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: 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
• 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

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。炎症性 大脑的变化被认为是阿尔茨海默病发生和发展的关键过程，但 目前尚不清楚神经炎症是否提供神经保护、加速退行性变或 可能两者都有。如果我们要开始临床试验，在活人身上这样的理解是至关重要的。 FDA批准的一系列免疫调节药物在未来。我们建议补充- 介导的神经炎症在AD早期具有保护作用，而对补体的抑制 活动伴随着更大的认知缺陷和更快的认知衰退。 我们来自多个队列的初步数据支持了这一假设，因为它显示了1)降低的 脑脊液补体相关标志物出现在痴呆期，但不轻微 2)脑脊液补体相关标志物降低和升高 脑脊液白介素10(IL-10)水平与AD下降更快有关；3)脑脊液炎症 蛋白质的改变揭示了细胞和蛋白质调节的网络。在当前，在当前 应用，我们将建立补体相关蛋白和 阿尔茨海默病患者认知功能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， 不同的炎性细胞类型调节，与神经炎症的影像相关性。这 应用程序利用我们团队在进行脑脊液细胞因子测量方面的优势 神经炎症的正电子发射断层扫描免疫表型和分子成像 (PET)和铁增强MRI，以及通过一种新的生化-生物信息学进行网络分析 输油管道。我们将直接鉴定伴随着的单个和网络的可溶性脑脊液细胞因子 阿尔茨海默病从MCI到痴呆期的过渡与补体及其他改变的相关性 通过两种现代PET示踪剂(11C-PBR28和18F-FEPPA)激活小胶质细胞的途径， 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 应用程序首次尝试在个人层面和集团层面将CSF关联起来 以及神经炎症的成像方法。如果成功，此应用程序将推进 通过平行方法了解AD的神经炎症，形成新的基础 生物标记物面板(和算法)通过联合使用退行性疾病和 炎症标志物，并加速未来治疗药物的靶点识别 调节AD的免疫系统。

项目成果

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

Weak associations between depressive symptom severity, depressive symptom clusters, and cognitive performance in young to middle-aged men without clinical depression.

• DOI: 10.1080/13825585.2020.1840505
• 发表时间: 2021-11
• 期刊: Neuropsychology, development, and cognition. Section B, Aging, neuropsychology and cognition
• 作者: Szymkowicz SM;Dotson VM;Vanderploeg RD
• 通讯作者: Vanderploeg RD

Vascular depression in Black Americans: A systematic review of the construct and its cognitive, functional, and psychosocial correlates.

• DOI: 10.1080/13854046.2021.1933188
• 发表时间: 2022-02
• 期刊: CLINICAL NEUROPSYCHOLOGIST
• 影响因子: 3.9
• 作者: Bogoian, Hannah R.;Dotson, Vonetta M.
• 通讯作者: Dotson, Vonetta M.

Incidence of post-stroke depression symptoms and potential risk factors in adults with aphasia in a comprehensive stroke center.

综合性卒中中心成人失语症患者卒中后抑郁症状的发生率和潜在危险因素。

• DOI: 10.1080/10749357.2022.2070363
• 发表时间: 2023
• 期刊: Topics in stroke rehabilitation
• 影响因子: 2.2
• 作者: Zanella,Christina;Laures-Gore,Jacqueline;Dotson,VonettaM;Belagaje,SamirR
• 通讯作者: Belagaje,SamirR

Lessons Learned in Time-Is Neurodegeneration Still Something Unpredictable?

及时吸取的教训——神经退行性变仍然是不可预测的吗？

• DOI: 10.1007/s13311-023-01412-1
• 发表时间: 2023
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Hu,WilliamT