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

项目摘要 糖尿病视网膜病变（DR）是糖尿病最常见的并发症之一。检测 从糖尿病开始，临床DR体征可能需要数年时间;因此，长期的临床前阶段应该 提供一个窗口，以应用干预措施，可以减缓或防止进展到临床终点（轻度至中度）， 严重视力损害）。事实上，早期发现和治疗DR可以预防90%以上的视力 损失然而，目前尚未满足的临床挑战是找到适当的工具或技术来检测 由于视网膜血管是糖尿病视网膜病变的早期和普遍目标， 损伤，结构和功能性血管变化的敏感标识符具有很大的潜力， 生物标志物。视网膜成像技术的最新进展使得血管的可视化更好 特色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， 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， 存在限制（例如，扫描时间长、视野有限、运动伪影和需要专家 操作员），这阻止了这些技术成为有效的临床前检测工具， 设置.因此，非常需要增强检测灵敏度和定量手段来分析 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 关键的未满足的临床需求，我们已经开发了一种新的动态示踪动力学模型，以定量测量 基于荧光素视频血管造影术（FVA）的血管通透性和血流变化。该方法是 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 建议，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与更高的 其灵敏度和特异性优于其他视网膜成像模式，如OCTA和AOSLO。具体目标1将 根据金标准优化/验证视网膜血管渗透性和血流测量 渗透性（埃文斯蓝）和血流（微球）技术。具体目标2将证明， 通过我们的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。具体目标3将描述纵向变化 在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 通过动态示踪剂动力学模型证明临床前DR检测的灵敏度高于光学 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）。

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).