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

基本信息

批准号：
10645017
负责人：
Jennifer Ann Frontera
金额：
$ 138.92万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/10645017
关键词：
2019-nCoV Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Amyloid beta-Protein Atrophic Biological Markers Blood - brain barrier anatomy Blood brain barrier dysfunction 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 Development Disease Down-Regulation Encephalopathies Enrollment Enzymes Exclusion FGF2 gene Ferritin Fibrin fragment D Glial Fibrillary Acidic Protein Grant Hemorrhage Hospitalization Hospitals Hypoxia Image Impaired cognition Individual Infection Inflammation Inflammatory Injury Interferon Type II Interleukin-6 Interleukins Intervention Laboratories 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 UCHL1 gene Up-Regulation Vascular Endothelial Growth Factor D Viral Work 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 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

项目摘要

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。在我们对 4,491 人进行的前瞻性研究中，个人和具有痴呆症风险因素的人尤其面临风险。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在这组患者中，48% 的患者患有阿尔茨海默病或相关痴呆症 (AD/ADRD)。我们发现，出院后 6 个月，新冠肺炎前正常的电话 MoCA 评分异常 (<18)。神经变性/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。我们认为患有 COVID-19 的老年受试者，特别是那些患有炎症的受试者。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，阿尔茨海默病进展或相关痴呆症将招募 3 组老年患者。 ≥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 个月内出现主观或客观认知症状 (COVID+Cog-) 和 3) SARS-CoV-2 阴性、神经/认知正常的受试者，参加纽约大学 ADRC 临床核心（对照）。排除 SARS-CoV-2 感染前有 MCI 或 AD/ADRD 病史的个体。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]) 3 个组的 5 年研究次要结果将包括：血浆差异。目标 1：表征和比较 3 组随时间变化的放射学 AD/ADRD 生物标志物。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 在入组时和随时间推移（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。