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的急性后遗症患者的主要症状。年龄较大在我们自己对4,491个人和患有痴呆症风险因素的人的前瞻性研究中，尤其处于危险中。住院的Covid-19患者，中位年龄为65岁，606（14％）发展了新的神经系统疾病（最常见的是脑病）在住院期间阿尔茨海默氏病或相关诱变（AD/ADRD）。在这一组中，有48％的认知患者正常前旋转的电话MOCA得分异常（<18）6个月后出院。我们确定了神经变性/AD的血浆生物标志物的显着升高，包括总TAU，P-TAU-181，UCH-L1，神经丝轻链（NFL）和GFAP在住院的Covid-19患者中，患有脑病的患者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-二聚体显着相关炎症的度量。我们假设与19岁的老年受试者，特别是新的后主观或客观的认知异常将增加等离子体和放射学广告/ADRD生物标志物，以及异常认知测试的可能性更大随着时间的流逝，阿尔茨海默氏病或相关痴呆症的发展。我们将注册3组年龄的患者 ≥60岁，包括：1）具有新的主观或客观认知的SARS-COV-2阳性受试者从指数SARS-COV-2感染（COVID+COG+）的症状≤6个月2）SARS-COV-2阳性受试者没有感染受感染的主观或客观认知症状≤6个月（COVID+COG-）； 3）SARS-COV-2 NYU ADRC临床核心（对照组）招募的阴性，神经/认知正常受试者。我们将在SARS-COV-2感染之前排除具有MCI或AD/ADRD史的个人。我们的主要结果将成为全球认知/功能轨迹的差异（临床痴呆率评级量表盒子的总和 [CDR-SB]）在这三个组的5年研究中。次要结果将包括：等离子体的差异在这三个组中，随着时间的推移，随着时间的推移，射线照相广告/ADRD生物标志物。目标1：特征和比较注册和随时间（每12个月）的认知和神经心理学异常， COVID+COG+，COVID+COG-和使用CDR-SB以及统一的数据集版本3。AIM2：表征和比较神经退行性，炎症和BBB的等离子体AD/ADRD相关的生物标志物在COVID+COG+，COVID+COG-和对照组中，入学率和随时间（每12个月）的功能障碍。 AIM 3：在Covid+Cog+，Covid+Cog-和使用3T MRI在注册时和随时间（每18个月）进行对照。总的来说，这些研究将阐明诱发相关认知异常的风险因素和生物标志物，提供机械见解进入潜在的发病机理，并提供有关长期结局的数据，包括发展AD/ADRD- 相关疾病。