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.

由于影响 关节创伤和过度使用伤害。它的社会经济影响很大，估计接近600亿美元 每年，没有改良疾病的治疗。协作计划（例如Care-ap）已经 提议开发一种用于创伤后骨关节炎（PTOA）的治疗方法，以挽救疼痛并改善 功能。 PTOA是由适应不良的修复反应引起的假设，包括激活 先天免疫的促炎途径又导致疼痛，功能丧失和结构性 下降已被广泛接受。为此，OA长期以来一直被描述为“磨损” 疾病，但现在被认为是一种细胞介导的疾病，涉及低级先天炎症影响 关节的所有组织（软骨，骨骼，滑膜，脂肪垫）。炎症过程增加了 膝盖OA（KOA）发作和进展，尽管炎症在KOA中的作用 成功的治疗尚不清楚。此外，结构变化的相关性导致 KOA的变性与该疾病中的疼痛发生器的变性至关重要。阿片类药物处方 由于急性和慢性肌肉骨骼疼痛，在2006年至2010年期间，骨骼疼痛访问量增加了50％。 KOA的MRI历史上一直集中在OA的组织特定驱动因素上，最著名的是软骨评估。我们的 过去的工作使KOA的整个关节率启动，考虑到了 软骨，半月板和软骨下骨。当前有关滑液流体的MRI文献， Infrapatillar脂肪垫（IFP）和骨髓受到限制，在MRI评估中存在显着差距 KOA。针对滑膜炎/积液的绝大多数MRI文献涉及静脉 基于对比的协议。在容易出现周围血管疾病的患者人群中（影响对比度 分娩）并且需要纵向随访，对比度是次优的。鉴于组织学 滑膜，IFP和骨髓中炎症途径的元素，非侵入性鉴定和 细胞浸润的表征及其与滑膜增生，纤维化和 组织中的血管性将代表理解炎症在OA中的作用的革命性步骤 限制频谱成像（RSI）是一种新型扩散加权 用于区分细胞内部限制扩散与其他水室的技术， 比标准扩散序列具有更高的分辨率，并且具有标准化的潜力 机构。 Ultrashort回声时间双回声稳态（UTE-DESS）将UTE和DESS结合在一起 表征具有一系列内在MR性能的组织，并允许对这些特性进行定量评估 属性（T1和T2）以及扩散数据。我们假设这些技术可用于 鉴定细胞浸润（RSI），并将其与纤维化和血管（UTE-DESS）区域区分开 在KOA的环境中，滑膜，IFP和骨髓。 该项目的总体目标是优化和验证新颖的非侵入性（RSI和UTE-DESS）MRI 关节炎症的生物标志物，可以识别和表征细胞浸润的炎症变化， 滑膜，IFP和骨髓中的纤维化和血管性。我们将部署这些先生的生物标志物 临床前动物模型（轻度，中度和重度KOA）中的炎症，并翻译优化 评估KOA受试者保守治疗的序列。我们将开发一个多变量统计模型 这结合了临床形态MRI的结果，新型的炎症MR生物标志物， MR光谱法创建了与KOA疼痛/功能相关的结构/生化框架。