Preclinical applications and clinical translation of QUTE-CE MRA technique for vascular imaging

Abstract

First, a background on magnetic resonance imaging (MRI) and angiography (MRA) is provided. With this context, an introduction to the prior development of the Quantitative Ultra-Short Time-to-Echo Contrast-Enhanced (QUTE-CE) MRI technique is provided, and the theory underlying the useful aspects of the technique is derived. We then apply QUTE-CE MRI to yield positive contrast angiograms with high clarity and definition in the whole live rat brain. A global map of quantitative cerebral blood volume (qCBV) in the awake resting state with unprecedented detail was created via the application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map, we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing, and vision, and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV, suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature, and cardiovascular function showed an increase in qCBV with anesthesia. During the awake CO$_2$ challenge, 84 regions showed significant increases relative to an awake baseline state. This CO$_2$ response provides a measure of cerebrovascular reactivity and regional perfusion reserve, with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization. Further preclinical neuroscience applications are briefly discussed. Next, we present first-in-human clinical results of the QUTE-CE MRA technique using the superparamagnetic iron oxide nanoparticle agent ferumoxytol for vascular imaging of the head and brain in 15 neurologically intact human subjects. The resulting angiograms provide high contrast snapshots of the arterial and venous networks with up to 10-fold higher image quality metrics than comparable MRA techniques (3D Time-of-Flight MRA and traditional T1-weighted blood-pool imaging with ferumoxytol or gadolinium). Artifacts due to susceptibility and flow are minimized, and vessel lumina are visualized with higher homogeneity compared with alternative approaches or previously reported in the literature. We show enhanced quantitative vessel morphometry is feasible and demonstrate and application to a clinically relevant case of non-occlusive thrombosis. The QUTE-CE MRA approach is potentially of great utility for the clinical assessment of vascular health and abnormalities present in vascular diseases while using a safe contrast agent with a long blood pool phase. This is followed by the application of the technique to kidney imaging in mice preclinically and an evaluation of the feasibility of QUTE-CE MRA for abdominal angiography in the human kidney. Four human subjects underwent ferumoxytol-enhanced MRA with the 3D UTE Spiral VIBE WIP sequence at 3T. Image quality metrics were quantified, specifically the blood Signal-to-Noise Ratio (SNR), blood-tissue Contrast-to-Noise Ratio (CNR), and Intraluminal Signal Heterogeneity (ISH) from both the aorta and inferior vena cava (IVC). Morphometric analysis of the vessels was performed using a manual approach and semi-automatic approach using Vascular Modeling ToolKit (VMTK). Image quality and branching order were compared between QUTE-CE MRA and the Gadolinium (Gd) CEMRA reference image. QUTE-CE MRA provides a bright blood snapshot that delineates arteries and veins equally in the same scan. The maximum SNR and CNR values were 3,282 ± 1,218 and 1,295 ± 580, respectively -- significantly higher than available literature values using other CEMRA techniques. QUTE-CE MRA had lower ISH and depicted higher vessel branching order (7th vs. 3rd) within the kidney compared to a standard dynamic clinical Gd CEMRA scan. The morphometric analysis yielded quantitative results for the total kidney volume, total cyst volume, and diameters of the branching arterial network down to the 7th branch. Vessel curvature was significantly increased (p < 0.001) in the presence of a renal cyst compared to equivalent vessels in normal kidney regions. QUTE-CE MRA is feasible for kidney angiography, providing greater detail of kidney vasculature, enabling quantitative morphometric analysis of the abdominal and intrarenal vessels, and yielding metrics relevant to vascular diseases while using a contrast agent ferumoxytol that is safe for chronic kidney disease (CKD) patients. The technique is then applied to evaluate a medical case in one subject of our ongoing studies. Next, the software and software platforms developed throughout this work are briefly explained. Finally, the key results are summarized, their broader impact is considered, and future directions are discussed.--Author's abstract