Molecular Magnetic Resonance Imaging of Fibrin Deposition in the Liver as an Indicator of Tissue Injury and Inflammation.

RATIONALE AND OBJECTIVES: Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation. METHODS: Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation. RESULTS: After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis. CONCLUSIONS: EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.

A Manganese Alternative to Gadolinium for MRI Contrast.

Contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used to diagnose soft tissue and vascular abnormalities. However, safety concerns limit the use of iodinated and gadolinium (Gd)-based CT and MRI contrast media in renally compromised patients. With an estimated 14% of the US population suffering from chronic kidney disease (CKD), contrast media compatible with renal impairment is sorely needed. We present the new manganese(II) complex [Mn(PyC3A)(H2O)](-) as a Gd alternative. [Mn(PyC3A)(H2O)](-) is among the most stable Mn(II) complexes at pH 7.4 (log KML = 11.40). In the presence of 25 mol equiv of Zn at pH 6.0, 37 °C, [Mn(PyC3A)(H2O)](-) is 20-fold more resistant to dissociation than [Gd(DTPA)(H2O)](2-). Relaxivity of [Mn(PyC3A)(H2O)](-) in blood plasma is comparable to commercial Gd contrast agents. Biodistribution analysis confirms that [Mn(PyC3A)(H2O)](-) clears via a mixed renal/hepatobiliary pathway with >99% elimination by 24 h. [Mn(PyC3A)(H2O)](-) was modified to form a bifunctional chelator and 4 chelates were conjugated to a fibrin-specific peptide to give Mn-FBP. Mn-FBP binds the soluble fibrin fragment DD(E) with Kd = 110 nM. Per Mn relaxivity of Mn-FBP is 4-fold greater than [Mn(PyC3A)(H2O)](-) and increases 60% in the presence of fibrin, consistent with binding. Mn-FBP provided equivalent thrombus enhancement to the state of the art Gd analogue, EP-2104R, in a rat model of arterial thrombosis. Mn metabolite analysis reveals no evidence of dechelation and the probe was >99% eliminated after 24 h. [Mn(PyC3A)(H2O)](-) is a lead development candidate for an imaging probe that is compatible with renally compromised patients.

Hexameric Mn(II) dendrimer as MRI contrast agent.

A Mn(II) chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine-derived [Mn(EDTA)(H2 O)](2-) moieties coupled to a cyclotriphosphazene core. Variable temperature (17) O NMR spectroscopy revealed a single water co-ligand per Mn(II) that undergoes fast water exchange (kex =(3.0±0.1)×10(8) s(-1) at 37 °C). The 37 °C per Mn(II) relaxivity ranged from 8.2 to 3.8 mM(-1) s(-1) from 0.47 to 11.7 T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(±0.02) ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H2 O)](2-) in mice at 4.7 T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H2 O)](2-) . Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn(II) containing dendrimer represents a potential alternative to Gd-based contrast agents, especially in patients with chronic kidney disease where the use of current Gd-based agents may be contraindicated.

Quadruple inversion-recovery b-SSFP MRA of the abdomen: initial clinical validation.

The purpose of this study is to assess the image quality and diagnostic accuracy of non-contrast quadruple inversion-recovery balanced-SSFP MRA (QIR MRA) for detection of aortoiliac disease in a clinical population. QIR MRA was performed in 26 patients referred for routine clinical gadolinium-enhanced MRA (Gd-MRA) for known or suspected aortoiliac disease. Non-contrast images were independently evaluated for image quality and degree of stenosis by two radiologists, using consensus Gd-MRA as the reference standard. Hemodynamically significant stenosis (≥50%) was found in 10% (22/226) of all evaluable segments on Gd-MRA. The sensitivity and specificity for stenosis evaluation by QIR MRA for the two readers were 86%/86% and 95%/93% respectively. Negative predictive value and positive predictive value were 98%/98% and 63%/53% respectively. For stenosis evaluation of the aortoiliac region QIR MRA showed good agreement with the reference standard with high negative predictive value and a tendency to overestimate mild disease presumably due to the flow-dependence of the technique. QIR MRA could be a reasonable alternative to Gd-MRA for ruling out stenosis when contrast is contraindicated due to impaired kidney function or in patients who undergo abdominal MRA for screening purposes. Further work is necessary to improve performance and justify routine clinical use.

Sagittal fresh blood imaging with interleaved acquisition of systolic and diastolic data for improved robustness to motion.

PURPOSE: To improve robustness to patient motion of "fresh blood imaging" (FBI) for lower extremity noncontrast MR angiography. METHODS: In FBI, two sets of three-dimensional fast spin echo images are acquired at different cardiac phases and subtracted to generate bright-blood angiograms. Routinely performed with a single coronal slab and sequential acquisition of systolic and diastolic data, FBI is prone to subtraction errors due to patient motion. In this preliminary feasibility study, FBI was implemented with two sagittal imaging slabs, and the systolic and diastolic acquisitions were interleaved to minimize sensitivity to motion. The proposed technique was evaluated in volunteers and patients. RESULTS: In 10 volunteers, imaged while performing controlled movements, interleaved FBI demonstrated better tolerance to subject motion than sequential FBI. In one patient with peripheral arterial disease, interleaved FBI offered better depiction of collateral flow by reducing sensitivity to inadvertent motion. CONCLUSIONS: FBI with interleaved acquisition of diastolic and systolic data in two sagittal imaging slabs offers improved tolerance to patient motion.

Comparison of nonenhanced MR angiographic subtraction techniques for infragenual arteries at 1.5 T: a preliminary study.

