SARS-CoV-2 and Precursors of Alzheimer's Disease and Related Dementias: An Ultrahigh Field (7T) MRI Study in a Diverse Multinational Cohort

SARS-CoV-2 和阿尔茨海默病及相关痴呆症的前体：在不同跨国队列中进行的超高场 (7T) MRI 研究

• 批准号: 10440085
• 负责人: Timothy D Girard
• 金额: $ 352.94万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440085
• 关键词: 2019-nCoV; Acceleration; Acute; Adverse effects; Affect; African American; Ageusia; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Anosmia; Anxiety; Ataxia; Autonomic Dysfunction; Behavioral; Behavioral Symptoms; Biological; Biological Markers; Blood; Blood Pressure; Blood Tests; Brain; Brain Injuries; Brain Pathology; COVID-19; COVID-19 treatment; Clinical; Cognition; Cognitive; Collaborations; Data; Data Analyses; Delirium; Dementia; Deposition; Dyspnea; Enrollment; Environmental Risk Factor; Event; Fatigue; Frequencies; Gait; Genetic; Glial Fibrillary Acidic Protein; Grant; Hippocampus (Brain); Hispanics; Hospitalization; IL1R1 gene; IL6 gene; Image; Immune response; Infection; Inflammation; Injury; Interleukin-10; International; Iron; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Memory Loss; Meningoencephalitis; Mental Depression; Moods; Motor; Nerve Degeneration; Neurobehavioral Manifestations; Neurocognitive; Neurologic; Neurologic Examination; Neurologic Symptoms; Neurotropism; Outcome; Participant; Pathologic; Pathology; Patients; Persons; Pneumonia; Pontine structure; Population Control; Predisposition; Presenile Alzheimer Dementia; Prevalence; Process; Protocols documentation; Quality of life; Race; Recording of previous events; Reporting; Research; Research Personnel; Resolution; Respiratory Signs and Symptoms; Risk; Role; SARS-CoV-2 infection; Scanning; Seizures; Sensory; Severities; Sex Differences; Signs and Symptoms; Site; Sleep; Smell Perception; Social isolation; Stroke; Structure; Survivors; Symptoms; TNF gene; Time; Universities; Viral; Virus; Virus Diseases; adverse outcome; affective disturbance; aged; antibody test; antigen test; case control; clinical risk; cognitive testing; cohort; coronavirus disease; data harmonization; ethnic minority population; functional outcomes; high risk; improved; lifestyle factors; locus ceruleus structure; member; men; mortality; multi-ethnic; neuroinflammation; neuropathology; neuropsychiatry; novel coronavirus; nutrition; pre-clinical; psychiatric symptom; racial minority; recruit; systemic inflammatory response; treatment effect; vascular cognitive impairment and dementia; vascular injury; vascular risk factor; white matter

SARS-CoV-2 virus displays neurotropism in some infected patients with reports of viral invasion, inflammation, meningoencephalitis, microvascular injury, stroke, delirium and delayed cognitive and psychiatric symptoms. It is unclear if there is any acceleration of neurodegenerative processes and increased risk of Alzheimer’s disease and related dementias (ADRD). Race-, ethnic- minorities and men are known to have a higher risk of dying from COVID and may also have a greater susceptibility to long-term neuropsychiatric sequelae. Ultrahigh field (7T) MRI has increased sensitivity and spatial resolution, compared to 3T MRI and can detect small changes in cortical and white matter structure, integrity and connectivity, inflammation, iron deposition, hippocampal subfields, venular injury and the locus coeruleus. The 7T MRI COVID Consortium is an international collaboration across 5 sites to enroll a diverse, multi-ethnic cohort of 780 persons, aged 55-80. Of these 260 persons will have well-documented SARS-CoV-2 infection (cases) and 260 will be ‘illness’ controls with a clinically similar non-COVID illness (e.g. pneumonia). Cases and controls will include >25% Hispanic and >25% African-Americans. Both groups will be compared to 260 healthy controls with documented normal cognition and no hospitalization in preceding 2 years. Additional data will be drawn from 40 persons with autosomal dominant early-onset AD and 180 population controls, all imaged with the same 7T MRI protocol. All participants will undergo 2 annual 7T MRI scans and 4 detailed exams comprising neurological, cognitive and psychiatric assessments, smell, gait, blood biomarkers of neurodegeneration (p-tau181, NFL, GFAP, amyloid) and systemic inflammation (CRP, IL6, IL10, TNF-alpha, IL1R) and surveillance for incident MCI, ADRD dementia. These exams will occur at the time of each MRI, and at 36, 48 months post-illness. We propose the following specific aims: Aim 1: Detail the range of (Aim 1a) Early (6-12 months) brain pathology in COVID survivors (Aim 1b) assess if early changes improve, persist or worsen at a delayed 7T MRI (12-18 months) and (Aim 1c) Compare findings in COVID survivors to MRI in preclinical EOAD. Aim 2: Compare cross-sectional prevalence of pre-illness ADRD and vascular injury (VCID) and of cognitive, behavioral, mood and functional outcomes across 3 groups. Aim 3: Relate early and delayed 7T MRI measures to subsequent risk of MCI, dementia and cognitive and gait trajectories. Aim 4: Explore if race/ethnic-, sex- differences, blood biomarkers, genetics, or early SARS-CoV-2 ‘treatments’ are effect-modifiers, mediators, or neither, of the associations noted in Aims 1-3. Investigators leading this grant are also members of other larger, less detailed COVID consortia permitting harmonized data analyses. Our study will permit a better biological understanding of mechanisms and modifiers of long-term neurological and psychiatric sequelae of COVID. It could also help illuminate the role of viral infections, inflammation and immune response in ADRD.

