Neuroprotective Potential of Vaccination Against SARS-CoV-2 in Nonhuman Primates

该项目将确定新冠肺炎相关脑功能和神经生物学变化的时间和解剖概况，以及已发现的变化是否与阿尔茨海默病(AD)中出现的脑变化有关。虽然新冠肺炎是一种新的冠状病毒疾病，但研究报告称，感染后出现认知缺陷的人的大脑结构和功能会受到显著影响。虽然目前尚不清楚新冠肺炎是否可能是痴呆的致病或加重因素，但最近的一项研究报告称，在住院的无痴呆史的COVID+患者中，与AD相关的外周生物标记物如t-tau、p-tau181、GFAP和NFL均升高。这些标志物与新冠肺炎疾病的严重程度相关(Frontera等人，2021年)。虽然在新冠肺炎患者中看到的许多神经症状在AD患者中也表现出，但目前尚不清楚这些标志物是否在感染前存在或是否因感染而改变。在新冠肺炎疾病过程的早期识别脑功能变化和神经退行性变的神经生物学标记物的能力，将有助于阐明特定大脑区域是否比其他区域更容易受到感染。我们最近采用横断面实验设计，在非人灵长类动物身上应用脑磁图(MEG)测试了一种新型冠状病毒疫苗的有效性，以记录接种和未接种SARS-CoV-2后动物的静息状态(RS)脑功能，发现两组之间的脑功能有显著差异。我们将在接种疫苗和感染之前将这些发现扩展到记录RS和感觉门控(SG)的大脑功能。基线大脑活动将证实我们在横断面研究中检测到的任何变化在接种疫苗和感染之前的基线是否存在。我们将测量接种了现代RNA疫苗或一种新型补骨脂素灭活病毒以及随后用活病毒攻击后的RS和SG的脑功能。这将使我们能够在感染过程的早期确定COVID感染引起的大脑活动变化的时间和解剖学特征。我们还将收集包括脑脊液和感染前和感染后的血液在内的生物样本，以跟踪由冠状病毒感染引起的神经退行性疾病的外周生物标志物的水平。我们将确定RS和SG大脑功能的变化，以关联特定大脑区域的变化，这些变化是认知缺陷自我报告的基础，包括COVID+患者在恢复期报告的与“长COVID”相关的困惑。我们将利用一个简单的双手协调任务作为一种行为测量，将大脑功能的变化与神经退行性变的标志联系起来。在感染和接种疫苗之前，然后在疾病过程的早期，能够捕获大脑功能、行为指标和生物标记物的基线测量的能力，将提供有价值的洞察，了解哪些大脑区域和神经退化标记物可能受到疾病过程的最大影响。

This project will determine the temporal and anatomic profile of COVID-19 related changes in brain function and neurobiology and whether identified changes relate to brain alterations seen in Alzheimer’s Disease (AD). Although COVID-19 is a novel coronavirus disease, studies have reported that brain structure and function is significantly impacted in humans who become infected and subsequently exhibit cognitive deficits. While it is unclear whether COVID-19 may be a causative or exacerbating factor for dementia, a recent study reported that AD-associated peripheral biomarkers such as t-tau, p-tau181, GFAP, and NfL were elevated in hospitalized COVID+ patients without a history of dementia. These markers correlated with severity of COVID-19 illness (Frontera et al., 2021). While many of the neurological symptoms seen in COVID-19 patients are also exhibited in AD patients, it remains unclear whether any of the markers were present prior to infection or changed because of infection. The ability to identify changes in brain function and neurobiological markers of neurodegeneration early in the COVID-19 disease process would help illuminate whether specific brain regions are more vulnerable than others to infection. Using a cross-sectional experimental design, we recently applied magnetoencephalography (MEG) in nonhuman primates to test the efficacy of a novel COVID vaccine to record resting state (RS) brain function in vaccinated and unvaccinated animals after infection with SARS-CoV-2 and found significant differences in brain function between the groups. We will extend these findings in vervet monkeys to record RS and sensory gating (SG) brain function PRIOR to vaccination and infection. Baseline brain activity will confirm whether any of the changes we detected in the cross-sectional study exist at baseline prior to vaccination and infection. We will measure RS and SG brain function AFTER vaccination with the Moderna mRNA vaccine or a novel psoralen inactivated virus and subsequent challenge with live virus. This will allow us to identify the temporal and anatomical profile of changes in brain activity that result from COVID infection early in the infection process. We will also collect biological samples including CSF and blood pre- and post-infection to track levels of peripheral biomarkers of neurodegenerative diseases that result from COVID infection. We will identify changes in RS and SG brain function to correlate changes in specific brain regions that underlie self-reports of cognitive deficits including ‘foggy brain’ and confusion related to “long COVID” that COVID+ patients report during the recovery period. We will utilize a simple bimanual coordination task as a behavioral measure with which to correlate changes in brain function and markers of neurodegeneration. The ability to capture baseline measures of brain function, behavioral measures and biomarkers prior to infection and vaccination and then early in the disease process will provide valuable insight into which brain regions and neurodegenerative markers may be most impacted by the disease process.