CSF, MRI, and PET biomarkers of neuroinflammation in Alzheimer's disease

阿尔茨海默病神经炎症的 CSF、MRI 和 PET 生物标志物

• 批准号: 9976071
• 负责人: William Tzu-lung Hu
• 金额: $ 9.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9976071
• 关键词: Acute; Algorithms; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Anti-Inflammatory Agents; Autopsy; Biochemical; Biological Assay; Biological Markers; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain imaging; Cells; Cerebrospinal Fluid; Cessation of life; Chronic; Clinical Trials; Cognitive; Cognitive deficits; Complement; Complement Activation; Complement Suppression; Data; Dementia; Development; Encephalitis; Event; FDA approved; Fractalkine; Future; Helper-Inducer T-Lymphocyte; Human; Image; Imaging ligands; Immune system; Immunomodulators; Immunophenotyping; Impaired cognition; Individual; Inflammation; Inflammatory; Interleukin-10; Interleukin-7; Iron; Label; Ligands; Link; Liquid substance; MRI Scans; Machine Learning; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Methods; Modality; Modernization; Neurodegenerative Disorders; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Patients; Pattern; Pattern Recognition; Peptides; Peripheral; Phagocytes; Phenotype; Population; Positron-Emission Tomography; Process; Proteins; Regulation; Role; Specificity; Symptoms; System; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tracer; bioinformatics pipeline; biomarker panel; brain dysfunction; cell type; chemokine; cohort; cytokine; demographics; genetic variant; imaging biomarker; inflammatory marker; insight; iron oxide; macrophage; migration; mild cognitive impairment; molecular imaging; neuroinflammation; neuropathology; neuroprotection; novel

ABSTRACT Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder. Inflammatory changes in the brain are thought to represent key processes in the onset and progression of AD, but it remains unclear whether neuroinflammation confers neuroprotection, accelerated degeneration, or possibly both. Such an understanding in living humans is critical if we are to begin clinical trials using the array of FDA-approved immunomodulatory drugs in the future. We propose that complement- mediated neuroinflammation is protective in the early AD stages, while suppression of complement activities is accompanied by the development of greater cognitive deficits and faster cognitive decline. Our preliminary data from multiple cohorts support this hypothesis by showing 1) reduced levels of cerebrospinal fluid (CSF) complement-related markers occur in the dementia stage but not mild cognitive impairment (MCI) stage of AD; 2) reduced CSF complement-related markers and elevated CSF interleukin-10 (IL-10) levels are associated with faster decline in AD; and 3) CSF inflammatory protein alterations reveal networks of cellular and protein regulations. In the In the current application, we will build on the association between complement related proteins and rates of cognitive decline in AD to identify associated changes in soluble CSF cytokines and chemokines, differential inflammatory cell type regulation, and imaging correlates of neuroinflammation. This application takes advantage of our group’s strengths in performing CSF cytokine measurements, CSF immunophenotyping, molecular imaging of neuroinflammation through positron emission tomography (PET) and iron-enhanced MRI, and network analysis through a novel biochemical-bioinformatics pipeline. We will directly identify individual and networks of soluble CSF cytokines that accompany the transition from the MCI to the dementia stage of AD, correlate the complement and other altered pathways with microglial activation through two modern PET tracers (11C-PBR28 and 18F-FEPPA), and measure changes in individual T helper cell (type 1, 2, 17) and non-T cell populations. This application represents the first attempt to correlate, at the individual level and at the group level, CSF and imaging measures of neuroinflammation. If successful, this application will advance the understanding of neuroinflammation in AD through parallel approaches, form the basis of a new biomarker panel (and algorithm) to diagnose AD through a combination of degenerative and inflammatory markers, and accelerate the target identification of future therapeutics aimed at modulating the immune system in AD.

摘要 阿尔茨海默病（AD）是最常见的神经退行性疾病。炎性 大脑的变化被认为是AD发病和进展的关键过程， 目前尚不清楚神经炎症是否能提供神经保护、加速变性或 可能两者都有。如果我们要开始临床试验， 一系列FDA批准的免疫调节药物。我们建议补充- 介导的神经炎症在早期AD阶段是保护性的，而抑制补体介导的神经炎症在早期AD阶段是保护性的。 活动伴随着更大的认知缺陷和更快的认知衰退的发展。 我们来自多个队列的初步数据支持这一假设，显示1）降低水平的 脑脊髓液（CSF）补体相关标志物出现在痴呆阶段，但不轻微 AD的认知损害（MCI）阶段; 2）CSF补体相关标志物减少和升高 CSF白细胞介素-10（IL-10）水平与AD的更快下降相关;和 蛋白质改变揭示了细胞和蛋白质调节的网络。在当前 应用中，我们将建立在补体相关蛋白质和发病率之间的关联， AD中的认知下降以鉴定可溶性CSF细胞因子和趋化因子的相关变化， 不同的炎性细胞类型调节和神经炎症的成像相关性。这 应用程序利用了我们小组在进行CSF细胞因子测量，CSF 免疫表型，通过正电子发射断层扫描神经炎症的分子成像 (PET)和铁增强MRI，并通过一种新的生化生物信息学网络分析， 渠道.我们将直接鉴定伴随的可溶性CSF细胞因子的个体和网络， 从MCI到AD痴呆阶段的转变，使补体和其他改变的 通过两种现代PET示踪剂（11 C-PBR 28和18F-FEPPA）的小胶质细胞活化途径， 并测量单个T辅助细胞（1、2、17型）和非T细胞群体的变化。这 应用程序代表了在个人水平和组水平上将CSF 和神经炎症的成像测量。如果成功，这项申请将推动 通过平行方法了解AD中的神经炎症，形成新的 生物标志物面板（和算法），以通过退行性和 炎症标志物，并加速未来治疗的目标识别， 调节AD中的免疫系统。