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.

抽象的 阿尔茨海默氏病（AD）是神经退行性疾病的最常见形式。炎症 人们认为大脑的变化代表了AD的发作和发展中的关键过程，但是 目前尚不清楚神经炎症是否承认神经保护，加速变性或 如果我们要使用 未来FDA批准的免疫调节药物阵列。我们建议完成 - 介导的神经炎症在AD早期受到保护，而抑制 活动是通过发展更大的认知缺陷和更快的认知能力下降来完成的。 我们来自多个队列的初步数据通过显示1）降低的水平来支持这一假设 脑脊液（CSF）补体相关标记发生在痴呆阶段，而不是中部 AD的认知障碍（MCI）阶段； 2）减少CSF补体相关标记并升高 CSF白介素10（IL-10）水平与AD更快下降有关； 3）CSF炎症 蛋白质改变揭示了细胞和蛋白质调节的网络。在电流中 应用，我们将建立在相关蛋白质与速率之间的关联基础上 AD的认知下降，以识别固体CSF细胞因子和趋化因子的相关变化， 差异炎症细胞类型调节和神经炎症的成像相关。这 应用利用我们小组在执行CSF细胞因子测量的优势，CSF 免疫表型，通过正电子发射断层扫描的神经炎症的分子成像 （PET）和铁增强的MRI，以及通过新型生化生物信息学的网络分析 管道。我们将直接确定固体CSF细胞因子的个人和网络，以帮助 从MCI到AD的痴呆阶段的过渡，将完成和其他变化相关联 通过两个现代宠物示踪剂（11C-PBR28和18F-FEPPA）进行小胶质激活的途径， 并测量单个T辅助细胞（类型1、2、17）和非T细胞群体的变化。这 应用程序代表了在单个级别和小组级别上关联CSF的首次尝试 和神经炎症的成像测量。如果成功，此应用程序将推进 通过平行方法了解AD中神经炎症的理解，构成了新的基础 生物标志物面板（和算法）通过退化和 炎症标记，并加速针对未来治疗的目标识别 调节AD中的免疫系统。