Microvascular Cerebral Blood Flow Monitoring with Diffuse Correlation Spectroscopy in Sickle Cell Anemia Children

项目总结/摘要 中风是镰状细胞性贫血（SCA）的一种毁灭性并发症，SCA是一种血液疾病， 患中风的可能性是同龄健康对照组的250倍。红细胞异常 导致血管闭塞，显著增加中风的风险。到20岁时，11%的SCA儿童 患者将经历明显的中风，并且到14岁时，大约40%的患者将具有无症状的梗塞。沉默 梗塞不表现出临床上明显的症状;它们只能在神经成像扫描中显现。 SCA患者的早期经颅多普勒超声（TCD）筛查，快速开始输血 成功地减少了明显的中风。然而，TCD具有较差的特异性， 明显中风（即，一些被认为是低风险的患者仍然会发生中风），并且它对 无症状梗塞风险。血流的微血管测量显示出作为TCD的补充工具的前景 测量.然而，测量微血管灌注的当前成像模态（即，MRI、PET）不是 适用于常规使用，因为需要造影和/或放射、成本高和/或6岁以下儿童的镇静。 因此，临床上需要一种常规测量微血管脑血流量的低成本工具 以检测脑血流中的任何异常，最终降低中风风险。 扩散相关光谱（DCS）是一种新兴的低成本（<5万美元），非侵入性光学模态 利用近红外光直接感知红细胞运动， 血流到目前为止，我们已经证明DCS测量更高的静息状态脑血流量（通过 3x）与健康对照组相比。然而，这一增长与 通常报告MRI/PET增加约1.5倍。由于这些SCA患者经历中度至重度 贫血和DCS对红细胞运动和密度敏感，我假设这个定量 DCS血流测量的差异可能归因于贫血。为了验证这个假设，我设计了， 开发并验证了一个微流控组织模拟平台，具有数百个嵌入式微通道。 这个平台使我能够系统地操纵流速，红细胞压积和血管大小， 镰状血我对健康血液的初步数据表明，红细胞压积对 DCS血流测量。我用我的初步数据开发了一个初始线性回归模型， 它与我发表的临床数据相一致，现在观察到镰状细胞和健康对照之间增加了约1.7倍。 在这个建议中，我将使用我的微流体组织模拟平台来确定红细胞压积的影响， DCS血流指数（Aim 1）。接下来，我将开发和验证DCS校正算法，以对抗“黄金- 标准”灌注模式，动脉自旋标记（ASL）MRI，以可靠地量化SCA中的脑血流量 患者（目标2）。在完成拟议的目标后，我将有足够的体外和临床数据来支持 进一步的实验将探索DCS的临床效用。

Project Summary/Abstract Stroke is a devastating complication of sickle cell anemia (SCA), a blood disorder, where SCA pediatric patients are 250 times more likely to have a stroke than age-matched healthy controls. Red blood cell abnormalities contribute to vascular occlusion, significantly increasing the risk of stroke. By age 20, 11% of SCA pediatric patients will experience an overt stroke, and by age 14, approximately 40% will have a silent infarct. Silent infarcts do not present with clinically apparent symptoms; they can only be visualized on neuroimaging scans. Early transcranial Doppler ultrasound (TCD) screening of SCA patients, with rapid initiation of transfusion therapy, has resulted in successful reduction of overt strokes. However, TCD suffers from poor specificity to overt stroke (i.e., some TCD deemed low-risk patients still develop a stroke), and it is completely insensitive to silent infarct risk. Microvascular measurements of blood flow show promise as a complementary tool to TCD measurements. Yet, current imaging modalities that measure microvascular perfusion (i.e., MRI, PET) are not applicable for routine use due to need for contrast and/or radiation, high costs, and/or sedation in children <6y. Thus, there is a clinical need for a low-cost tool that measures microvascular cerebral blood flow in a routine manner to detect any abnormalities in cerebral blood flow to ultimately mitigate stroke risk. Diffuse correlation spectroscopy (DCS) is an emerging low-cost (<$50k), non-invasive optical modality that utilizes near-infrared light to directly sense red blood cell movement and measure microvascular cerebral blood flow. To date, we have demonstrated that DCS measures a higher resting state cerebral blood flow (by 3x) in sickle cell children in comparison to healthy controls. However, this increase is not comparable to the commonly reported ~1.5x increase from MRI/PET. Since these SCA patients experience moderate to severe anemia and DCS is sensitive to red blood cell movement and density, I hypothesize that this quantitative difference in DCS blood flow measurements may be attributed to anemia. To test this hypothesis, I designed, developed, and validated a microfluidic tissue-simulating platform, with hundreds of embedded microchannels. This platform allows me to systematically manipulate flow rate, hematocrit, and vessel size for both healthy and sickle blood. My preliminary data with healthy blood demonstrates the confounding influence of hematocrit on DCS blood flow measurements. I used my preliminary data to develop an initial linear regression model, applied it to my published clinical data, and now observe a ~1.7x increase between sickle cell and healthy controls. In this proposal, I will use my microfluidic tissue-simulating platform to determine the effects of hematocrit on the DCS blood flow index (Aim 1). Next, I will develop and validate DCS correction algorithms against a “gold- standard” perfusion modality, arterial spin-labeled (ASL) MRI to reliably quantify cerebral blood flow in SCA patients (Aim 2). Upon completion of the proposed aims, I will have sufficient in vitro and clinical data to support further experiments that will explore the clinical utility of DCS.