Quantitative Endogenous MRI Imaging of Neuroinflammation in AD

AD 神经炎症的定量内源 MRI 成像

• 批准号: 10334974
• 负责人: QING WANG
• 金额: $ 78.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334974
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Amyloid deposition; Animal Disease Models; Antibodies; Astrocytes; Autopsy; Biological Assay; Biological Markers; Blood; Brain; CSF1R gene; Cells; Cerebrospinal Fluid; Clinical; Clinical Trials; Cognition; Cognitive; Data; Development; Diagnostic tests; Dictionary; Diffusion; Diffusion Magnetic Resonance Imaging; Discipline of Nuclear Medicine; Disease; FDA approved; Formalin; Functional disorder; Genetic Heterogeneity; Glial Fibrillary Acidic Protein; Image; Imaging Device; Imaging Techniques; Immune response; Immunohistochemistry; Immunotherapy; Infiltration; Inflammation; Infrastructure; Inherited; International; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Microglia; Neurofibrillary Tangles; Observational Study; Outcome; PHF-1; Participant; Pathogenesis; Pathologic; Pathology; Persons; Plasma; Play; Positioning Attribute; Positron-Emission Tomography; Research; Role; Sampling; Scanning; Senile Plaques; Severities; Site; Specificity; Specimen; Stains; Synapses; Tauopathies; Techniques; Testing; Tracer; Universities; Walking; Washington; Water; aging brain; autosomal dominant Alzheimer' s disease; base; clinical application; clinical imaging; cognitive change; cohort; cost; imaging biomarker; imaging capabilities; imaging modality; improved; in vivo; indexing; interest; molecular imaging; neuroimaging; neuroinflammation; neuron loss; novel; response; spatial relationship; targeted treatment; tau Proteins; therapy development

PROJECT SUMMARY/ABSTRACT Neuroinflammation plays a central role in the pathogenesis of Alzheimer’s disease (AD) and links strongly with AD’s neuropathological hallmarks, including amyloid plaques and neurofibrillary tangles. While there have been tremendous strides over the last decade in the development of novel cerebrospinal fluid, blood-based assays, positron emission tomography (PET), and magnetic resonance imaging (MRI) techniques, there still is a desperate need for a clinical imaging modality that can reliably image and quantify neuroinflammation in the aging brain and facilitate the identification of the key pathological players in different stages of AD. To address this unmet need and response to FOA “PAR-21-038”, we propose a new research direction to develop and establish a brand-new diffusion MRI (dMRI) technique, Diffusion Dictionary Imaging (DDI), as a safe, specific endogenous, and economical solution for the neuroinflammation imaging in AD. By tracking the random walk of water molecules using FDA-approved diffusion MRI sequence and compressed sensing technique, DDI measures and specifically extracts the microstructural changes associated with the activation and infiltration of the microglia and astrocyte in AD. Moreover, the previously collected dMRI data can be retrospectively analyzed with this new technique. Therefore, we are in a unique position to cost-effectively develop DDI by leveraging the longitudinal data-rich studies from the Knight Alzheimer’s Disease Research Center (ADRC) at Washington University (>800 Sporadic AD participants) and the multi-site international Dominantly Inherited Alzheimer Network (DIAN) observational study (>500 autosomal-dominant AD [ADAD] participants). In this project, we will develop the DDI technique and evaluate its capability of imaging neuroinflammation in the postmortem AD brains (Aim 1). We will examine the associations between the DDI neuroinflammation index and CSF and plasma inflammation biomarkers (YKL-40, sTREM2, and GFAP) in the Knight ADRC and DIAN cohorts (Aim 2). We will also cross-sectionally and longitudinally quantify the neuroinflammation using DDI in the Knight ADRC and DIAN cohorts and examine its connections with amyloid deposition and tauopathy measured by PET tracers and clinical outcomes (cognitive and progression) (Aim 3). The successful development of a quantitative endogenous DDI imaging biomarker of neuroinflammation will represent an important technological leap forward. The integration of DDI neuroinflammation biomarker into the DIAN and other clinical trial studies will provide clinically feasible neuroimaging surrogates that can significantly improve our understanding of the role of neuroinflammation in AD pathogenesis.

项目概要/摘要 神经炎症在阿尔茨海默病 (AD) 的发病机制中发挥着核心作用，并与阿尔茨海默病 (AD) 密切相关 AD 的神经病理学特征，包括淀粉样蛋白斑和神经原纤维缠结。虽然有 过去十年来，在新型脑脊液、基于血液的开发中取得了巨大进步 化验、正电子发射断层扫描（PET）和磁共振成像（MRI）技术，仍然存在 迫切需要一种能够可靠地成像和量化神经炎症的临床成像方式 大脑老化，有助于识别 AD 不同阶段的关键病理因素。致地址 这种未满足的需求和对 FOA“PAR-21-038”的响应，我们提出了一个新的研究方向来开发和 建立一种全新的扩散 MRI (dMRI) 技术——扩散字典成像 (DDI)，作为一种安全、 AD 神经炎症成像的特定内源性且经济的解决方案。通过跟踪 使用 FDA 批准的扩散 MRI 序列和压缩传感进行水分子的随机游动 技术，DDI 测量并专门提取与激活相关的微观结构变化 AD 中小胶质细胞和星形胶质细胞的浸润。此外，先前收集的 dMRI 数据可以 对此新技术进行了回顾性分析。因此，我们处于独特的地位，可以经济有效地 利用 Knight 阿尔茨海默病研究中心丰富的纵向数据研究开发 DDI 华盛顿大学中心 (ADRC)（超过 800 名零星 AD 参与者）和多地点国际中心 显性遗传阿尔茨海默病网络 (DIAN) 观察性研究（>500 例常染色体显性阿尔茨海默病 [ADAD] 参与者）。在这个项目中，我们将开发DDI技术并评估其成像能力 死后 AD 大脑中的神经炎症（目标 1）。我们将检查 DDI 之间的关联 神经炎症指数以及脑脊液和血浆炎症生物标志物（YKL-40、sTREM2 和 GFAP） Knight ADRC 和 DIAN 队列（目标 2）。我们还将横向和纵向量化 在 Knight ADRC 和 DIAN 队列中使用 DDI 检测神经炎症，并检查其与淀粉样蛋白的关系 通过 PET 示踪剂测量沉积和 tau 蛋白病以及临床结果（认知和进展）（目标 3）。 神经炎症定量内源性 DDI 成像生物标志物的成功开发将 代表着重要的技术飞跃。将 DDI 神经炎症生物标志物整合到 DIAN 和其他临床试验研究将提供临床上可行的神经影像替代物，可以显着 提高我们对神经炎症在 AD 发病机制中的作用的理解。