1H MRI Research Articles

Novel S-Gal® analogs as 1H MRI reporters for in vivo detection of β-galactosidase

The quantitative assessment of gene expression and related enzyme activity in vivo could be important for the characterization of gene altering diseases and therapy. The development of imaging techniques, based on specific reporter molecules may enable routine non-invasive assessment of enzyme activity and gene expression in vivo. We recently reported the use of commercially available S-Gal® as a β-galactosidase reporter for 1H MRI, and the synthesis of several S-Gal® analogs with enhanced response to β-galactosidase activity. We have now compared these analogs in vitro and have identified the optimal analog, C3-GD, based on strong T1 and T2 response to enzyme presence (ΔR1 and ΔR2~1.8 times S-Gal®). Moreover, application is demonstrated in vivo in human breast tumor xenografts. MRI studies in MCF7-lacZ tumors implanted subcutaneously in athymic nude mice (n=6), showed significant reduction in T1 and T2 values (each~13%) 2h after intra-tumoral injection of C3-GD, whereas the MCF7 (wild type) tumors showed slight increase. Thus, C3-GD successfully detects β-galactosidase activity in vivo and shows promise as a lacZ gene 1H MR reporter molecule.

Effect of protein denaturation degree on texture and water state of cooked meat

We prepared cooked meat with varied denaturation degrees that were predicted based on 3D finite element heat transfer analysis and reaction kinetics. Using a meat sample with a clear denaturation distribution, we performed stress-relaxation measurements to obtain the elastic modulus and identified the state of water in the meat by using proton magnetic resonance imaging (1H MRI) for quantification of a transverse relaxation time (T2). Even after the complete denaturation of myosin, the elastic modulus did not exceed 14kPa, which is not large compared with 6kPa for unheated meat. However, when actin denaturation was initiated, the elastic modulus dramatically increased while the T2 value at the meat surface remarkably decreased. The difference in the state of water between the surface and the core reflected the uneven denaturation distribution in the meat caused by heating. When actin denaturation was complete, the elastic modulus reached 60kPa, which was the equilibrium value, and T2 decreased and its distribution became more flat.

Alleviating artifacts in 1H MRI thermometry by single scan spatiotemporal encoding

Recent years have seen an increased interest in combining MRI thermometry with devices capable of destroying malignancies by heat ablation. Expected from the MR protocols are accurate and fast thermal characterizations, providing real time feedback on restricted tissue volumes and/or rapidly moving organs like liver. This article explores the potential advantages of relying on spatiotemporally encoded (SPEN) sequences for retrieving real-time thermometric images based on the water's proton resonance frequency (PRF) shifts. Hybrid spatiotemporal/k-space encoding single-scan MRI experiments were implemented on animal and human scanners, and their abilities to deliver single- and multi-slice real-time thermometric measurements based on PRF-derived phase maps in phantoms and in vivo, were compared against echo planar imaging (EPI) and gradient-echo counterparts. Under comparable acquisition conditions, SPEN exhibited advantages vis-à-vis EPI in terms of dealing with inhomogeneous magnetic field distortions, with shifts arising due to changes in the central frequency offsets, with PRF distributions, and for zooming into restricted fields-of-view without special pulse sequence provisions. This work confirms the ability of SPEN sequences, particularly when implemented under fully-refocused conditions, to exploit their built-in robustness to shift- and field-derived inhomogeneities for monitoring thermal changes in real-time under in vitro and in vivo conditions.

A noninvasive tumor oxygenation imaging strategy using magnetic resonance imaging of endogenous blood and tissue water

To present a novel imaging strategy for noninvasive measurement of tumor oxygenation using MR imaging of endogenous blood and tissue water. The proposed approach for oxygen partial pressure (pO2) estimation is based on intravoxel incoherent motion diffusion MRI and the dependence of the blood R2 relaxation rate on the inter-echo spacing measured using a multiple spin-echo Carr-Purcell-Meiboom-Gill sequence and weak-field diffusion model. The accuracy of the approach was validated by comparison with (19)F MRI oximetry. The results in eight rats at 4.7 T showed that tumors have longer T1 (1980 ± 186 ms) and T2 (59 ± 9 ms) relaxation times, heterogeneous blood volume fraction (0.23 ± 0.1), oxygen saturation level (Y) (0.53 ± 0.12), and pO2 (36 ± 15 mmHg) distributions compared with normal muscle (T1 1480 ± 86 ms, T2 29 ± 2 ms, blood volume fraction 0.22 ± 0.03, Y 0.49 ± 0.06, and pO2 39 ± 5 mmHg). pO2 estimates based on the novel (1)H approach were essentially identical with (19)F observations. The study indicates that noninvasive measurement of tumor pO2 using (1)H MRI derived multiparametric maps is feasible and could become a valuable tool to evaluate tumor hypoxia.

