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病毒在一些感染的患者中表现出神经嗜性，据报道病毒入侵，炎症， 脑膜脑炎、微血管损伤、中风、精神错乱以及认知和精神症状延迟。它 目前尚不清楚是否存在神经退变过程的加速和阿尔茨海默氏症风险的增加 疾病及相关痴呆(ADRD)。众所周知，种族、少数民族和男性患癌症的风险更高。 死于冠状病毒病，也可能更容易出现长期的神经精神后遗症。 与3T MRI相比，超高场(7T)MRI具有更高的灵敏度和空间分辨率，并可以检测到 皮质和白质结构、完整性和连接性、炎症、铁沉积、 海马区、小静脉损伤和蓝斑。7T MRI COVID联盟是一家 在5个地点进行国际合作，招募年龄在55岁至80岁之间的780名不同种族的人。的 这260人将有详细记录的SARS-CoV-2感染病例，260人将成为“疾病”控制者。 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 还有25%的非裔美国人。这两组人将与260名记录正常的健康对照组进行比较 认知状况良好，前2年无住院史。其他数据将从40名具有 常染色体显性遗传早发性阿尔茨海默病和180例人群对照，均采用相同的7T磁共振成像方案。 所有参与者将接受两次年度7T核磁共振扫描和四次详细的检查，包括神经、认知 和精神评估，嗅觉，步态，神经变性的血液生物标记物(p-tau181，NFL，GFAP， 淀粉样蛋白)和全身炎症(C反应蛋白、白介素6、白介素10、肿瘤坏死因子-α、白介素1R)和监测发生的MCI， ADRD痴呆症。这些检查将在每次核磁共振检查时进行，并在患病后36、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)脑病理的范围 COVID幸存者(目标1b)在延迟的7T MRI(12-18)中评估早期变化是改善、持续还是恶化 月)和(Aim 1c)将COVID幸存者的结果与临床前Eoad的MRI进行比较。目标2：比较 病前ADRD和血管损伤(VCID)以及认知、行为、情绪的横断面患病率 以及3组患者的功能结果。目标3：将早期和延迟的7T MRI措施与后续措施联系起来 罹患MCI、痴呆症以及认知和步态轨迹的风险。目标4：探索种族/民族、性别差异、血液 生物标记物、遗传学或早期SARS-CoV-2‘治疗’是效应修饰物、介体或两者都不是 目标1-3中提到的协会。领导这笔拨款的调查人员也是其他规模较大、不太详细的 COVID联合体允许进行统一的数据分析。我们的研究将使我们能够更好地了解生物学 COVID的长期神经和精神后遗症的机制和修饰物。这也可能会有帮助 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.