Imaging Cerebral and Retinal Microvasculature in Cerebral Small Vessel Disease

项目总结（家长奖） 虽然阿尔茨海默氏病（AD）是痴呆症的最常见原因，但血管因素对痴呆症的贡献是多方面的。 认知障碍和痴呆症正越来越多地被认识到。血管性认知障碍与 痴呆（VCID）最常见的是由脑小血管病（SVD）引起的。到目前为止，大脑小 现有的成像技术无法访问包括小动脉、毛细血管和小静脉在内的血管。 MRI上的特征性实质病变，如腔隙性梗死、白色病变和微出血， 已被采纳为SVD的标志物。然而，这些实质病变是SVD的后果 而不是微血管变化的替代标志物，并且不适合早期干预， 改变VCID的进程在过去的几年里，我们集团率先开发了一套 最先进的MRI技术，用于体内和无创评估微血管结构， 功能，包括（1）用于穿支动脉直接成像的高分辨率黑血MRI;（2）动脉自旋 标记（ASL）技术，用于标测微血管灌注、动脉硬度或血管顺应性（VC） 小动脉/小动脉的血流速度和穿过血脑屏障（BBB）的水交换率。而且我们 最近开发的定量度量视网膜毛细血管密度和形态使用FDA批准的 光学相干断层扫描血管造影（OCTA）平台。该方法允许临床上可行的、体内的和 视网膜小动脉和毛细血管的完全无创成像，空间分辨率约为10微米。 凭借我们广泛的技术专长和长期的VCID临床研究记录，我们 我提出了这个UH 2/UH 3项目，以进一步开发和评估一套MRI和OCTA标记物，用于评估 大脑和视网膜微血管的结构和功能，在一个队列的拉丁裔受试者参加了 洛杉矶拉丁裔眼科研究（LALES）和墨西哥人常染色体显性AD研究 来源（Estudio de Enfermedad de Alzheimer en Jalisciences，或EEAJ）。在UH 2阶段，我们将进一步 开发和评价拟议的SVD MRI和OCTA成像标志物，建立其重测 重复性和临床实用性。我们将与其他参与研究中心和协调中心合作 建立联合体的合作参数和协议。在UH 3阶段，我们将 促进和执行联合体设计的跨地点研究。我们将统一执行 以及对LALES队列进行全面的临床、认知、成像、遗传和生化评估 和EEAJ参与者，并按照联合体的要求进行数据分析。在这场比赛结束时， 项目，我们期望开发出一套微血管成像标记物，为进入大规模 多中心临床验证研究，以获得FDA对小型临床试验II期和III期的资格 预防和治疗VCID。

Project Summary (Parent Award) While Alzheimer's disease (AD) is the most common cause of dementia, the contribution of vascular factors to cognitive impairment and dementia is becoming increasingly recognized. Vascular cognitive impairment and dementia (VCID) is most commonly caused by cerebral small vessel disease (SVD). To date, cerebral small vessels including arterioles, capillaries and venules are inaccessible to existing imaging technologies. Characteristic parenchymal lesions on MRI, such as lacunar infarcts, white matter lesions, and microbleeds, have been adopted as markers of SVD. However, these parenchymal lesions are the consequences of SVD rather than the surrogate markers of microvascular changes, and are unsuitable for early interventions to change the course of VCID. During the past few years, our group has spearheaded the development of a suite of cutting edge MRI technologies for in vivo and noninvasive assessment of microvascular structure and function, including (1) high-resolution black blood MRI for direct imaging of perforating arteries; (2) arterial spin labeling (ASL) techniques for mapping microvascular perfusion, arterial stiffness or vascular compliance (VC) of small arteries/arterioles, and water exchange rate across the blood-brain barrier (BBB). Furthermore, we recently developed quantitative metrics for retinal capillary density and morphology using an FDA approved optical coherence tomography angiography (OCTA) platform. This method allows clinically feasible, in vivo and completely noninvasive imaging of retinal arterioles and capillaries with a spatial resolution of ~10 microns. Capitalizing on our extensive technical expertise and longstanding track record of clinical studies on VCID, we propose this UH2/UH3 project to further develop and evaluate a suite of MRI and OCTA markers for assessing the structure and function of cerebral and retinal microvasculature, in a cohort of Latino subjects enrolled in the Los Angeles Latino Eye Study (LALES) and in the study of autosomal dominant AD in persons of Mexican origin (Estudio de Enfermedad de Alzheimer en Jalisciences, or EEAJ). During the UH2 phase, we will further develop and evaluate the proposed MRI and OCTA imaging markers of SVD, establish their test-retest repeatability and clinical utility. We will work with the other participating sites and with the Coordinating Center to establish collaborative parameters and agreements of the consortium. During the UH3 phase, we will contribute to and execute cross-site research studies as designed by the consortium. We will perform unified and comprehensive clinical, cognitive, imaging, genetic and biochemical assessments on the cohort of LALES and EEAJ participants locally and perform data analyses as required by the consortium. At the closing of this project, we expect to develop the suite of microvascular imaging markers to readiness to enter into large-scale multi-site clinical validation studies toward FDA qualification for phase II and phase III clinical trials on small vessel disease to prevent and treat VCID.