Optimized whole-lung mapping of the oxygen concentration in human lungs, using Hy

描述（申请人提供）：肺科医学面临着广泛的未满足的临床需求，主要原因有三个：（1）缺乏关于肺功能的区域和定量信息，特别是在阻塞性疾病中;（2）缺乏儿科肺部疾病的无辐射诊断模式，以在正确的时间开始治疗;（3）缺乏间质性肺疾病炎症活动和扩散屏障的分级量表。一种安全、负担得起且高度定量的肺功能三维成像模式的可用性将改善疾病的早期诊断和鉴别，加速制药公司对疗法的测试，并有助于儿童和成人患者的个性化疾病管理和干预决策。超极化氙（HSP 70）MRI是解决这一需求的领先候选者。由于肺中受阻原子的去极化由顺磁性氧气分子的存在主导，因此确定信号损失速率的成像序列可以被解释为局部肺泡氧浓度的图。我们最近在HPLOSE生产技术上进行了百倍的改进，可提供多升数量的高极化HPLOSE。我们将这项技术整合到一个紧凑的平台中，交付给临床合作伙伴，并在几个月的时间内远程操作。我们的氙调谐32元件并行接收线圈与集成的非对称鸟笼发射线圈实现了高度均匀的翻转角，具有最大的加速系数，允许在一次屏气中获得多个3D图像。我们的I期项目通过实施和执行脉冲序列（可确定肺动脉阻塞的信号丢失率）、应用新型图像配准技术以及估计由于阻塞进入血流而导致的校正，证明了稳健、定量、高分辨率方案的可行性。 在这个第2阶段的项目中，我们建议建立局部肺泡氧的HALTH映射作为临床验证和商业上可行的诊断协议。我们将实施成像序列，用三种最先进的加速方案重建氧诱导的信号丢失，以比较它们的分辨率、SNR、对伪影的敏感性和生物标志物的准确性。我们将这些序列与三个真值标准进行比较：精确混合的气体袋，健康志愿者进行潮气呼吸，呼出气体经过气体浓度分析校准，过度换气的健康志愿者呼出气体经过气体浓度分析校准。将潮气呼吸后的测量结果与过度通气后的测量结果进行比较，将允许校准和改进我们的模型，以校正<10%的氙信号损失到血流中。最后，我们将探讨并证明该方案在COPD（通气异常）、间质性疾病（气体交换异常）和镰状细胞病（灌注异常）患者的诊断和严重程度分期中的实用性。美国FDA已批准我们的超极化氙用于肺部疾病受试者的2期试验。 公共卫生相关性：采用超极化氙的肺功能磁共振成像是一项最近改进了两个数量级的技术，有可能解决管理各种肺部疾病（包括COPD、哮喘、囊性纤维化和间质性疾病）方面未满足的需求。我们建议开发一种创新的，强大的，和定量的探头区域肺泡氧浓度与高分辨率的三维和验证它对真理的标准。这种非电离、耐受性良好、快速且经济实惠的成像方式将为从儿童到成人患者的肺科医生提供肺功能的最高测量图：局部氧气交换到血流中。

DESCRIPTION (provided by applicant): Pulmonary medicine is facing a broad spectrum of unmet clinical needs, mainly for three reasons: (1) Lack of regional and quantitative information about lung function especially in obstructive disease; (2) Lack of a radiation-free diagnostic modality in pediatric lung diseases to initiate treatment at the right time; (3) Lack of a grading scale for inflammatory activity and diffusion barriers in interstitial lung disease. The availability of a safe, affordable, and highly quantitative modality for 3-D imaging of lung function would improve early diagnosis and discrimination of diseases, accelerate testing of therapies by pharmaceutical companies, and assist in personalized disease management and intervention decisions for children and adult patients. Hyperpolarized xenon (HXe) MRI is a leading candidate to address this need. Since the depolarization of HXe atoms in lungs is dominated by the presence of paramagnetic oxygen gas molecules, an imaging sequence that determines the rate of signal loss can be interpreted as a map of the local alveolar oxygen concentration. Our recent hundred-fold improvements in HXe production technology deliver high polarizations of HXe in multi-liter quantities. We have incorporated this technology into a compact platform, delivered it to clinical partners, and operated it remotely over periods of several months. Our xenon-tuned 32-element parallel receive coil with integrated asymmetric birdcage transmit coil achieves highly uniform flip angles with maximal speed-up factors, allowing several 3D images in a single breath hold. Our Phase I project demonstrated feasibility for a robust, quantitative, high resolution protocol by implementing and performing pulse sequences that determine the rate of signal loss of pulmonary HXe, applying novel image registration techniques, and estimating corrections due to loss of HXe into the bloodstream. In this Phase 2 project we propose to establish HXe mapping of local alveolar oxygen as a clinically validated and commercially viable diagnostic protocol. We will implement imaging sequences that reconstruct oxygen-induced signal loss with three state-of-the-art acceleration schemes to compare their resolution, SNR, susceptibility to artifacts, and biomarker accuracy. We will compare these sequences against three truth standards: precisely mixed bags of gas, healthy volunteers performing tidal breathing with their exhaled gases calibrated with gas concentration analysis, and hyperventilated healthy volunteers with exhaled gases calibrated with gas concentration analysis. Comparing measurements after tidal breathing to others after hyperventilating will allow calibration and improvement of our models correcting for <10% xenon signal lost to the bloodstream. Finally we will explore and demonstrate the utility of this protocol in the diagnosis and severity staging of several patients with COPD (ventilation abnormalities), interstitial disease (gas exchange abnormalities), and sickle cell disease (perfusion abnormalities). The US FDA has approved our hyperpolarized xenon for Phase 2 trials in subjects with lung disease. PUBLIC HEALTH RELEVANCE: Pulmonary functional magnetic resonance imaging with hyperpolarized xenon, a technology which recently improved by two orders of magnitude, has the potential to address unmet needs in managing a full range of lung diseases, including COPD, asthma, cystic fibrosis, and interstitial diseases. We propose to develop an innovative, robust, and quantitative probe of regional alveolar oxygen concentration with high resolution in three-dimensions and validate it against truth standards. This non-ionizing, well-tolerated, quick, and affordable imaging modality would provide pulmonologists caring for children through adult patients with maps of the highest measure of lung function: regional oxygen exchange into the bloodstream.