Comprehensive Neonatal Cardiac, Feed and Wrap, Non-contrast, Non-sedated, Free-breathing Compressed Sensing 4D Flow MRI Assessment.

BACKGROUND: Cardiac MRI is an important imaging tool in congenital cardiac disease, but its use has been limited in the neonatal population as general anesthesia has been needed for breath-holding. Technological advances in four-dimensional (4D) flow MRI have now made nonsedated free-breathing acquisition protocols a viable clinical option, but the method requires prospective validation in neonates. PURPOSE: To test the feasibility of compressed sensing (CS) 4D flow MRI in the neonatal population and to compare with standard previously validated two-dimensional (2D) phase-contrast (PC) flow MRI. STUDY TYPE: Prospective, cohort, image quality. POPULATION: A total of 14 healthy neonates (median [range] age: 2.5 [0-80] days; 8 male). FIELD STRENGTH AND SEQUENCE: Noncontrast 2D cine gradient echo sequence with through-plane velocity encoding (PC) sequence and compressed sensing (CS) three-dimensional (3D), time-resolved, cine phase-contrast MRI with 3D velocity-encoding (4D flow MRI) at 3 T. ASSESSMENT: Aortic 2D PC, and aortic, pulmonary trunk and superior vena cava CS 4D flow MRI were acquired using the feed and wrap technique (nonsedated) and quantified using commercially available software. Aortic flow and peak velocity were compared between methods. Internal consistency of 4D flow MRI was determined by comparing mean forward flow of the main pulmonary artery (MPA) vs. the sum of left and right pulmonary artery flows (LPA and RPA) and by comparing mean ascending aorta forward flow (AAo) vs. the sum of superior vena cava (SVC) and descending aorta flows (DAo). STATISTICAL TESTS: Flow and peak-velocity comparisons were assessed using paired t-tests, with P < 0.05 considered significant, and Bland-Altman analysis. Interobserver and intraobserver agreement and internal consistency were analyzed by intraclass correlation co-efficient (ICC). RESULTS: There was no statistically significant difference between ascending aortic forward flow between 2D PC and CS 4D Flow MRI (P = 0.26) with a bias of 0.11 mL (-0.59 to 0.82 mL) nor peak velocity (P = 0.11), with a bias of -5 cm/sec and (-26 to 16 cm/sec). There was excellent interobserver and intraobserver agreement for each vessel (interobserver ICC: AAo 1.00; DAo 0.94, SVC 0.90, MPA 0.99, RPA 0.98, LPA 0.96; intraobserver ICC: AAo 1.00; DAo 0.99, SVC 0.98, MPA 1.00, RPA 1.00, LPA 0.99). Internal consistency measures showed excellent agreement for both mean forward flow of main pulmonary artery vs. the sum of left and right pulmonary arteries (ICC: 0.95) and mean ascending aorta forward flow vs. the sum of superior vena cava and descending aorta flows (ICC: 1.00). CONCLUSION: Sedation-free neonatal feed and wrap MRI is well tolerated and feasible. CS 4D flow MRI quantification is similar to validated 2D PC free-breathing imaging with excellent interobserver and intraobserver agreement. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange.

Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this area's most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H labeling in both the agent and catalyst and achieve polarization lifetimes of ca 2 min with 50% polarization in the case of methyl-4,6-d2 -nicotinate. Because a 1.5-T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique's generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.

Achieving High Levels of NMR-Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination Using SABRE.

Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1 H NMR signals in a range of substrates in aqueous media. To achieve this outcome, phase-transfer catalysis is exploited, which leads to less than 1.5×10-6  mol dm-3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline-based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called catalyst separated hyperpolarization through signal amplification by reversible exchange or CASH-SABRE. We illustrate this method for the substrates pyrazine, 5-methylpyrimidine, 4,6-d2 -methyl nicotinate, 4,6-d2 -nicotinamide and pyridazine achieving 1 H signal gains of approximately 790-, 340-, 3000-, 260- and 380-fold per proton at 9.4 T at the time point at which phase separation is complete.

Extending the Scope of 19F Hyperpolarization through Signal Amplification by Reversible Exchange in MRI and NMR Spectroscopy.

