Brain signature of SARS-CoV-2 Infection and its impact on long-term cognitive functioning in older adults

SARS-CoV-2 感染的大脑特征及其对老年人长期认知功能的影响

• 批准号: 10650316
• 负责人: GIOVANNI SCHIFITTO
• 金额: $ 75.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650316
• 关键词: 2019-nCoV; Acceleration; Address; Affect; Age; Aging; Alzheimer' s Disease; Arginine; Arteries; Autopsy; Blood - brain barrier anatomy; Blood Coagulation Disorders; Blood Vessels; Blood capillaries; Brain; Brain hemorrhage; COVID-19; COVID-19 patient; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical; Cognition; Cognitive; Complement 3b; Critical Care; Data; Dementia; Deposition; Diagnosis; Elderly; Endothelial Cells; Endothelium; Fingers; Future; Glial Fibrillary Acidic Protein; Goals; Hemorrhage; Hospitalization; Image; Impaired cognition; Individual; Infection; Injury; Intervention; Iron; Light; Link; Long-Term Effects; Macrophage; Magnetic Resonance; Magnetic Resonance Imaging; Maps; Measurable; Measures; Microcirculation; Microglia; Multimodal Imaging; Neurites; Neurocognitive; Neurodegenerative Disorders; Neurologic; Pathogenesis; Pathology; Penetration; Peripheral; Phase; Plasma; Platelet Activation; Population; Predisposition; Process; Recording of previous events; Recovery; Reporting; SARS-CoV-2 infection; Secondary to; Severities; Structure; Subcortical Infarctions; Symptoms; Techniques; Tissues; Vascular Dementia; White Matter Hyperintensity; Width; age related neurodegeneration; aged; arteriole; brain parenchyma; central nervous system injury; cerebral atrophy; cerebral microbleeds; cerebrovascular; cognitive function; cognitive performance; cohort; comparison control; cytokine; density; design; endothelial dysfunction; exosome; gray matter; imaging detection; indexing; interest; leukocyte activation; monocyte; neurofilament; neurologic sequelae of COVID-19; neurovascular unit; reactive hyperemia; sex; venule; white matter

Several reports have highlighted the presence of cognitive and psychiatric manifestation associated with severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) infection. Autopsy and CSF studies suggest that COVID-19 associated injury of the central nervous system derives from a combination of coagulopathy, endothelial injury with subsequent alteration of the blood brain barrier, infection and activation of microglia and macrophages followed by release of cytokines. The neurocognitive symptoms may persist in the subacute phase of the recovery while it remains to be determined what the long-term effects will be. The documented involvement of the brain microcirculation by SARS-CoV-2 infection, is likely to contribute to cerebral small vessel disease (CSVD). CSVD pathogenesis is not fully understood and is likely multifactorial. Among the factors that may link COVID-19 to CSVD are direct injury to endothelial cells, platelets and leukocyte activation. These processes can then lead to an altered blood brain barrier (BBB) with increased crossing of activated monocytes into the brain parenchyma. CSVD is clinically quite relevant since it is a leading cause of cognitive impairment and dementia. There are several unknowns that justify the implementation of this proposal. We do not know whether there is an increased burden of CSVD in those older adults who have been infected by SARS-CoV-2 and whether there will be an accelerated progression of CSVD in this population. It is also unclear whether the initial endothelial dysfunction induced by the infection may persist in a milder form that is sufficient to maintain a chronically altered cerebral microcirculation. If this occurs, it will contribute to several neurodegenerative disorders including vascular dementia and Alzheimer disease. In this proposal, we will focus on older individuals aged between ≥65 and 80, who were infected with SARS- CoV-2 at least six months prior to study enrolment, who were hospitalized but not admitted to a critical care unit and did not have a significant neurological history prior to SARS-CoV-2 infection. We will match by age and sex, 150 COVID-19 patients with 150 controls who will be followed for two years. CSVD will be assessed via state- of the-art magnetic resonance multimodality imaging. We will address the specific aims listed below. AIM 1: To assess the severity and progression of CSVD in individuals previously infected by SARS-CoV-2 compared to age and sex matched controls. Sub-AIM 1: To assess the impact of SARS-CoV-2 on brain microstructure integrity. AIM 2: To assess in individuals previously infected by SARS-CoV-2, compared to controls, changes in cerebrovascular function and its association to peripheral makers of endothelial function and altered blood brain barrier. AIM 3: To assess changes in cognitive performance and its relation to imaging metrics in individuals previously infected by SARS-CoV-2 compared to controls.

有几份报告强调，存在认知和精神症状， 严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）感染。尸检和脑脊液研究表明 COVID-19相关的中枢神经系统损伤源于凝血功能障碍， 内皮损伤，随后改变血脑屏障，感染和激活小胶质细胞， 巨噬细胞随后释放细胞因子。神经认知症状可能在亚急性期持续存在 但长期影响如何仍有待确定。 有记录的SARS-CoV-2感染对脑微循环的影响可能有助于 脑小血管病（CSVD）。CSVD的发病机制尚未完全了解，可能是多因素的。 可能将COVID-19与CSVD联系起来的因素包括对内皮细胞、血小板和白细胞的直接损伤 activation.然后，这些过程可导致改变的血脑屏障（BBB），其中增加的血脑屏障的穿过。 激活单核细胞进入脑实质。CSVD在临床上非常相关，因为它是导致 认知障碍和痴呆。 有几个未知数证明了执行这项建议的合理性。我们不知道 在那些感染了SARS-CoV-2的老年人中，CSVD的负担增加， 在这一人群中CSVD的进展会加速。目前还不清楚最初是否 由感染诱导的内皮功能障碍可能以足以维持内皮功能的较轻度形式持续存在。 大脑微循环的慢性改变如果发生这种情况，它将有助于几个神经退行性疾病 包括血管性痴呆和阿尔茨海默病的疾病。 在这项建议中，我们将重点关注年龄在65岁以上和80岁之间的老年人，他们感染了SARS- 研究入组前至少6个月存在CoV-2，住院但未入住重症监护室 并且在SARS-CoV-2感染之前没有明显的神经系统病史。我们将根据年龄和性别配对， 将对150名COVID-19患者和150名对照患者进行为期两年的随访。CSVD将通过国家评估- 最先进的磁共振多模态成像技术我们将致力于实现下列具体目标。 目的1：评估既往感染SARS-CoV-2的个体中CSVD的严重程度和进展 与年龄和性别匹配的对照组相比。Sub-AIM 1：评估SARS-CoV-2对大脑的影响 微观结构完整性 目的2：评估先前感染SARS-CoV-2的个体与对照组相比， 脑血管功能及其与内皮功能外周标记物和改变的血脑的关系 屏障目的3：评估个体认知能力的变化及其与成像指标的关系 与对照组相比，