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

基本信息

批准号：
10518656
负责人：
William Tzu-lung Hu
金额：
$ 80.14万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-15 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518656
关键词：
CSF MRI PET biomarkers neuroinflammation

项目摘要

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.

抽象的阿尔茨海默病（AD）是最常见的神经退行性疾病。大脑的变化被认为代表了 AD 发病和进展的关键过程，但是目前尚不清楚神经炎症是否会带来神经保护、加速退化或如果我们要开始使用这些药物进行临床试验，那么对活人的这种理解可能是至关重要的。我们建议未来 FDA 批准一系列免疫调节药物。介导的神经炎症在早期 AD 阶段具有保护作用，而补体抑制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）补体相关标志物出现在痴呆阶段，但不轻微 AD 认知障碍 (MCI) 阶段；2) 脑脊液补体相关标志物减少且升高脑脊液白细胞介素 10 (IL-10) 水平与 AD 的更快下降有关；3) 脑脊液炎症；蛋白质的改变揭示了细胞和蛋白质调节网络。应用程序中，我们将建立补体相关蛋白与补体率之间的关联 AD 认知能力下降，以确定可溶性脑脊液细胞因子和趋化因子的相关变化，差异炎症细胞类型调节以及神经炎症的影像学相关性。应用程序利用了我们小组在进行脑脊液细胞因子测量、脑脊液免疫表型分析，通过正电子发射断层扫描进行神经炎症分子成像 (PET) 和铁增强 MRI，以及通过新型生化生物信息学进行网络分析我们将直接识别伴随的可溶性脑脊液细胞因子的个体和网络。从 MCI 到 AD 痴呆阶段的过渡，与补体和其他改变相关通过两种现代 PET 示踪剂（11C-PBR28 和 18F-FEPPA）观察小胶质细胞激活途径，并测量个体 T 辅助细胞（1、2、17 型）和非 T 细胞群的变化。应用程序代表了在个人层面和群体层面将 CSF 关联起来的首次尝试如果成功，该应用将推动神经炎症的成像和成像测量。通过并行方法了解 AD 中的神经炎症，形成新的基础生物标志物组（和算法）通过退化和退化的组合来诊断 AD 炎症标志物，并加速未来治疗的靶标识别调节 AD 中的免疫系统。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reporting and social construction of race in Alzheimer's disease clinical trials.

阿尔茨海默病临床试验中种族的报告和社会建构。

DOI：
发表时间：
2022-04
期刊：
影响因子：
0
作者：
Hu; William T
通讯作者：
William T

Subthreshold depressive symptoms relate to cuneus structure: Thickness asymmetry and sex differences.

DOI：
10.1016/j.jpsychires.2021.12.013
发表时间：
2021-12-12
期刊：
Journal of psychiatric research
影响因子：
4.8
作者：
Dotson VM;Bogoian HR;Gradone AM;Taiwo Z;Minto LR
通讯作者：
Minto LR

Interleukin 9 alterations linked to alzheimer disease in african americans.

白细胞介素 9 的改变与非裔美国人的阿尔茨海默病有关。

DOI：
发表时间：
2019-09
期刊：
影响因子：
11.2
作者：
Wharton, Whitney;Kollhoff, Alexander L;Gangishetti, Umesh;Verble, Danielle D;Upadhya, Samsara;Zetterberg, Henrik;Kumar, Veena;Watts, Kelly D;Kippels, Andrea J;Gearing, Marla;Howell, J Christina;Parker, Monica W;Hu, William T
通讯作者：
Hu, William T

Charting the Next Road Map for CSF Biomarkers in Alzheimer's Disease and Related Dementias.

绘制阿尔茨海默病和相关痴呆症脑脊液生物标志物的下一个路线图。