Quantitative Endogenous MRI Imaging of Neuroinflammation in AD

AD 神经炎症的定量内源 MRI 成像

• 批准号: 10596110
• 负责人: QING WANG
• 金额: $ 75.68万
• 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/10596110
• 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; 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; Location; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Microglia; Neurofibrillary Tangles; Observational Study; Outcome; PHF-1; Participant; Pathogenesis; Pathologic; Pathology; Patients; Persons; Plasma; Play; Positioning Attribute; Positron-Emission Tomography; Research; Role; Sampling; Scanning; Senile Plaques; Severities; Site; Specificity; Specimen; Stains; Synapses; Tauopathies; Techniques; Technology; Testing; Tracer; Universities; Walking; Washington; Water; aging brain; autosomal dominant Alzheimer' s disease; 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; neuropathology; 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.

项目摘要/摘要 神经炎症在阿尔茨海默病(AD)的发病机制中起着核心作用，并与 AD的神经病理特征，包括淀粉样斑块和神经原纤维缠结。在那里有 在过去的十年里，在开发基于血液的新型脑脊液方面取得了巨大的进步 化验、正电子发射断层扫描(PET)和磁共振成像(MRI)技术，仍然有 迫切需要一种临床成像方式，能够可靠地成像和量化患者的神经炎症 老化的大脑，有助于识别AD不同阶段的关键病理参与者。致信地址 这一未得到满足的需求和对FAR-21-038的回应，我们提出了一个新的研究方向，以开发和 建立一种全新的扩散磁共振成像(DMRI)技术--扩散字典成像(DDI)，作为一种安全、 针对AD患者神经炎性显象的特定内源性、经济的解决方案。通过跟踪 利用FDA批准的扩散磁共振序列和压缩传感技术实现水分子的随机行走 技术，DDI测量并具体提取与激活相关的微观结构变化 小胶质细胞和星形胶质细胞在阿尔茨海默病中的分布。此外，先前收集的dMRI数据可以 用这项新技术进行了回顾分析。因此，我们处于一个独特的位置，能够经济高效地 通过利用奈特阿尔茨海默病研究中心丰富的纵向数据研究来开发DDI 华盛顿大学ADRC中心(&gt；800名零星的AD参与者)和多个地点的国际 显性遗传性阿尔茨海默病网络(DIAN)观察性研究(&gt；500常染色体显性AD[ADAD] 参与者)。在本项目中，我们将开发DDI技术，并对其成像能力进行评估 死后阿尔茨海默病脑内的神经炎症(目标1)。我们将研究DDI之间的关联 神经炎症指数与脑脊液和血浆炎症生物标志物(YKL-40、sTREM2和GFAP)的关系 骑士、民主与和解委员会和DIAN队列(目标2)。我们还将横向和纵向量化 DDI在骑士ADRC和DIAN队列中的神经炎症研究及其与淀粉样蛋白的关系 通过PET示踪剂和临床结果(认知和进展)测量沉积和颈椎病(目标3)。 神经炎症的定量内源性DDI成像生物标记物的成功开发将 代表着一项重要的技术飞跃。DDI神经炎症生物标记物的整合 Dian和其他临床试验研究将提供临床上可行的神经成像替代品，这些替代品可以显著 提高对神经炎症在AD发病机制中作用的认识。