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

摘要 认知障碍是COVID-19急性期后后遗症患者的主要症状。老年 个别人士和有痴呆症风险因素的人士尤其容易患上痴呆症。在我们对4，491人的前瞻性研究中， 住院COVID-19患者，中位年龄为65岁，606（14%）出现新的神经系统疾病 (most通常是脑病），表明人群处于发展的高风险， 阿尔茨海默病或相关性痴呆（AD/ADRD）。在这组患者中，48%的患者 正常的COVID前患者在出院后6个月的电话MoCA评分异常（<18）。我们确定 神经变性/AD的血浆生物标志物显著升高，包括总tau、p-tau-181、UCH-L1， 发生脑病的住院COVID-19患者的神经丝轻链（NfL）和GFAP 与那些没有的人相比。这些生物标志物与IL-6、CRP、铁蛋白和D-二聚体显著相关 炎症的测量。我们假设患有COVID-19的老年受试者，特别是那些 新的COVID后主观或客观认知异常，将增加血浆和 影像学AD/ADRD生物标志物，以及认知测试异常的可能性更大， 随着时间的推移发展为阿尔茨海默病或相关痴呆症。我们将招募3组患者，年龄 ≥ 60岁，包括：1）有新的主观或客观认知障碍的SARS-CoV-2阳性受试者 症状≤ 6个月从索引SARS-CoV-2感染（COVID + Cog+）2）SARS-CoV-2阳性受试者没有 感染后6个月内出现主观或客观认知症状（COVID + Cog-）; 3）SARS-CoV-2 阴性、神经学/认知正常受试者，入组NYU ADRC临床核心（对照）。我们将 排除在SARS-CoV-2感染前有MCI或AD/ADRD病史的个体。我们的主要成果将 是整体认知/功能轨迹的差异（临床痴呆评定量表方框总和 [CDR-SB]）。次要结局将包括：血浆 以及3组间随时间推移的放射学AD/ADRD生物标志物。目标1：表征和 比较入组时和随时间推移（每12个月）的认知和神经心理学异常，包括： 使用CDR-SB和统一数据集版本3的COVID + Cog+、COVID + Cog-和对照。目标二： 表征并比较神经变性、炎症和BBB的血浆AD/ADRD相关生物标志物 在COVID + Cog+、COVID + Cog-和对照组中，在入组时和随时间推移（每12个月）的功能障碍。 目的3：表征和比较COVID + Cog+、COVID + Cog-和 在入组时和随时间推移（每18个月）使用3T MRI进行对照。这些研究将阐明 诱发风险因素和生物标志物的COVID相关的认知异常，提供机制的见解 研究潜在的发病机制，并提供长期结局的数据，包括AD/ADRD的发展- 相关疾病。

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.