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病毒在一些感染患者中显示出嗜神经性，有报告称病毒入侵，炎症， 脑膜脑炎、微血管损伤、中风、谵妄和迟发性认知和精神症状。它 目前还不清楚是否有任何加速神经退行性过程和增加阿尔茨海默氏症的风险 疾病及相关痴呆（ADRD）。种族，少数民族和男性被认为有更高的风险， 死于COVID，也可能更容易患上长期的神经精神后遗症。 与3 T MRI相比，超高场（7 T）MRI具有更高的灵敏度和空间分辨率，可以检测 皮质和白色物质结构、完整性和连通性的微小变化、炎症、铁沉积， 海马亚区、小静脉损伤和蓝斑。7 T MRI COVID联盟是一个 在5个研究中心开展国际合作，招募780名年龄在55-80岁之间的多元化、多种族人群。的 这260人将有充分记录的SARS-CoV-2感染（病例），260人将是“疾病”对照组 患有临床上类似的非COVID疾病（例如肺炎）。病例和对照将包括>25%的西班牙裔 25%的非洲裔美国人。两组将与260名健康对照者进行比较， 在过去的2年里，没有住院治疗。将从40名患者中提取额外数据， 常染色体显性早发性AD患者和180名对照人群，均采用相同的7 T MRI方案成像。 所有受试者将接受2次年度7 T MRI扫描和4次详细检查，包括神经系统、认知功能、 和精神评估、嗅觉、步态、神经变性的血液生物标志物（p-tau 181，NFL，GFAP， 淀粉样蛋白）和全身性炎症（CRP、IL 6、IL 10、TNF-α、IL 1 R）以及监测偶发MCI， ADRD痴呆。这些检查将在每次MRI时以及患病后36个月和48个月进行。我们 提出以下具体目标：目标1：详细说明（目标1a）早期（6-12个月）脑病理学的范围， COVID幸存者（目标1b）在延迟7 T MRI中评估早期变化是否改善、持续或恶化（12-18 月）和（目标1c）比较COVID幸存者与临床前EOAD的MRI结果。目标2：比较 患病前ADRD和血管损伤（VCID）以及认知、行为、情绪 和功能结局。目的3：将早期和延迟的7 T MRI测量与随后的 MCI、痴呆、认知和步态轨迹的风险。目的4：探索种族/民族、性别差异、血液 生物标志物、遗传学或早期SARS-CoV-2“治疗”是效应调节剂、介质或两者都不是， 目标1-3中提到的协会。领导这项拨款的调查人员也是其他更大、更不详细的机构的成员。 COVID财团允许协调数据分析。我们的研究将有助于更好地了解生物学 COVID长期神经和精神后遗症的机制和修饰剂。它还可以帮助 阐明病毒感染、炎症和免疫反应在ADRD中的作用。

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.