑雾症状 感染后，58.6%的人在蒙特利尔认知评估中筛查出认知障碍阳性 （莫卡）14个月。重要的是，在急性感染期间测量的平均包被血小板水平是 与未来莫卡评分显著负相关。最后，在一个单独的退伍军人队列中， 认知障碍、SARS-CoV-2感染和年龄是痴呆进展的重要预测因素， 18个月SARS-CoV-2感染前后的脑成像比较显示， 感染后发生的SBI。我们的中心假设，由我们的初步支持， 研究发现，患有COVID-19后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，SBIs在那些包被血小板水平升高的人中加速- CoV-2感染。我们的长期目标是制定预防认知能力下降的策略， 从COVID-19中康复。本申请的目的是确定包被的血小板的作用， COVID-19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将证实和扩展我们的初步研究结果，表明涂层之间的关联- 从COVID-19中恢复后的血小板水平和认知功能障碍。将测定包被血小板水平 在有SARS-CoV-2感染史的退伍军人中， 正式的神经心理学测试和2）MRI上确定的SBI的存在。目标2将描述 目标1中入组后每6个月测量的包被血小板水平之间的纵向关系， 和1）重复神经心理测试中认知能力下降的比率和2）重复测试中SBI的发生率 18个月时的MRI。目的3将验证血小板泛连接蛋白与包被血小板相关的假说。 有COVID-19后综合征认知表现的退伍军人的水平。血小板泛连接蛋白-1和 将使用RT-qPCR和ELISA测量来自受试者的血液中的泛连接蛋白-2 mRNA和蛋白水平 入组Aim 1并与包被血小板水平进行比较。同期非感染对照和历史对照 （大流行前）控制将用于比较目的。考虑到年龄和血管风险 退伍军人的负担，以及SARS-CoV后认知障碍率飙升的重大影响， 2大流行，风险分层和干预策略，以防止COVID后认知能力下降， 潜在的巨大利益。该项目利用血栓前血小板反应性的新范例， 开发一种创新的血液生物标志物方法，如果成功，也将产生新的治疗靶点。

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.