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

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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.