Real‐Time Multipoint Gastrointestinal 19‐Fluorine Catheter Tracking

To develop MR based real-time gastrointestinal 19-Fluorine (19F) catheter tracking and visualization allowing for real-time detection and feedback of 3D catheter shape and movement as well as catheter-driven adjustments of 1H imaging geometry parameters. Data were acquired on a 3T clinical system using 3D Golden Angle radial sampling. Two gastrointestinal catheters incorporating four fiducial 19F markers (65 or 50 µL marker volume) were tracked while being pulled through a gel phantom by an operator inside the MR room with velocities of 2-18 mm/s. During continuous acquisition, k-space profiles were transferred in real-time to an external computer for concurrent reconstruction of 3D 19F images and detection and visualization of marker positions. Based on αthe marker positions, automatic adjustments of 1H imaging planes to facilitate targeted anatomical scanning was implemented. Mean tracking reliabilities were 94.5 and 83.6% (catheters 1 and 2) for temporal resolutions 185-740 ms. Reconstruction times of 196 ms were achieved. Real-time visual feedback allowed the operator to accurately control the catheter movement. Catheter-guidance for 1H imaging was reliable. The presented real-time 19F MR based framework for the tracking of 19F labeled devices is applicable to combined 19F and 1H MRI guidance of gastrointestinal devices in vivo.

Water-soluble gold nanoparticles (AuNP) functionalized with a gadolinium(iii) chelate via Michael addition for use as a MRI contrast agent.

A contrast agent suitable for magnetic resonance imaging based on small, water soluble gold nanoparticles (AuNP) conjugated to over 50 Gd3+ chelators has been prepared by using an interfacial Michael addition in aqueous media. The resultant chelator-AuNP conjugates have been successfully characterised by 1H NMR spectroscopy, IR spectroscopy, ICP-OES, ζ-potential analysis, TEM and MRI. T1-weighted in vivo images of mouse kidney were obtained using the agent at 9.4 T. A preliminary in vivo experiment produced no ill effects and the clearance profile of the agent suggests it is suitable for animal testing at clinically relevant concentrations.

Microencapsulated cell tracking

Microencapsulation of therapeutic cells has been widely pursued to achieve cellular immunoprotection following transplantation. Initial clinical studies have shown the potential of microencapsulation using semi-permeable alginate layers, but much needs to be learned about the optimal delivery route, in vivo pattern of engraftment, and microcapsule stability over time. In parallel with noninvasive imaging techniques for 'naked' (i.e. unencapsulated) cell tracking, microcapsules have now been endowed with contrast agents that can be visualized by (1) H MRI, (19) F MRI, X-ray/computed tomography and ultrasound imaging. By placing the contrast agent formulation in the extracellular space of the hydrogel, large amounts of contrast agents can be incorporated with negligible toxicity. This has led to a new generation of imaging biomaterials that can render cells visible with multiple imaging modalities.

1H MRI study of small-diameter silk vascular grafts in water

Small-diameter vascular grafts (VG) made from silk fibroin (SF) fibers by a double-raschel knitting method were prepared by coating their interior and exterior with different materials, such as SF or polyurethane (PU). The 1H spin density, 1H spin–spin relaxation time (T2) and diffusion coefficient (D) of the water molecules in the layer of the VG coated by these materials were non-destructively observed in water using 1H NMR imaging. The inner and outer coating materials significantly affected the amount and mobility of water molecules in the VG. The water content of the SF-coated VG was considerably higher than that of PU-coated VG. The T2 value of the water molecules in the SF-coated VG layer was smaller than that of the PU-coated VG, which means that the rotational motion of the water molecules in the layer of the SF-coated VG was restricted by the intermolecular interaction between the SF and water molecules. The diffusion coefficient (D) of the water molecules in the SF-coated VG layer was larger than that of the PU-coated VG, indicating that the water molecules were confined to the pores in the graft layer of the PU-coated VG. The images of 1H spin density, 1H T2 and diffusion coefficient (D) of water molecules in the layer of silk-based vascular grafts (VG) coated by different materials that are silk fibroin or polyurethane were non-destructively observed in water using 1H MR imaging. The inner and outer coating materials affect significantly the amount and mobility of water molecules in the VG.

Novel Fe3+-Based 1H MRI β-Galactosidase Reporter Molecules**

There is increasing interest in the development of reporter agents to reveal enzyme activity in vivo using small animal imaging. We have previously demonstrated the feasibility of detecting lacZ gene activity using the commercially available 3,4-cyclohexenoesculetin-β-D-galactopyranoside (S-Gal™) as a 1H MRI reporter. Specifically, β-galactosidase (β-gal) releases the aglycone, which forms an MR contrast-inducing paramagnetic precipitate in the presence of Fe3+. Contrast was primarily T2-weighted signal loss, but T1 effects were also observed. Since T1-contrast generally provides signal enhancement as opposed to loss, it appeared attractive to explore whether analogues could be generated with enhanced characteristics. We now report the design and successful synthesis of novel analogues together with characterization of 1H MRI contrast based on both T1 and T2 response to β-gal activity in vitro for the lead agent.

Chest MRI in children: Why bother?

Chest MRI in children: Why bother?

