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).

项目概要 糖尿病视网膜病变（DR）是与糖尿病相关的最常见并发症之一。检测 从糖尿病发病起，临床 DR 症状可能需要数年时间；因此，漫长的临床前阶段应该 提供一个应用干预措施的窗口，这些干预措施可以减缓或防止进展到临床终点（轻度至 严重视力障碍）。事实上，早期发现和治疗 DR 可以阻止 90% 以上的视力 损失。然而，当前未解决的临床挑战是​​寻找合适的工具或技术来检测 DR 的临床前体征（生物标志物）。由于视网膜血管是糖尿病的早期和普遍目标 损伤，结构和功能血管变化的敏感识别器具有巨大的潜力，因为 生物标志物。视网膜成像技术的最新进展可以更好地显示血管 特征。自适应光学扫描激光检眼镜 (AOSLO) 和 OCT 血管造影 (OCTA) 最近的研究表明，在临床前阶段可能存在过渡性血管重塑 糖尿病患者。虽然这些技术的主要好处是数据采集的非侵入性， 存在局限性（例如，扫描时间长、视野有限、运动伪影以及需要专家 操作员）阻止这些技术成为临床前有效的检测工具用于临床 环境。因此，非常需要增强检测灵敏度和定量分析手段 早期临床前脉管系统的变化可以很容易地转化为临床实践。为了解决这个问题 未满足的关键临床需求，我们开发了一种新型动态示踪剂动力学模型来定量测量 基于荧光素视频血管造影（FVA）的血管通透性和血流变化。方法是 如我们的初步数据所示，可立即转化为在患者中收集的 FVA 数据。在这个 建议，我们将证明我们的动态示踪动力学模型可以以更高的检测精度检测临床前 DR 与其他视网膜成像方式（例如 OCTA 和 AOSLO）相比，其灵敏度和特异性更高。具体目标 1 将 根据金标准优化/验证视网膜血管通透性和血流量测量 渗透性技术（伊文思蓝）和血流技术（微球）。具体目标 2 将证明 我们的模型检测到的视网膜血管通透性和血流量的纵向临床前变化将 在糖尿病啮齿动物模型中发生在临床视网膜病变之前。具体目标 3 将描述纵向变化 正常人和糖尿病患者的视网膜血管通透性和血流量。具体目标 4 将 证明动态示踪剂动力学模型比光学检测的临床前 DR 检测具有更高的灵敏度 相干断层扫描血管造影（OCTA）和自适应光学扫描激光检眼镜（AOSLO） 无临床视网膜病变的糖尿病患者（DMnoDR）。