MR Biomarkers of Inflammation in Knee Osteoarthritis

膝骨关节炎炎症的 MR 生物标志物

• 批准号: 10476943
• 负责人: CHRISTINE B CHUNG
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10476943
• 关键词: 15q; Acute; Address; Affect; Animal Model; Biochemical; Biological Markers; Blood Vessels; Bone Marrow; Cadaver; Caring; Cartilage; Cells; Cellularity; Clinical; Cumulative Trauma Disorders; Data; Degenerative polyarthritis; Detection; Diffusion; Disease; Elements; Evaluation; Exhibits; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Funding; Goals; Histologic; Hyperplasia; Image; Infiltration; Inflammaging; Inflammation; Inflammatory; Institution; Intervention; Intravenous; Joints; Knee; Knee Osteoarthritis; Length; Literature; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maps; Marrow; Measures; Mediating; Meniscus structure of joint; Morphology; Multivariate Analysis; Mus; Natural Immunity; Outcome; Pain; Pathway interactions; Patients; Peripheral Vascular Diseases; Process; Property; Protocols documentation; Protons; Quantitative Evaluations; Resolution; Restriction Spectrum Imaging; Risk; Role; Saturated Fatty Acids; Scanning; Standardization; Statistical Models; Synovial Fluid; Synovial Membrane; Synovitis; Techniques; Time; Tissue Donors; Tissues; Translating; Traumatic Arthropathy; Veterans; Visit; Water; Work; bone; chromosome 5q loss; chronic musculoskeletal pain; clinical translation; cohort; density; diffusion weighted; economic impact; effusion; follow-up; functional improvement; joint inflammation; joint injury; knee replacement arthroplasty; loss of function; magnetic resonance imaging biomarker; military service; mouse model; novel; osteoarthritis pain; pain relief; patient population; pre-clinical; prescription opioid; programs; repaired; response; service member; socioeconomics; subchondral bone; treatment response

Osteoarthritis (OA) is highly prevalent in U.S. military service members and Veterans due to the impact of joint trauma and overuse injury. Its socioeconomic impact is substantial, estimated to approach $60 billion per year, and no disease-modifying treatments exist. Collaborative programs (such as CaRe-AP) have been proposed to develop a treatment for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. The hypothesis that PTOA is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate immunity that in turn result in pain, loss of function and structural decline have been broadly accepted. To this end, OA has long been characterized as a ‘wear and tear’ disease but is now considered a cell-mediated condition involving low-grade innate inflammation affecting all tissues of the joint (cartilage, bone, synovium, fat pads). Inflammatory processes increase the risk of knee OA (kOA) onset and progression, though the role of inflammation in the kOA, and as a determinant in successful treatments is unclear. Further, correlation of structural changes that result in progression of degeneration in kOA with those that serve as pain generators in this disease is crucial. Opioid prescriptions due to acute and chronic musculoskeletal pain visits increased by 50% between 2006 and 2010. MRI of kOA has historically focused on tissue specific drivers of OA, most notably cartilage evaluation. Our past work has pioneered a whole-joint approach to kOA, taking into consideration interactions between cartilage, meniscus and subchondral bone. The current MRI literature on the synovium, synovial fluid, infrapatellar fat pad (IFP) and bone marrow are limited, presenting a significant gap in MRI evaluation of kOA. The overwhelming majority of MRI literature addressing synovitis/effusion involves intravenous contrast-based protocols. In a patient population prone to peripheral vascular disease (affecting contrast delivery) and requiring longitudinal follow-up, contrast administration is suboptimal. Given the histologic elements of the inflammatory pathway in synovium, IFP and bone marrow, non-invasive identification and characterization of cellular infiltrates as well as their distinction from synovial hyperplasia, fibrosis and vascularity in tissues would represent a revolutionary step in understanding the role of inflammation in OA progression and response to therapy. Restriction Spectrum Imaging (RSI) is a novel diffusion-weighted technique that has been used to distinguish restricted diffusion within cells from other water compartments, has higher resolution than standard diffusion sequences, and has the potential to be standardized across institutions. Ultrashort Echo Time Dual Echo Steady State (UTE-DESS) combines UTE and DESS to characterize tissues with a range of intrinsic MR properties and allows quantitative evaluation of those properties (T1 and T2) as well as diffusion data. We hypothesize that these techniques can be used to identify cellular infiltrates (RSI) and distinguish them from regions of fibrosis and vascularity (UTE-DESS) in synovium, IFP and bone marrow in the setting of kOA. The overall goal of this project is to optimize and validate novel non-invasive (RSI and UTE-DESS) MRI biomarkers of joint inflammation that can identify and characterize inflammatory changes of cellular infiltrates, fibrosis and vascularity in synovium, IFP and bone marrow. We will deploy these MR biomarkers of inflammation in a preclinical animal model (mild, moderate and severe kOA) and translate optimized sequences to assess conservative therapy in kOA subjects. We will develop a multi-variate statistical model that incorporates outcomes from clinical morphologic MRI, novel optimized MR biomarkers of inflammation, MR spectroscopy to create a structural/ biochemical framework to correlate with kOA pain/function.

