Alzheimer’s Disease Related Biomarkers following SARS-CoV-2 Infection

摘要 认知障碍是新冠肺炎急性后遗症患者的主要症状。更老的 个人和那些有痴呆症风险因素的人尤其危险。在我们自己对4491名学生进行的前瞻性研究中 住院的新冠肺炎患者，中位年龄为65岁，606例(14%)出现新的神经功能障碍 (最常见的是脑病)在住院期间，表明该人群患上脑炎的风险很高 阿尔茨海默病或相关痴呆症(AD/ADRD)。在这组人中，48%的患者在认知上 正常的前COVID患者在出院6个月后电话MoCA评分(&lt；18)异常。我们确认了 神经变性/AD的血浆生物标志物包括总tau、p-tau-181、Uch-L1、 新冠肺炎脑病住院患者神经丝轻链和胶质纤维酸性蛋白的变化 与那些没有这样做的人相比。这些生物标志物与IL-6、CRP、铁蛋白和D-二聚体显著相关 炎症指标。我们假设年长的新冠肺炎受试者，特别是那些患有 新的COVID后主观或客观认知异常，将增加血浆和 放射学AD/ADRD生物标志物，以及认知测试异常和 随着时间的推移发展为阿尔茨海默病或相关的痴呆。我们将招收3组老年患者 ≥60年包括：1)SARS-CoV-2阳性对象有新的主客观认知 症状≤-CoV-2感染(冠状病毒+Cog+)2)SARS-CoV-2阳性者无 主客观认知症状≤感染6个月(冠状病毒+冠状病毒-)；3)SARS-CoV-2 阴性，神经学/认知正常的受试者，登记在纽约大学ADRC临床核心(对照)。我们会 排除在SARS-CoV-2感染前有MCI或AD/ADRD病史的个人。我们的主要结果将是 是整体认知/功能轨迹的差异(临床痴呆症评定量表总和 [CDR-SB])进行了为期5年的研究。次要结果将包括：血浆中的差异 和放射学AD/ADRD生物标志物随时间的变化进行比较。目标1：描述和 比较注册时和一段时间内(每12个月)的认知和神经心理异常： COVID+Cog+、COVID+Cog-以及使用CDR-SB和统一数据集版本3的控制。目标2： 神经退行性变、炎症和血脑屏障AD/ADRD相关生物标志物的特征和比较 在COVID+Cog+、COVID+Cog-和对照组中，在登记时和随着时间的推移(每12个月)，功能障碍。 目的3：鉴定和比较COVID+Cog+、COVID+Cog-和COVID+Cog-的AD/ADRD神经影像标志物 在登记时和随时间推移(每18个月)使用3T MRI进行对照。总的来说，这些研究将阐明 COVID相关认知异常的易感风险因素和生物标志物提供机械性洞察 研究潜在的发病机制，并提供关于长期结果的数据，包括AD/ADRD的发展- 相关的障碍。

ABSTRACT Cognitive impairment is a major symptom among patients with post-acute sequelae of COVID-19. Older individuals and those with dementia risk factors are particularly at risk. In our own prospective study of 4,491 hospitalized COVID-19 patients, the median age was 65 years, 606 (14%) developed new neurological disorders (most commonly encephalopathy) during hospitalization, indicating a population at high risk for development of Alzheimer’s Disease or Related-Dementia (AD/ADRD). Of this group, 48% of patients who were cognitively normal pre-COVID had abnormal telephone MoCA scores (<18) 6-months post hospital discharge. We identified significant elevations in plasma biomarkers of neurodegeneration/AD including total tau, p-tau-181, UCH-L1, neurofilament light chain (NfL) and GFAP in hospitalized COVID-19 patients who developed encephalopathy compared to those who did not. These biomarkers significantly correlated with IL-6, CRP, ferritin and D-Dimer measures of inflammation. We hypothesize that older subjects with COVID-19, in particular those with new post-COVID subjective or objective cognitive abnormalities, will have increased plasma and radiographic AD/ADRD biomarkers, and a greater likelihood of abnormal cognitive testing and progression to Alzheimer’s disease or related dementias over time. We will enroll 3 groups of patients aged ≥60 years including: 1) SARS-CoV-2 positive subjects who have a new subjective or objective cognitive symptoms ≤6 month from index SARS-CoV-2 infection (COVID+Cog+) 2) SARS-CoV-2 positive subjects without subjective or objective cognitive symptoms ≤6 month from infection (COVID+Cog-); and 3) SARS-CoV-2 negative, neurologically/cognitively normal subjects, enrolled in the NYU ADRC Clinical Core (Controls). We will exclude individuals with a history of MCI or AD/ADRD prior to SARS-CoV-2 infection. Our primary outcome will be the differences in trajectories of global cognition/function (Clinical Dementia Rating Scale Sum of Boxes [CDR-SB]) over the 5-year study across the 3 groups. Secondary outcomes will include: differences in plasma and radiographic AD/ADRD biomarkers over time compared across the 3 groups. Aim 1: Characterize and compare cognitive and neuropsychological abnormalities at enrollment and over time (every 12 months), among: COVID+Cog+, COVID+Cog- and controls using the CDR-SB, and Uniform Data Set Version 3. Aim 2: Characterize and compare plasma AD/ADRD-related biomarkers of neurodegeneration, inflammation and BBB dysfunction at enrollment and over time (every 12 months), among COVID+Cog+, COVID+Cog- and controls. Aim 3: Characterize and compare AD/ADRD neuroimaging biomarkers in COVID+Cog+, COVID+Cog- and controls at enrollment and over time (every 18 months) using 3T MRI. Collectively, these studies will elucidate predisposing risk factors and biomarkers for COVID-related cognitive abnormalities, provide mechanistic insights into underlying pathogenesis, and provide data on long-term outcomes, including the development of AD/ADRD- related disorders.