Diffuse optical spectroscopies to assess cerebral hemodynamics in pediatric sickle cell disease

项目摘要 无症状性脑梗死是镰状细胞病（SCD）的一种严重后果，约40%的患者受到以下影响： 15岁。虽然这些损伤会神秘地累积，但它们与认知缺陷、减少上学时间、 表现，并增加明显中风的风险。我们的长期目标是开发一种低成本的大脑监测 一种可以筛查儿童SCD中无症状梗死风险的工具，以促进及时的治疗干预， 优化这些干预措施以减轻不良事件。SCD中的无症状性梗死被认为是由贫血引起的- 诱导的微血管灌注异常和随后的脑血管储备减少， 不足以满足组织代谢需求。因此，定量微血管脑内异常 血流量、血管反应性和/或氧气提取可能有助于识别梗死风险。事实上，最近 MRI研究表明，患有无症状性梗死的SCD儿童在两种情况下的氧摄取均全面升高， 白色和灰色物质与无梗死的患者相比。然而，目前量化微血管的方法， 血液动力学参数（例如，PET、MRI）昂贵得令人望而却步，具有有限的可用性，并且需要 麻醉的儿童<6岁，使其不适合作为常规筛查工具。经颅多普勒 大血管血流速度的超声测量在降低明显的动脉粥样硬化风险方面取得了巨大的成功， 大血管系统卒中的发生率<80%;然而，超声对无症状的微血管梗死不敏感。 因此，存在对微血管、组织水平敏感的低成本、非侵入性工具的未满足的临床需求。 儿科SCD中的脑血流动力学异常，以检测有无症状性梗死风险的儿童。 漫射光谱（即频域近红外光谱与漫射光谱相结合） 相关光谱，FDNIRS/DCS）可以提供一个用户友好的，成本效益的替代电流 技术.这些非侵入性技术使用近红外光将测量到的光强度变化联系起来 在组织表面检测到的血流动力学特性与下层组织的血流动力学特性之间的关系。联合，FDNIRS/DCS 能够评估氧摄取、脑血流量指数和脑氧指数 新陈代谢.此外，使用简单的屏气激发，FDNIRS/DCS可以评估脑血管反应性， 血管系统对二氧化碳的扩张能力我们的初步结果表明，FDNIRS/DCS 可以检测SCD患者脑氧提取和血流的预期趋势（即，相比升高 与血红蛋白呈负相关）。此外，我们还制定了新的分析战略， 通过考虑血细胞比容的影响来提高DCS测量的血流指数的准确性。 基于这些初步数据，本提案的总体目标是验证我们的DCS红细胞压积- 根据“金标准”灌注MRI进行校正，以确定FDNIRS/DCS是否对脑损伤敏感。 无症状性梗死患者的血流动力学异常，并证明FDNIRS/DCS可以评估真实的- 输血期间脑血流动力学的时间变化，这降低了SCD患者的无症状性梗死风险。

Project Summary Silent cerebral infarction is a serious consequence of sickle cell disease (SCD), affecting ~40% of patients by age 15. Although these injuries accumulate occultly, they are linked with cognitive deficits, diminished school performance, and increased risk of overt stroke. Our long-term goal is to develop a low-cost brain monitoring tool that can screen for silent infarct risk in pediatric SCD to facilitate timely therapeutic intervention and that can optimize these interventions to mitigate adverse events. Silent infarcts in SCD are thought to arise from anemia- induced microvascular perfusion abnormalities and subsequent reduced cerebrovascular reserve that is insufficient to meet tissue metabolic demands. Thus, quantification of abnormalities in microvascular cerebral blood flow, vascular reactivity, and/or oxygen extraction may be useful in identifying infarct risk. Indeed, recent MRI studies have shown that SCD children with silent infarcts have globally elevated oxygen extraction in both white and grey matter compared to those without infarct. However, current modalities that quantify microvascular hemodynamic parameters (e.g., PET, MRI) are prohibitively expensive, have limited availability, and require anesthesia in children <6y, making them inappropriate as routine screening tools. Transcranial Doppler ultrasound measures of macrovascular blood flow velocity have had great success in reducing the risk of overt strokes of the macrovasculature by <80%; however, ultrasound is not sensitive to silent microvascular infarcts. Thus, there is an unmet clinical need for a low-cost, non-invasive tool sensitive to microvascular, tissue-level cerebral hemodynamic abnormalities in pediatric SCD to detect children at risk for silent infarcts. Diffuse optical spectroscopies (namely frequency domain near-infrared spectroscopy combined with diffuse correlation spectroscopy, FDNIRS/DCS) may provide a user-friendly, cost-effective alternative to current technologies. These non-invasive techniques use near-infrared light to relate measured changes in light intensity detected at the tissue surface to hemodynamic properties of the underlying tissue. Combined, FDNIRS/DCS enable assessment of oxygen extraction, an index of cerebral blood flow, and an index of cerebral oxygen metabolism. Further, using a simple breath hold challenge, FDNIRS/DCS can assess cerebrovascular reactivity, the vasculature’s ability to dilate in response to carbon dioxide. Our preliminary results show that FDNIRS/DCS can detect expected trends in brain oxygen extraction and blood flow in SCD patients (i.e., elevated compared to controls, inverse correlation with hemoglobin). Moreover, we have developed new analytical strategies that improve the accuracy of the DCS-measured blood flow index by accounting for the influence of hematocrit. Building on this preliminary data, the overall objective of this proposal is to validate our DCS hematocrit- correction against “gold-standard” perfusion MRI, to determine if FDNIRS/DCS is sensitive to cerebral hemodynamic abnormalities in patients with silent infarcts, and to demonstrate FDNIRS/DCS can assess real- time changes in cerebral hemodynamics during transfusion, which reduces silent infarct risk in SCD patients.