Dynamic Tracer Kinetic Model to Detect Preclinical Diabetic Retinopathy (DR)

用于检测临床前糖尿病视网膜病变 (DR) 的动态示踪动力学模型

• 批准号: 10220617
• 负责人: JENNIFER J Kang-Mieler
• 金额: $ 53.08万
• 依托单位: ILLINOIS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220617
• 关键词: Address; Angiography; Angiotensin II Receptor; Angiotensin-Converting Enzyme Inhibitors; Animals; Biochemical; Biological Markers; Blindness; Blood Vessels; Blood flow; Cellular Structures; Centers for Disease Control and Prevention (U.S.); Characteristics; Clinical; Data; Detection; Diabetes Mellitus; Diabetic Retinopathy; Diagnostic; Diagnostic Imaging; Dose; Early Diagnosis; Early treatment; Evans blue stain; Fluorescein; Fluorescein Angiography; Genetic; Goals; Gold; Growth Factor Inhibition; Hyperglycemia; Imaging Device; Imaging technology; Intervention; Measurement; Measures; Methods; Microspheres; Modeling; Morphologic artifacts; Motion; Nature; Optical Coherence Tomography; Patients; Perfusion; Pericytes; Permeability; Phase; Protein Kinase C; ROC Curve; Receiver Operating Characteristics; Reporting; Retina; Retinal Diseases; Rodent Model; Scanning; Sensitivity and Specificity; Severities; Specificity; Structure; Surrogate Endpoint; Techniques; Technology; Testing; Time; Tracer; Translating; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vascular remodeling; Vision; Visual impairment; Visualization; X-Ray Computed Tomography; adaptive optics scanning laser ophthalmoscopy; base; blood flow measurement; clinical examination; clinical practice; data acquisition; detection sensitivity; diabetic; diabetic patient; high risk; imaging modality; kinetic model; novel; novel therapeutics; polyol; pre-clinical; prevent; retina blood vessel structure; retinal damage; retinal imaging; statistics; success; tool; uptake

Project Summary Diabetic retinopathy (DR) is one of the most common complications associated with diabetes. Detection of clinical DR signs can take several years from the onset of diabetes; hence, the long preclinical phase should provide a window to apply interventions that can slow or prevent progression to clinical endpoint (mild to severe visual impairment). In fact, early detection and treatment of DR can prevent more than 90% of vision loss. However, the current unmet clinical challenge is finding an appropriate tool or technology to detect preclinical signs (biomarkers) of DR. Since the retinal vessels are early and prevalent targets of diabetic damage, sensitive identifiers of structural and functional blood vessel changes hold great potential as biomarkers. Recent advances in retinal imaging technology have allowed a better visualization of vessel characteristics. Adaptive Optics Scanning Laser Ophthalmoscopy (AOSLO) and OCT angiography (OCTA) studies recently suggested that there may be a transitional vascular remodeling during the preclinical phase in diabetic patients. Though the main benefit of these technologies is the non-invasive nature of data acquisition, there are limitations (e.g., long scan times, limited field-of-view, motion artifacts and need for an expert operator) that prevent these technologies to be effective preclinical detection tools to be used in a clinical setting. Therefore, there is a great need for enhanced detection sensitivity and quantitative means to analyze the early preclinical vasculature changes that can be readily translated into clinical practice. To address this critical unmet clinical need, we have developed a novel dynamic tracer kinetic model to measure quantitatively vascular permeability and blood flow changes based on fluorescein video-angiography (FVA). The approach is immediately translatable to FVA data collected in patients as demonstrated by our preliminary data. In this proposal, we will demonstrate that our dynamic tracer kinetic model can detect preclinical DR with a higher sensitivity and specificity than other retinal imaging modalities such as OCTA and AOSLO. Specific Aim 1 will optimize/validate the retinal vascular permeability and blood flow measurements against gold standard techniques of permeability (Evans-blue) and blood flow (microspheres). Specific Aim 2 will demonstrate that longitudinal preclinical changes in the retinal vascular permeability and blood flow detected by our model will occur before clinical retinopathy in diabetic rodent model. Specific Aim 3 will characterize longitudinal changes in retinal vascular permeability and blood flow in both normal subjects and diabetic patients. Specific Aim 4 will demonstrate higher sensitivity of preclinical DR detection by the dynamic tracer kinetic model over optical coherence tomography angiography (OCTA) and adaptive optics scanning laser ophthalmoscopy (AOSLO) in diabetic patients without clinical retinopathy (DMnoDR).

项目摘要 糖尿病性视网膜病（DR）是与糖尿病有关的最常见并发症之一。检测 临床DR症状可能从糖尿病开始时需要几年。因此，长临床前阶段应该 提供一个窗口，以采用可以减慢或防止临床终点进展的干预措施（轻度到 严重的视觉障碍）。实际上，早期检测和治疗DR可以预防90％以上的视力 损失。但是，目前未满足的临床挑战是​​找到合适的工具或技术来检测 博士的临床前迹象（生物标志物）。由于视网膜血管是糖尿病患者的早期和普遍的靶标 损害，结构和功能性血管变化的敏感标识符具有很大的潜力，因为 生物标志物。视网膜成像技术的最新进展允许更好地可视化船只 特征。自适应光学扫描激光眼镜检查（AOSLO）和OCT血管造影（八八） 最近的研究表明，在临床前阶段可能会进行过渡性血管重塑 糖尿病患者。尽管这些技术的主要好处是数据获取的非侵入性质，但 有局限性（例如，扫描时间长，视野有限，运动伪像，对专家的需求 操作员）防止这些技术是在临床上使用的有效临床前检测工具 环境。因此，非常需要增强检测灵敏度和定量手段来分析 早期的临床前脉管系统可以很容易地转化为临床实践。解决这个问题 关键的未满足临床需求，我们开发了一种新型的动态示踪动力学模型，以定量测量 基于荧光素视频学（FVA），血管通透性和血流变化。方法是 如我们的初步数据所证明的那样，可以立即转换为患者收集的FVA数据。在这个 提案，我们将证明我们的动态示踪剂动力学模型可以检测临床前DR 敏感性和特异性比其他视网膜成像模态（例如八章和aoslo）。具体目标1将 优化/验证针对黄金标准的视网膜血管通透性和血流测量值 渗透率（Evans-Blue）和血流（微球）的技术。具体目标2将证明 我们模型检测到的视网膜血管通透性和血流的纵向临床前变化将 发生在糖尿病啮齿动物模型中的临床视网膜病变之前。特定的目标3将表征纵向变化 正常受试者和糖尿病患者的视网膜血管通透性和血流中。具体目标4将 通过光学的动态示踪剂动力学模型证明了临床前DR检测的较高灵敏度 一致性层析成像血管造影（OCTA）和自适应光学扫描激光眼镜检查（AOSLO） 没有临床视网膜病（DMNODR）的糖尿病患者。