PURPOSE: To evaluate diagnostic performance of three nonenhanced methods: variable-refocusing-flip angle (FA) fast spin-echo (SE)-based magnetic resonance (MR) angiography (variable FA MR) and constant-refocusing-FA fast SE-based MR angiography (constant-FA MR) and flow-sensitive dephasing (FSD)-prepared steady-state free precession MR angiography (FSD MR) for calf arteries, with dual-injection three-station contrast material-enhanced MR angiography (gadolinium-enhanced MR) as reference. MATERIALS AND METHODS: This prospective study was institutional review board approved and HIPAA compliant, with informed consent. Twenty-one patients (13 men, eight women; mean age, 62.6 years) underwent calf-station variable-FA MR, constant-FA MR, and FSD MR at 1.5 T, with gadolinium-enhanced MR as reference. Image quality and stenosis severity were assessed in 13 segments per leg by two radiologists blinded to clinical data. Combined constant-FA MR and FSD MR reading was also performed. Methods were compared (logistic regression for correlated data) for diagnostic accuracy. RESULTS: Of 546 arterial segments, 148 (27.1%) had a hemodynamically significant (≥ 50%) stenosis. Image quality was satisfactory for all nonenhanced MR sequences. FSD MR was significantly superior to both other sequences (P < .0001), with 5-cm smaller field of view; 9.6% variable-FA MR, 9.6% constant-FA MR, and 0% FSD MR segmental evaluations had nondiagnostic image quality scores, mainly from high diastolic flow (variable-FA MR) and motion artifact (constant-FA MR). Stenosis sensitivity and specificity were highest for FSD MR (80.3% and 81.7%, respectively), compared with those for constant-FA MR (72.3%, P = .086; and 81.8%, P = .96) and variable-FA MR (75.9%, P = .54; and 75.6%, P = .22). Combined constant-FA MR and FSD MR had superior sensitivity (81.8%) and specificity (88.3%) compared with constant-FA MR (P = .0076), variable-FA MR (P = .0044), and FSD MR (P = .0013). All sequences had an excellent negative predictive value (NPV): 93.2%, constant-FA MR; 94.7%, variable-FA MR; 91.7%, FSD MR; and 92.9%, combined constant-FA MR and FSD MR. CONCLUSION: At 1.5 T, all evaluated nonenhanced MR angiographic methods demonstrated satisfactory image quality and excellent NPV for hemodynamically significant stenosis. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120859/-/DC1.

Noncontrast MR angiography for comprehensive assessment of abdominopelvic arteries using quadruple inversion-recovery preconditioning and 3D balanced steady-state free precession imaging.

PURPOSE: To develop a noncontrast magnetic resonance angiography (MRA) method for comprehensive evaluation of abdominopelvic arteries in a single 3D acquisition. MATERIALS AND METHODS: A noncontrast MRA (NC MRA) pulse sequence was developed using four inversion-recovery (IR) pulses and 3D balanced steady-state free precession (b-SSFP) readout to provide arterial imaging from renal to external iliac arteries. Respiratory triggered, high spatial resolution (1.3 × 1.3 × 1.7 mm(3)) noncontrast angiograms were obtained in seven volunteers and ten patients referred for gadolinium-enhanced MRA (CE MRA). Images were assessed for diagnostic quality by two radiologists. Quantitative measurements of arterial signal contrast were also performed. RESULTS: NC MRA imaging was successfully completed in all subjects in 7.0 ± 2.3 minutes. In controls, image quality of NC MRA averaged 2.79 ± 0.39 on a scale of 0-3, where 3 is maximum. Image quality of NC MRA (2.65 ± 0.41) was comparable to that of CE MRA (2.9 ± 0.32) in all patients. Contrast ratio measurements in patients demonstrated that NC MRA provides arterial contrast comparable to source CE MRA images with adequate venous and excellent background tissue suppression. CONCLUSION: The proposed noncontrast MRA pulse sequence provides high-quality visualization of abdominopelvic arteries within clinically feasible scan times.

Tailoring the flow sensitivity of fast spin-echo sequences for noncontrast peripheral MR angiography.

There has recently been renewed interest in noncontrast techniques for peripheral MR angiography following the discovery of an association between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with renal insufficiency. The "fresh blood imaging" technique proposed by Miyazaki et al. involves the subtraction of two three-dimensional fast spin-echo image sets, one acquired in systole, when the arteries appear dark due to flow-related dephasing, and the other obtained in diastole, when the arteries are brighter. Our goal was to investigate how parameters of the fast spin-echo sequence influence its flow sensitivity, and how that in turn impacts the depiction of large and small arteries. Results from phantom experiments and human studies in the calf suggest that the flow sensitivity is governed largely by the flip angle of the radiofrequency refocusing pulses. The area of the spoiler gradients has a lesser effect, and at low flip angles the echo time plays a role. These parameters can be optimized to obtain good depiction of the calf arteries in healthy subjects. It remains to be seen whether they provide sufficient control over flow sensitivity to achieve diagnostic-quality images in other vascular beds and in the presence of pathology.

Three-dimensional electrocardiographically gated variable flip angle FSE imaging for MR angiography of the hands at 3.0 T: initial experience.

After institutional review board approval and informed consent were obtained for this HIPAA-compliant investigation, a three-dimensional electrocardiographically gated variable flip angle (VFA) fast spin-echo magnetic resonance (MR) angiography technique was evaluated as an unenhanced method for imaging hand arteries in 13 subjects (including four patients) at 3.0 T; this included evaluation of vessel visualization with warming and cooling in seven subjects. Examinations were evaluated for image quality and vessel conspicuity. Clear separation of arteries from veins was achieved in all subjects, with excellent vessel conspicuity and depiction of stenoses. Warming improved vessel visualization in healthy volunteers. VFA MR angiography is a high-spatial-resolution technique that enables the assessment of vascular reactivity in response to temperature challenge.