Monitoring Oxidative Capacity in Peripheral Artery Disease Patients using MR Imaging

摘要 据估计，850万美国人患有外周动脉疾病（PAD），它不仅干扰 一个人积极的生活方式;但也增加了心脏病发作和中风的风险。大多数PAD患者 无症状，表现为非典型疼痛，少数患者面临严重的肢体威胁后果。一旦 诊断为PAD，有一系列基于证据的治疗和介入选择， 包括监督锻炼，抗血栓药物，通过导管和手术恢复循环， 干预措施可用。这些都有可能改善患者的功能状态，并减少 mortality.已知骨骼肌中的氧化磷酸化（OXPHOS）能力在骨骼肌中受损。 需要PAD和工具（成像或其他）来帮助早期识别PAD患者 并监测监督运动和血运重建的效果。磷（31 P）磁共振 光谱学（31 PMRS）传统上被用作评估OXPHOS能力的非侵入性工具， 运动骨骼肌细胞内pH值的变化。然而，它的缺点是覆盖率低，空间差， 分离度和相对于磷酸肌酸半衰期的非常高的变异系数（COV）（约20-30%） 回收率（τPCr）。我们的团队以前开发了一种新的2D MRI方法，命名为肌酸化学交换 饱和转移（CrCEST）成像，作为具有改进的空间分辨率（~ 1x 1 mm 2）和 时间分辨率（τRes）约为30 s。最近，我们进一步改进了这种方法，以实现3D覆盖 同时保持相同的τRes 30 s。基于体素的肌酸恢复半衰期（τCr）估计 由于粗略的时间分辨率（30秒）与低有效信号相结合， 3D-CrCEST时间序列的噪声比（eSNR）（<20）。相反，我们进行了肌肉群特定的配合， 以体素方式固有的解剖/生理变化形式的有用信息被牺牲， 增加SNR。在另一个重要的发展中，我们开发了一种空间正则化重建方法， 在τCr ≥ 4τRes的条件下，证明了噪声鲁棒重建的可行性。考虑到 对于我们的跖屈运动方案，健康对照为约45- 80 s，需要改进τRes约10- 12 s。 在这个提议中，我们的目标是通过实现锁孔来提高CrCEST的时间分辨率： 成像与频率偏移（FO）方案中的改变相结合。通过将τRes提高一个因子， 在约2-3x的情况下，CrCEST时间序列中存在的信息内容将充分增加，以使噪声 τ Cr映射的鲁棒重建。为了减少生理来源的变异性成分，我们计划 调整运动负荷，以避免灌注曲线发生不可预测的剧烈变化。为了验证，我们 将比较所提出的方法与我们目前的3D CrCEST方案的结果， 感兴趣区域（ROI）。最后，我们将检验我们的假设，即临床上显著的功能状态变化， 血运重建后的PAD患者将通过τCr的可测量变化来反映。

ABSTRACT An estimated 8.5 million Americans suffer from peripheral artery disease (PAD) and it not only interferes with one’s active lifestyle; but also increases the risks for heart attacks and strokes. Most PAD patients are asymptomatic, present with atypical pain, and a minority face serious consequence of a threatened limb. Once diagnosed with PAD, a range of evidence-based therapeutic and interventional options are available, which includes supervised exercise, antithrombotic medications, and restoring circulation through catheter and surgical interventions are available. These have potentials to improve the functional status of the patient and reduce the mortality. Oxidative phosphorylation (OXPHOS) capacity in skeletal muscle are known to get compromised in PAD and hence, tools (imaging or otherwise) are needed for aiding in the early identification of patients with PAD and to monitor the effect of supervised exercise and revascularization. Phosphorus (31P) magnetic resonance spectroscopy (31PMRS) has traditionally been used as a noninvasive tool to evaluate the OXPHOS capacity and the change in intracellular pH of exercised skeletal muscle. However, it suffers from low coverage, poor spatial resolution and a very high coefficient of variation (COV) (~20-30%) with respect to half-life of phosphocreatine recovery (τPCr). Our team previously developed a novel 2D MRI method, named creatine chemical exchange saturation transfer (CrCEST) imaging, as an alternative with improved spatial resolution (~1x1 mm2) and a temporal resolution (τRes) of ~30s. Recently, we further improved on this method to enable the 3D coverage while maintaining the same τRes of 30s. The estimation of creatine recovery half-time (τCr) on a voxel-wise basis is currently not feasible due to the coarse temporal resolution (30s) combined with the low effective signal to noise ratio (eSNR) (<20) of 3D-CrCEST time-series. Rather, we performed muscle-group-specific fit, where the useful information in form of a voxel-wise inherent anatomic/physiological variation were sacrificed in return for increased SNR. In another important development, we developed a spatial regularized reconstruction approach and showed the feasibility of a noise robust reconstruction, provided τCr ≳4τRes. Given that the typical τCr of healthy control is ~45-80s for our plantar flexion exercise protocol, there is a need to improve on τRes ~10-12s. In this proposal, we aim to improve on the temporal resolution: τRes of CrCEST by implementing keyhole imaging in combination with the alteration in frequency offset (FO) schemes. By aiming to improve τRes by a factor of ~2-3x, the information content present in CrCEST time series would be sufficiently increased to enable a noise robust reconstruction of τCr-map. To reduce the component of variability with physiological origins, we plan to adjust the exercise load to avoid unpredictable and drastic changes in perfusion profile. For the validation, we will compare the findings from the proposed approach against our current 3D CrCEST protocol for comparable region of interest (ROI). Finally, we will test our hypothesis that clinical significant changes in function status of PAD patients post revascularization will be reflected by measurable changes in τCr‘s.