Optimizing Tissue Iron Quantification at 3 Tesla

摘要 铁超载是一种令人惊讶的常见临床并发症，由过度吸收引起，如 遗传性血色素沉着症和中间地中海贫血，或来自反复输血的患者 血红蛋白病或骨髓衰竭。铁会悄悄积累多年，但最终会毒害肝脏， 内分泌腺和心脏。我们实验室率先使用1.5特斯拉(1.5T)核磁共振对铁进行定量 心脏、肝脏、胰腺和脑下垂体的负担，根据MRI参数对临床风险进行分层， R2和R2*。因此，磁共振成像对肝脏和心脏铁的估计已成为 血红蛋白病中心，并被接受为铁螯合疗法临床试验的代用品。 到目前为止，铁的量化仅限于1.5吨磁铁；然而，新开发的3特斯拉(3T) 磁铁有可能提高对末端器官毒性的认识，并深入了解 组织铁沉积，但需要新的方法来成像观察到的高肝铁浓度(LIC) 一些病人。我们的第一个具体目标是交叉校准和临床验证3T时的R2和R2*估计值。 接受1.5T扫描以确定临床适应症的患者(大约每周4次)将被邀请参加 接受联合研究、3T检查和内分泌/肝功能的血清学评估。 将对患者进行分层，以提供器官铁负担和潜在疾病状态的广泛样本； 将进行心脏、肝脏和胰腺检查(n=100)和脑垂体检查。 测量(n=60)。我们假设R2和R2*在3T时将相对于测量值线性缩放 在1.5T，但在不同的坡度。我们进一步假设，器官体积和脂肪的3T评估 浓度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，以克服当前的动态范围 3T时肝铁定量的局限性及HIGH改进的组织定征 实地测量。快速信号损耗电流防止在3T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域自由感应衰减和自旋- 回波采集，以精确测量3T时的高LIC。线圈本地化多回波自旋回波采集将 也可用于测量含铁血黄素聚集体和胞浆铁蛋白的差示信号衰减特性。 肝脏。我们推测，停止铁离子螯合治疗一周会明显增加胞浆。 在保持含铁血黄素池不变的情况下，肝脏中的铁蛋白池；恢复治疗应该会逆转 观察结果。在如此短的时间内跟踪肝脏铁存储的变化的能力可能被证明是有价值的 用于快速评估对治疗的反应以及研究肝铁的机制和动力学 摄取和清除。这项工作将拓宽患者获得非侵入性铁评估的途径，改进检测 对临床前铁毒性的研究，并对铁储存池的动态变化提供了新的见解。

ABSTRACT 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 for 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.