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

SARS-CoV-2 感染后阿尔茨海默病相关的生物标志物

• 批准号: 10439240
• 负责人: Jennifer Ann Frontera
• 金额: $ 137.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439240
• 关键词: 2019-nCoV; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Atrophic; Biological Markers; Blood - brain barrier anatomy; COVID-19; COVID-19 pandemic; COVID-19 patient; COVID-19 severity; Cerebrovascular Circulation; Cerebrum; Clinical; Clinical Trials; Clinical dementia rating scale; Cognition; Cognitive; Data; Data Set; Dementia; Development; Disease; Down-Regulation; Encephalopathies; Enrollment; Enzymes; FGF2 gene; Ferritin; Fibrin fragment D; Functional disorder; Glial Fibrillary Acidic Protein; Grant; Hospitalization; Hospitals; Hypoxia; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Injury; Interferon Type II; Interleukin-6; Interleukins; Intervention; Laboratories; Lead; Light; Link; Magnetic Resonance Imaging; Measures; Metabolic Brain Diseases; Nerve Degeneration; Neurobehavioral Manifestations; Neurologic; Neuropsychology; Outcome; Oxygen; Pathogenesis; Pathology; Pathway interactions; Patients; Plasma; Population; Populations at Risk; Post-Acute Sequelae of SARS-CoV-2 Infection; Prevention strategy; Prospective Studies; Recording of previous events; Risk; Risk Factors; SARS-CoV-2 infection; SARS-CoV-2 negative; SARS-CoV-2 positive; Sum; Symptoms; TNF gene; Telephone; Testing; Time; Up-Regulation; Vascular Endothelial Growth Factor D; Viral; age related neurodegeneration; aged; blood-brain barrier disruption; brain fog; brain volume; cognitive performance; cognitive testing; coronavirus disease; dementia risk; endothelial dysfunction; functional decline; high risk; imaging biomarker; indexing; inflammatory marker; insight; metabolic rate; nervous system disorder; neurofilament; neuroimaging marker; neuroinflammation; neurologic sequelae of COVID-19; neurovascular injury; novel; post SARS-CoV-2 infection; post-COVID-19; primary outcome; radiological imaging; response; secondary outcome; targeted treatment; tau Proteins; tau-1; white matter injury

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.

抽象的 认知障碍是 COVID-19 急性后遗症患者的主要症状。年长的 个人和具有痴呆症危险因素的人尤其面临风险。在我们对 4,491 名患者进行的前瞻性研究中 住院的 COVID-19 患者，中位年龄为 65 岁，606 名（14%）出现新的神经系统疾病 （最常见的脑病）在住院期间，表明人群处于发生脑病的高风险 阿尔茨海默病或相关痴呆症 (AD/ADRD)。在该组中，48% 的患者存在认知障碍 出院后 6 个月，新冠病毒感染前正常的患者电话 MoCA 评分异常 (<18)。我们确定了 神经退行性变/AD 的血浆生物标志物显着升高，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-二聚体显着相关 炎症措施。我们假设患有 COVID-19 的老年受试者，特别是那些患有 新冠肺炎后主观或客观认知异常，血浆和 放射学 AD/ADRD 生物标志物，以及异常认知测试和异常的可能性更大 随着时间的推移，进展为阿尔茨海默病或相关痴呆症。我们将招募 3 组年龄的患者 ≥60岁，包括：1）有新的主观或客观认知的SARS-CoV-2阳性受试者 症状 自 SARS-CoV-2 感染 (COVID+Cog+) 起 ≤6 个月 2) SARS-CoV-2 阳性受试者，无 感染后 6 个月以内的主观或客观认知症状 (COVID+Cog-)； 3) SARS-CoV-2 阴性、神经/认知正常受试者，参加纽约大学 ADRC 临床核心（对照）。我们将 排除 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（临床痴呆评定量表框总和 [CDR-SB]）对 3 个组进行了为期 5 年的研究。次要结果将包括： 血浆差异 并比较 3 组随时间变化的放射学 AD/ADRD 生物标志物。目标 1：表征和 比较入组时和一段时间内（每 12 个月）的认知和神经心理学异常： COVID+Cog+、COVID+Cog- 和使用 CDR-SB 的控制以及统一数据集版本 3。目标 2： 表征并比较神经退行性变、炎症和 BBB 的血浆 AD/ADRD 相关生物标志物 COVID+Cog+、COVID+Cog- 和对照组在入组时和一段时间内（每 12 个月）出现功能障碍。 目标 3：表征并比较 COVID+Cog+、COVID+Cog- 和 COVID+Cog- 中的 AD/ADRD 神经影像生物标志物 使用 3T MRI 在入组时和一段时间内（每 18 个月）进行控制。总的来说，这些研究将阐明 诱发新冠肺炎相关认知异常的危险因素和生物标志物，提供机制见解 深入了解潜在的发病机制，并提供长期结果的数据，包括 AD/ADRD 的发展 相关疾病。