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: 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
• 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' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' 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

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.

摘要