Fluorinated ligands have a variety of uses in chemistry and industry, but it is their medical applications as 18F-labelled positron emission tomography (PET) tracers where they are most visible. In this work, we illustrate the potential of using 19F-containing ligands as future magnetic resonance imaging (MRI) contrast agents and as probes in magnetic resonance spectroscopy studies by significantly increasing their magnetic resonance detectability through the signal amplification by reversible exchange (SABRE) hyperpolarization method. We achieve 19F SABRE polarization in a wide range of molecules, including those essential to medication, and analyze how their steric bulk, the substrate loading, polarization transfer field, pH, and rate of ligand exchange impact the efficiency of SABRE. We conclude by presenting 19F MRI results in phantoms, which demonstrate that many of these agents show great promise as future 19F MRI contrast agents for diagnostic investigations.

Using signal amplification by reversible exchange (SABRE) to hyperpolarise 119Sn and 29Si NMR nuclei.

The hyperpolarisation of the 119Sn and 29Si nuclei in 5-(tributylstannyl)pyrimidine (ASn) and 5-(trimethylsilyl)pyrimidine (BSi) is achieved through their reaction with [IrCl(COD)(IMes)] (1a) or [IrCl(COD)(SIMes)] (1b) and parahydrogen via the SABRE process. 1a exhibits superior activity in both cases. The two inequivalent pyrimidine proton environments of ASn readily yielded signal enhancements totalling ∼2300-fold in its 1H NMR spectrum at a field strength of 9.4 T, with the corresponding 119Sn signal being 700 times stronger than normal. In contrast, BSi produced analogous 1H signal gains of ∼2400-fold and a 29Si signal that could be detected with a signal to noise ratio of 200 in a single scan. These sensitivity improvements allow NMR detection within seconds using micromole amounts of substrate and illustrate the analytical potential of this approach for high-sensitivity screening. Furthermore, after extended reaction times, a series of novel iridium trimers of general form [Ir(H)2Cl(NHC)(µ-pyrimidine-κN:κN')]3 precipitate from these solutions whose identity was confirmed crystallographically for BSi.

Creating a hyperpolarised pseudo singlet state through polarisation transfer from parahydrogen under SABRE.

The creation of magnetic states that have long lifetimes has been the subject of intense investigation, in part because of their potential to survive the time taken to travel from the point of injection in a patient to the point where a clinically diagnostic MRI trace is collected. We show here that it is possible to harness the signal amplification by reversible exchange (SABRE) process to create such states in a hyperpolarised form that improves their detectability in seconds without the need for any chemical change by reference to the model substrate 2-aminothiazole. We achieve this by transferring Zeeman derived polarisation that is 1500 times larger than that normally available at 400 MHz with greater than 90% efficiency into the new state, which in this case has a 27 second lifetime.

Investigating pyridazine and phthalazine exchange in a series of iridium complexes in order to define their role in the catalytic transfer of magnetisation from para-hydrogen.

The reaction of [Ir(IMes)(COD)Cl], [IMes = 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene, COD = 1,5-cyclooctadiene] with pyridazine (pdz) and phthalazine (phth) results in the formation of [Ir(COD)(IMes)(pdz)]Cl and [Ir(COD)(IMes)(phth)]Cl. These two complexes are shown by nuclear magnetic resonance (NMR) studies to undergo a haptotropic shift which interchanges pairs of protons within the bound ligands. When these complexes are exposed to hydrogen, they react to form [Ir(H)2(COD)(IMes)(pdz)]Cl and [Ir(H)2(COD)(IMes)(phth)]Cl, respectively, which ultimately convert to [Ir(H)2(IMes)(pdz)3]Cl and [Ir(H)2(IMes)(phth)3]Cl, as the COD is hydrogenated to form cyclooctane. These two dihydride complexes are shown, by NMR, to undergo both full N-heterocycle dissociation and a haptotropic shift, the rates of which are affected by both steric interactions and free ligand pKa values. The use of these complexes as catalysts in the transfer of polarisation from para-hydrogen to pyridazine and phthalazine via signal amplification by reversible exchange (SABRE) is explored. The possible future use of drugs which contain pyridazine and phthalazine motifs as in vivo or clinical magnetic resonance imaging probes is demonstrated; a range of NMR and phantom-based MRI measurements are reported.