Mechanisms underlying COVID-19 induced Neurocognitive Dysfunction

COVID-19 诱发神经认知功能障碍的机制

• 批准号: 10736414
• 负责人: PAUL E SCHULZ
• 金额: $ 63.96万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736414
• 关键词: 2019-nCoV; Address; Age; Anatomy; Anti-Inflammatory Agents; Anxiety; Attention; Basic Science; Biological Markers; Blood; COVID-19; COVID-19 impact; COVID-19 mortality; Cerebrospinal Fluid; Characteristics; Cognitive; Data; Development; Disease; Distress; Elderly; Ethnic Origin; Exhibits; Female; Functional disorder; Goals; Hospitalization; Hospitals; Image; Immunoglobulin Therapy; Immunosuppressive Agents; Impaired cognition; Infection; Inflammation; Inflammatory; Infrastructure; Institution; Intervention; Intravenous Immunoglobulins; Lead; Learning; Link; Medical; Medical Records; Memory; Mental Depression; Mood Disorders; Neurocognitive; Neurocognitive Deficit; Neurologic; Neurologic Symptoms; Neurons; Neuropsychological Tests; Participant; Pathway interactions; Patients; Peripheral; Persons; Plasma Exchange; Positron-Emission Tomography; Probability; Quality of life; Race; Reporting; Research Personnel; Risk; Risk Factors; Role; SARS-CoV-2 infection; Screening procedure; Serum; Stress; Stroke; Survivors; Testing; Thick; Time; Translational Research; Underrepresented Populations; Work; biobank; brain size; cognitive change; cognitive testing; cohort; comorbidity; comparison control; coronavirus disease; digital; executive function; functional disability; global health; gray matter; infection rate; inflammatory marker; innovation; neuroinflammation; neuropsychiatric disorder; neuropsychiatry; older patient; pandemic disease; participant enrollment; post-COVID-19; processing speed; prospective; screening; severe COVID-19; sex; tau-1; therapy design; verbal

PROJECT SUMMARY/ABSTRACT Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, which causes Coronavirus Disease 2019 (COVID-19), has become a global health crisis. To date, more than 6.5 million deaths from COVID-19 have been reported worldwide. Amongst survivors, neurocognitive dysfunction and neuropsychiatric disorders, such as anxiety and depression, are increasingly recognized and can persist for months, or even years. This enduring neurocognitive and neuropsychiatric distress obligates us to address critical questions about their duration, risk factors, and underlying mechanisms. The goal of this project is to test the hypothesis that SARS-CoV-2 promotes cognitive decline in subjects who were previously normal via stimulating inflammatory pathways, with the greatest risk being in older adults, females, and those from underrepresented groups. We propose to utilize patients in our biorepository, who were hospitalized with SARS-CoV-2 infection, to achieve three Specific Aims: (1) to determine the type and duration of neurocognitive dysfunction present; (2) to ascertain risk factors for ongoing cognitive decline, including sex, age, race/ethnicity and comorbidities; and, (3) to verify that persistent neuroinflammation underlies cognitive decline. To achieve these Aims, our team has established a well-curated, highly diverse biorepository of more than 650 patients hospitalized with COVID-19. About 15% have succumbed to COVID-related illnesses; however, 37% have continued to return for testing at 3-6 and 12-months post hospitalization. Preliminary data demonstrates that 30% of subjects returning at one year show progressive cognitive decline, which is associated with elevated markers of inflammation and neuronal stress. Here we propose to follow these patients and perform detailed cognitive testing and assess biomarkers from their blood- serum, spinal fluid, and imaging to explicate the type and time course of cognitive changes present, the risk factors associated with cognitive dysfunction, and whether inflammation-induced neuronal distress underlies progressive neurocognitive impairment. This proposal is innovative because we are evaluating the long-term neurocognitive consequences of severe COVID-19 from a cohort that we have followed since the onset of the pandemic, which has provided preliminary data supporting our Aims. Moreover, we have brought together investigators with expertise in cognitive assessment and treatment, and basic and translational research, all in the setting of a strong institutional infrastructure. Our work is significant because understanding the role of persistent neuroinflammation in COVID-19-induced cognitive dysfunction will greatly enhance our ability to rationally test immunosuppressants for this very debilitating disorder.

项目概要/摘要 严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 感染，导致冠状病毒病 2019 年（COVID-19）已成为一场全球健康危机。迄今为止，已有超过 650 万人死于 COVID-19 已被全世界报道。在幸存者中，神经认知功能障碍和神经精神疾病，例如 焦虑和抑郁等症状越来越受到人们的重视，并且可能持续数月甚至数年。这种经久不衰的 神经认知和神经精神困扰迫使我们解决有关其持续时间、风险的关键问题 因素和潜在机制。该项目的目标是检验 SARS-CoV-2 促进的假设 通过刺激炎症途径，以前正常的受试者的认知能力下降 老年人、女性和代表性不足群体的风险最大。我们建议利用 我们的生物样本库中因 SARS-CoV-2 感染而住院的患者，以实现三个具体目标： (1) 确定存在的神经认知功能障碍的类型和持续时间； (2) 确定风险因素 持续的认知能力下降，包括性别、年龄、种族/民族和合并症； (3) 验证持久性 神经炎症是认知能力下降的基础。为了实现这些目标，我们的团队建立了精心策划的、 高度多样化的生物样本库，包含 650 多名住院的 COVID-19 患者。大约15%已经屈服 与新冠肺炎相关的疾病；然而，37% 的人在术后 3-6 个月和 12 个月继续返回进行测试 住院治疗。初步数据表明，一年后返回的受试者中有 30% 表现出进展 认知能力下降，这与炎症和神经元应激标志物升高有关。在这里我们 建议跟踪这些患者并进行详细的认知测试并评估他们血液中的生物标志物 血清、脊髓液和影像学来阐明存在的认知变化的类型和时间过程、风险 与认知功能障碍相关的因素，以及炎症引起的神经元窘迫是否是其背后的原因 进行性神经认知障碍。这个提议是创新的，因为我们正在评估长期 自疫情爆发以来我们一直跟踪的队列中严重的 COVID-19 的神经认知后果 大流行，它提供了支持我们目标的初步数据。此外，我们还汇集了 具有认知评估和治疗以及基础和转化研究专业知识的研究人员 建立强有力的制度基础设施。我们的工作意义重大，因为了解 COVID-19 引起的认知功能障碍中的持续神经炎症将大大增强我们的能力 合理测试免疫抑制剂对这种非常衰弱的疾病的作用。