Expanding insights into FTD disease mechanisms

扩大对 FTD 疾病机制的认识

• 批准号: 10401522
• 负责人: LEONARD PETRUCELLI
• 金额: $ 96.36万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401522
• 关键词: 2019-nCoV; Acute; Admission activity; Affect; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid beta-Protein; Area; Autopsy; Axon; Behavioral; Biological; Biological Markers; Blood; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain imaging; Brain region; COVID-19; COVID-19 patient; Cells; Cerebral Infarction; Cerebral hemisphere hemorrhage; Cerebrum; Clinical; Cognition; Cognitive; Consent; Data; Deposition; Disease; Doctor of Philosophy; Dose; Encephalitis; Etiology; Fogs; Frequencies; Frontotemporal Lobar Degenerations; Funding Mechanisms; Goals; Haplotypes; Hospitalization; Hospitals; Hypoxemia; Impaired cognition; Individual; Injury; Intensive Care Units; Laboratories; Length; Lesion; Light; Link; Long-Term Effects; Longitudinal Studies; Longitudinal cohort study; Measurement; Measures; Mechanical ventilation; Medicine; Megakaryocytes; Metabolic; Motion; Nervous System Trauma; Neurodegenerative Disorders; Neurologic; Neurologic Effect; Neurologic Symptoms; Neurological status; Neuronal Injury; Neurons; Neuropsychology; Observational Study; Operative Surgical Procedures; Outcome; Parents; Pathogenesis; Pathology; Patients; Positron-Emission Tomography; Predisposition; Proteins; Research; Risk; Seizures; Serum; Severities; Stroke; Syndrome; Testing; Virus; Visit; abeta deposition; acute infection; astrogliosis; base; behavioral impairment; behavioral neurology; beta amyloid pathology; brain tissue; cerebral hypoperfusion; cognitive change; cognitive function; cohort; cooking; experience; flexibility; follow-up; functional outcomes; functional status; imaging biomarker; insight; interest; mitochondrial membrane; multidisciplinary; neurofilament; neuroinflammation; neuropathology; novel; radiotracer; response; tau Proteins; white matter; white matter damage; white matter injury

ABSTRACT Up to two thirds of hospitalized COVID-19 patients show neurologic signs and symptoms. For example, some patients with COVID-19 experience cognitive changes (or brain fog) or suffer strokes and seizures. It is hypothesized that COVID-19-induced brain inflammation and white matter damage underpin the neurological manifestations experienced by patients with COVID-19. Since neuroinflammation and white matter damage are also implicated in Alzheimer’s disease related dementias (ADRDs), COVID-19 may increase the risk of developing an ADRD. Nevertheless, many questions remain answered, and the subacute and long-term neurological effects of COVID-19 are unknown. We thus propose to undertake a comprehensive longitudinal study of patients with COVID-19 requiring hospitalization. To identify patients at risk of long-term neurological complications and warranting follow-up visits, levels of serum neurofilament light chain (NFL), a marker of neuron injury, will be measured in hospital. We based this on our recent findings that ~53% of an initial cohort of 142 hospitalized patients with COVID-19 had elevated serum NFL, and that higher NFL concentrations correlated with worse clinical outcomes, including the need for mechanical ventilation, intensive care unit admission, longer lengths of hospitalization and poor functional outcomes. As such, NFL measurements provide an efficient means to estimate the extent of neurological injury associated with the acute infection and pending systemic metabolic disturbances. We will follow consenting patients 3 months, 1 year and 2 years after discharge, and examine blood biomarkers of neuronal and astroglial injury, ADRD pathologies and neuroinflammation, imaging markers of neuroinflammation and Aβ deposition, and cognitive outcomes. These data will allow us to determine whether blood biomarker levels during hospitalization predict the emergence and severity of ADRD-related neurological signs and symptoms. We will also extend our prior neuropathological studies in patients with COVID-19 and ADRDs, and assess anoxic-ischemic cerebral white matter damage, neuroinflammation and microglial activation.

摘要 多达三分之二的住院COVID-19患者表现出神经系统体征和症状。比如一些 患有COVID-19的患者会经历认知变化（或脑雾）或遭受中风和癫痫发作。是 假设COVID-19引起的脑部炎症和白色物质损伤是神经系统疾病的基础， COVID-19患者经历的症状。由于神经炎症和白色物质损伤 COVID-19也与阿尔茨海默病相关痴呆（ADRD）有关，可能会增加 发展ADRD。尽管如此，许多问题仍然有答案，亚急性和长期 COVID-19对神经系统的影响尚不清楚。因此，我们建议进行全面的纵向研究， 对需要住院治疗的COVID-19患者的研究。识别有长期神经系统疾病风险的患者 血清神经丝轻链（NFL）水平，神经元标记物， 受伤，将在医院进行测量。我们基于我们最近的发现，在142名初始队列中， COVID-19住院患者血清NFL升高，较高的NFL浓度与 临床结局更差，包括需要机械通气、重症监护室入院、 住院时间长和功能结果差。因此，NFL测量提供了一种有效的方法， 估计与急性感染相关的神经损伤的程度， 干扰.我们将在患者出院后3个月、1年和2年对知情同意的患者进行随访， 神经元和星形胶质细胞损伤、ADRD病理和神经炎症的血液生物标志物，成像标志物 神经炎症和Aβ沉积，以及认知结果。这些数据将使我们能够确定 住院期间血液生物标志物水平可预测ADRD相关神经系统疾病的发生和严重程度 体征和症状。我们还将扩大我们先前对COVID-19患者的神经病理学研究， ADRD，并评估缺氧缺血性脑白色物质损伤、神经炎症和小胶质细胞活化。