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

项目摘要 无症状性脑梗塞是镰状细胞病(SCD)的严重后果，约40%的患者因 15岁。虽然这些伤害是潜移默化的，但它们与认知缺陷、学习成绩下降有关 表现，并增加了明显中风的风险。我们的长期目标是开发一种低成本的大脑监测器 一种工具，可以筛查儿童SCD中无症状的脑梗塞风险，以促进及时的治疗干预，并可以 优化这些干预措施以减少不良事件。SCD中的无症状脑梗塞被认为是由贫血引起的- 诱发的微血管灌注异常和随后的脑血管储备减少，即 不足以满足组织代谢需求。因此，脑微血管异常的量化 血流、血管反应性和/或氧摄取可能有助于识别梗死风险。事实上，最近 核磁共振研究表明，患有无症状脑梗塞的SCD儿童在两个部位的氧摄取率均显著升高。 脑白质和灰质与非梗死组比较。然而，目前量化微血管的方式 血流动力学参数(例如，PET、MRI)昂贵得令人望而却步，可获得性有限，并且需要 麻醉在儿童中的应用，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临床风险方面取得了巨大成功。 大血管卒中减少80%；然而，超声对静止性微血管梗塞不敏感。 因此，对一种对微血管、组织水平敏感的低成本、非侵入性工具的临床需求尚未得到满足。 儿童SCD的脑血流动力学异常以检测有无症状脑梗塞风险的儿童。 漫反射光谱(即频域近红外光谱与漫反射相结合 相关光谱，FDNIRS/DCS)可以提供一种用户友好的、成本效益高的替代当前 技术。这些非侵入性技术使用近红外光来关联测量到的光强度变化。 在组织表面检测到下面组织的血流动力学特性。FDNIRS/集散控制系统组合 能够评估氧摄取率、脑血流量指数和脑氧量指数 新陈代谢。此外，使用简单的屏气挑战，FDNIRS/DCS可以评估脑血管反应性， 血管系统对二氧化碳的反应能力。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量的预期趋势(即，与 与对照组相比，与血红蛋白呈负相关)。此外，我们还开发了新的分析策略， 通过计入红细胞压积的影响，提高了DCS测量血流指数的准确性。 在此初步数据的基础上，本提案的总体目标是验证我们的分布式控制系统的红细胞压积。 校正“金标准”磁共振灌注成像，以确定FDNIRS/DCS对脑部是否敏感 无症状性脑梗塞患者的血流动力学异常，并证明FDNIRS/DCS可以评估真实的 在输血过程中脑血流动力学的时间变化，从而降低SCD患者的无症状性脑梗塞风险。

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.