骨关节炎（OA）在美国军人和退伍军人中非常普遍，这是由于以下因素的影响： 关节创伤和过度使用损伤。其社会经济影响巨大，估计接近600亿美元 每年，没有疾病修饰治疗存在。合作项目（如Care-AP）已经 建议开发一种治疗创伤后骨关节炎（PTOA）的方法， 功能PTOA是由适应不良的修复反应引起的假说， 先天免疫的促炎途径，这反过来又导致疼痛，功能和结构的丧失， 下降被广泛接受。为此，OA一直被定性为'磨损' 疾病，但现在被认为是一种细胞介导的条件，涉及低度先天性炎症， 关节的所有组织（软骨、骨、滑膜、脂肪垫）。炎症过程会增加 膝关节OA（kOA）的发病和进展，虽然炎症在kOA中的作用，并作为一个决定因素， 成功的治疗方法尚不清楚。此外，导致疾病进展的结构变化的相关性 在kOA与那些在这种疾病中作为疼痛发生器的退化是至关重要的。阿片类药物处方 2006年至2010年，因急性和慢性肌肉骨骼疼痛就诊的人数增加了50%。 kOA的MRI历来专注于OA的组织特异性驱动因素，最值得注意的是软骨评价。我们 过去的工作已经开创了一种整体联合的方法来解决kOA问题，考虑了 软骨、半月板和软骨下骨。目前关于滑膜，滑液， 髌下脂肪垫（IFP）和骨髓是有限的，在MRI评估中存在显著差距， kOA。绝大多数关于滑膜炎/积液的MRI文献涉及静脉内 基于对比度的协议。在易患外周血管疾病（影响造影剂）的患者人群中 递送）并且需要纵向随访，造影剂施用是次优的。鉴于组织学 滑膜、IFP和骨髓中炎症途径的要素，非侵入性鉴定， 细胞浸润的表征以及它们与滑膜增生、纤维化和 组织中的血管分布将代表理解炎症在OA中的作用的革命性步骤 进展和对治疗的反应。限制谱成像（RSI）是一种新型的弥散加权成像技术， 已经用于区分细胞内的受限扩散与其他水隔室的技术， 具有比标准扩散序列更高的分辨率，并且有可能被标准化， 机构职能体系超短回波时间双回波稳态（UTE-DESS）结合了UTE和DESS， 表征具有一系列固有MR特性的组织，并允许对这些组织进行定量评价。 特性（T1和T2）以及扩散数据。我们假设这些技术可以用来 识别细胞浸润（RSI）并将其与纤维化和血管化区域（UTE-DESS）区分开来， 滑膜、IFP和骨髓。 本项目的总体目标是优化和验证新型无创（RSI和UTE-DESS）MRI 关节炎症的生物标志物，其可以识别和表征细胞浸润的炎性变化， 滑膜、IFP和骨髓中的纤维化和血管化。我们将部署这些MR生物标志物， 在临床前动物模型（轻度、中度和重度kOA）中观察炎症并优化翻译 序列，以评估kOA受试者的保守治疗。我们将建立一个多变量统计模型 它结合了临床形态MRI的结果，新的优化的炎症MR生物标志物， 磁共振波谱，以创建与kOA疼痛/功能相关的结构/生化框架。