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

描述(申请人提供)：肺医学面临着广泛的未得到满足的临床需求，主要有三个原因：(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)在儿童肺部疾病中缺乏无辐射的诊断方法，以便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障碍的分级标准。提供一种安全、负担得起和高度定量的肺功能三维成像方法将改善对疾病的早期诊断和鉴别，加快制药公司对治疗方法的测试，并帮助儿童和成人患者进行个性化的疾病管理和干预决策。超极化氙气磁共振成像(HXE)是解决这一需求的主要候选方法。由于肺中HXE原子的去极化是由顺磁性氧气分子的存在所主导的，因此确定信号损失率的成像序列可以被解释为局部肺泡氧浓度的MAP。我们最近在HXE生产技术方面进行了数百倍的改进，提供了多升数量的高极化HXE。我们已经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，并在几个月的时间里进行远程操作。我们的氙气调谐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度和最大的加速系数，允许在单个屏气中获得多个3D图像。我们的第一阶段项目通过实施和执行脉冲序列来确定肺HXE的信号丢失率，应用新的图像配准技术，并估计由于HXE丢失而进入血流的校正，从而证明了稳健、定量、高分辨率协议的可行性。在这个第二阶段的项目中，我们建议建立局部肺泡氧气的HXE图谱，作为一种临床验证和商业可行的诊断方案。我们将使用三种最先进的加速方案来实施重建氧诱导的信号丢失的成像序列，以比较它们的分辨率、信噪比、对伪影的敏感性和生物标记物的准确性。我们将把这些序列与三个真实标准进行比较：精确混合的气体袋，健康志愿者用气体浓度分析校准的呼出气体进行潮气呼吸，以及呼吸过度的健康志愿者呼出的气体用气体浓度分析校准。将潮气呼吸后的测量结果与过度换气后的其他测量结果进行比较，可以对我们的模型进行校准和改进，以校正血液中丢失的10%氙气信号。最后，我们将探索和演示该方案在几个COPD(呼吸异常)、间质性疾病(气体交换异常)和镰状细胞疾病(血流异常)患者的诊断和严重程度分期中的应用。美国FDA已经批准我们的超极化氙气用于肺部疾病患者的第二阶段试验。 公共卫生相关性：超极化氙气肺功能磁共振成像技术最近改进了两个数量级，有可能解决在管理包括COPD、哮喘、囊性纤维化和间质性疾病在内的各种肺部疾病方面未得到满足的需求。我们建议开发一种创新的、健壮的、定量的三维高分辨率局部肺泡氧浓度探头，并对照TRUE标准进行验证。这种非电离、耐受性好、快速和负担得起的成像方式将为通过成年患者照顾儿童的肺科医生提供最高肺功能指标的地图：进入血液的局部氧气交换。

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.