Optimizing Tissue Iron Quantification at 3 Tesla

描述（由申请人提供）：铁过载是一种令人惊讶的常见临床并发症，由吸收过度引起，如遗传性血色病和中间型地中海贫血，或由血红蛋白病或骨髓衰竭患者的反复输血引起。铁会默默地积累多年，但最终会毒害肝脏、内分泌腺和心脏。我们的实验室率先使用1.5特斯拉（1.5T）MRI来量化心脏、肝脏、胰腺和脑垂体中的铁负荷，并根据MRI参数R2和R2* 对临床风险进行分层。因此，MRI衍生的肝脏和心脏铁的估计已成为血红蛋白病中心的标准护理，并被接受为铁螯合治疗临床试验的替代品。 到目前为止，铁的定量仅限于1.5T磁体;然而，新开发的3特斯拉（3 T）磁体可能提供对终末器官毒性的更好识别，并深入了解组织铁沉积物的大小和种类，但需要新的方法来成像在一些患者中观察到的高肝脏铁浓度（LIC）。我们的第一个具体目标是在3 T下交叉校准和临床验证R2和R2* 估计值。将邀请因临床适应症接受1.5T扫描（约每周4次）的患者接受联合研究3 T检查和内分泌/肝功能血清学评估。将对患者进行分层，以提供器官铁负荷和基础疾病状态的广泛样本;将进行心脏、肝脏和胰腺评估（n=100）和垂体测量（n=60）检查。我们假设3 T下的R2和R2* 将相对于1.5T下的测量值线性缩放，但斜率不同。我们进一步假设，器官体积和脂肪浓度的3 T评估将比单独的铁评估更好地区分靶器官毒性。 我们的第二个目标是开发和验证新的成像工具，以克服目前在3 T下肝脏铁定量的动态范围限制，并利用高场测量产生的改进的组织表征。快速的信号损失电流阻止了在3 T下测量高LIC值。我们将使用新的方法，包括超短回波时间技术和线圈局部自由感应衰减和自旋回波采集，以准确测量3 T下的高LIC。线圈定位多回波自旋回波采集也将用于测量肝脏中含铁血黄素聚集体和胞质铁蛋白的差异信号衰减特性。我们推测，停止铁螯合治疗一周将可检测地增加肝细胞溶质铁蛋白池，而血铁黄素池不变;恢复治疗应逆转观察结果。在如此短的时间尺度上跟踪肝脏铁储备变化的能力可能被证明对于快速评估对治疗的反应以及研究肝脏铁摄取和清除的机制和动力学是有价值的。这项工作将扩大患者对非侵入性铁估计的访问，改善临床前铁毒性的检测，并提供铁储存库动态变化的新见解。

DESCRIPTION (provided by applicant): Iron overload is a surprisingly common clinical complication, resulting from hyperabsorption, as in hereditary hemochromatosis and thalassemia intermedia, or from recurrent blood transfusions in patients with hemoglobinopathies or bone-marrow failure. Iron accumulates silently for years but ultimately poisons the liver, endocrine glands and heart. Our laboratory has pioneered the use of 1.5 Tesla (1.5T) MRI to quantify the iron burden in the heart, liver, pancreas, and pituitary gland, stratifying clinical risk according to the MRI parameters, R2 and R2*. As a result, MRI-derived estimates of liver and heart iron have become the standard of care in hemoglobinopathy centers and are accepted surrogates for clinical trials of iron chelation therapy. To date, iron quantification has been limited to 1.5T magnets; however, newly developed 3 Tesla (3T) magnets potentially offer improved recognition of end-organ toxicity and insight into the size and species of tissue iron deposits, but require new approaches to imaging the high liver iron concentrations (LIC) observed in some patients. Our first specific aim is to cross-calibrate and clinically validate R2 and R2* estimates at 3T. Patients who undergo 1.5T scanning for clinical indications (approximately 4 per week) will be invited to undergo a combined research 3T examination and serologic assessment of endocrine/hepatic function. Patients will be stratified to provide a broad sampling of organ iron burdens and underlying disease states; examinations will be performed for heart, liver, and pancreas assessment (n=100) and for pituitary measurements (n=60). We hypothesize that R2 and R2* at 3T will scale linearly with respect to measurements at 1.5T but at different slopes. We further hypothesize that 3T assessments of organ volume and fat concentration will better discriminate target organ toxicity than iron assessment alone. Our second aim is to develop and validate new imaging tools to overcome current dynamic range limitations of liver iron quantification at 3T and to exploit the improved tissue-characterization produced by high field measurements. Rapid signal loss current prevents measurement of high LIC values at 3T. We will use novel approaches, including ultrashort echo time techniques and coil-localized free induction decay and spin- echo acquisitions, to accurately measure high LIC at 3T. Coil-localized multi-echo spin-echo acquisitions will also be used to measure differential signal decay properties of hemosiderin aggregates and cytosolic ferritin in liver. We postulate that withholding iron chelation therapy fo one week will detectably increase the cytosolic ferritin pool in the liver while leaving the hemosiderin pool unchanged; resumption of therapy should reverse the observation. The ability to track changes in liver iron store on such a short-time scale may prove valuable for rapidly evaluating response to therapy as well as for studying the mechanisms and dynamics of hepatic iron uptake and clearance. This work will broaden patient access to noninvasive iron estimation, improve detection of preclinical iron toxicity, and offer new insights in dynamic changes of iron storage pools.