SARS-COV-2病毒显示一些感染病毒侵袭，炎症，炎症， 脑膜脑炎，微血管损伤，中风，del妄以及延迟的认知和精神症状。它 目前尚不清楚神经退行性过程是否有任何加速和阿尔茨海默氏症的风险增加 疾病和相关痴呆症（ADRD）。众所周知，种族，少数民族和男人的风险更高 死于Covid，并且可能对长期神经精神后遗症具有更大的敏感性。 与3T MRI相比，超高场（7T）MRI具有提高的灵敏度和空间分辨率 皮质和白质结构，完整性和连通性，感染，铁沉积， 海马子场，静脉损伤和基因座围栏。 7T MRI Covid联盟是 跨5个地点的国际合作，以55-80岁的780人组成的多样性，多民族队列。的 这260人将有充分记录的SARS-COV-2感染（病例）和260人将是“疾病”控制 患有临床上相似的非卵巢疾病（例如肺炎）。案件和控件将包括> 25％的西班牙裔 和> 25％的非裔美国人。两组将与260个健康对照进行比较 认知和前2年没有住院。其他数据将来自40人 常染色体主导的早发广告和180个人口对照，均使用相同的7T MRI方案成像。 所有参与者将接受2次年度7T MRI扫描和4项详细检查，以完成神经系统认知 和精神病评估，气味，步态，神经退行性的血液生物标志物（p-tau181，NFL，GFAP， 淀粉样蛋白）和全身感染（CRP，IL6，IL10，TNF-Alpha，IL1R）和监视MCI的监视， 痴呆症。这些考试将在每次MRI时进行，并在36、48个月后进行。我们 提案以下具体目的：目标1：详细介绍（目标1a）早期（6-12个月）脑病理学的范围 COVID存活率（AIM 1B）评估早期变化在7T MRI时是否有所改善，持续或更糟（12-18 几个月）和（AIM 1C）将Covid存活中的发现与临床前EOAD中的MRI进行了比较。目标2：比较 易元前和血管损伤（VCID）以及认知，行为，情绪的横断面患病率 和3组的功能结果。 AIM 3：提前和延迟的7T MRI措施与后续 MCI，痴呆，认知和步态轨迹的风险。目标4：探索种族/族裔，性别差异，血液 生物标志物，遗传学或早期SARS-COV-2“治疗”是效应模型，介体或均不是 AIMS 1-3中指出的协会。领导这笔赠款的调查人员也是其他较大，详细的成员 共同联盟允许统一的数据分析。我们的研究将允许更好的生物学理解 长期神经和精神后遗症的机理和修饰符它也可以帮助 阐明ADRD病毒感染，感染和免疫冲源的作用。

项目成果

Blood biomarkers: ready for clinical practice?

• DOI: 10.1136/jnnp-2022-330958
• 发表时间: 2023-06
• 期刊: Journal of neurology, neurosurgery, and psychiatry