Effect of implantation site and growth of hepatocellular carcinoma on apparent diffusion coefficient of water and sodium MRI

Hepatocellular carcinoma (HCC) and liver metastases are an increasing problem worldwide. Non-invasive methods for the early detection of HCC and understanding of the tumor growth mechanisms are highly desirable. Both the diffusion-weighted (1)H (DWI) and (23)Na MRI reflect alterations in tissue compartment volumes in tumors, as well as physiological and metabolic transformation in cells. Effects of untreated growth on apparent diffusion coefficient of water (ADC), single quantum (SQ) and triple quantum-filtered (TQF) (23)Na MRI were compared in intrahepatically and subcutaneously implanted HCCs in rats. Animals were examined weekly for 4 weeks after injection of N1S1 cells. ADC of intrahepatic HCC was 1.5-times higher compared to the nearby liver tissue, and with growth, the ADC did not increase. ADC of subcutaneous HCC was lower compared to intrahepatic HCC and it increased with growth. Untreated growth of both intrahepatic and subcutaneous HCCs was associated with an increase in SQ and TQF (23)Na signal intensity suggesting an increase in tissue Na(+) and intracellular Na(+) (Na(+)(i)), respectively, most likely due to an increase in relative extracellular space and Na(+)(i) concentration as a result of changes in tissue structure and cellular metabolism. Thus, SQ and TQF (23)Na MRI may be complementary to diffusion imaging in areas susceptible to motion for characterizing hepatic tumors and for other applications, such as, predicting and monitoring therapy response.

Effects of gadolinium chelate on the evolution of the nanoscale structure in peptide hydrogels

Small-angle X-ray scattering (SAXS) was used to monitor peptide hydrogelation with and without the MRI contrast agent gadolinium chelate (Gd(III)-chelate). The gelators are a pair of decapeptides that are self-repulsive but mutually attractive. Gd(III)-chelate was either free or covalently bound to one of the decapeptides. Free and conjugated Gd(III)-chelate have the opposite effects on peptide gelation: free Gd(III)-chelate slows down gelation while having little effect on the cross-sectional area of peptide fibers; covalently conjugated Gd(III)-chelate speeds up gelation and results in peptide fibers with significantly greater cross-sectional area. After 24 h of gelation, the cross-sectional areas of hydrogels with no Gd(III)-chelate, with free Gd(III)-chelate and with conjugated Gd(III) chelate are 3700, 3800, and 6300 Å(2), respectively. Free Gd(III)-chelate is not incorporated into peptide fibers and remains in solution with little effect on MRI intensity upon gelation. In contrast, covalently conjugated Gd(III)-chelate is not only incorporated into peptide fibers, but further aggregates toward the center of the peptide fibers. In conclusion, to visualize hydrogelation using (1)H MRI, it is necessary to conjugate Gd(III)-chelate to the material covalently and use T(2)-weighted imaging.

SU-F-BRA-08: Development of Novel 1H Magnetic Resonance Imaging Methods to Map Lung Structure and Function

Purpose: Our objective was to develop novel non‐invasive pulmonary protonmagnetic resonance imaging (1H MRI) for simultaneous regional evaluation of lung function and structure in smoking‐related lung disease. Currently there is no pulmonary structure/function 1H MRI technique that can be made universally available for conventional clinical MRI systems. We focused on short echo time (TE) and Fourier‐decomposition (FD) methods providing critical technological steps required to develop lung 1H MRI for therapy guidance. Methods: In this pilot study, nine healthy never‐smokers and 11 COPD subjects underwent same‐day plethysmography, spirometry, short echo time ((TE) =1.2ms) 1H and hyperpolarized 3HeMRI at 3.0T. High resolution x‐ray computed tomography (HRCT) was also performed to measure the relative area less than 950 Houndsfield units (HU) (RA950) and lung density at the 15th percentile (HU15%). Results: We showed the feasibility of FD 1H MRI to obtain lung ventilation maps and also showed that 1H MRI signal intensity (SI) was significantly correlated with 3He apparent diffusion coefficients ADC (r=−.58, p=.008), CT measurements of emphysema (RA950 r=−.69, p=.02 and HU15%, r=.66, p=.03) and conventional measurements of pulmonary function. Conclusions: These findings suggest 1H MRI can be developed as a non‐invasive structure/function imaging tool for monitoring lung disease. Pulmonary lung structure/function 1H MRI requires minimal patient compliance, can be accomplished in less than 5 minutes of image acquisition time and is not dependent on gating techniques, creating an opportunity for serial studies of lung functional changes in lung cancer and COPD.

Lateral diffusion of manganese in the rat brain determined by T1 relaxation time measured by 1H MRI

In order to optimize manganese ion-enhanced MRI in thalamic and hypothalamic nuclei, we analyzed the diffusion of manganese in the brain followed by the intra-cerebroventricular application of manganese-bicine (Mn-bicine). T(1)-weighted MRI intensities, with 9-pixel ROIs in the hypothalamus perpendicular to the third ventricle, were measured during continuous infusion of Mn-bicine solution in the lateral cerebroventricle. Using a relationship between the image intensity of T(1)-weighted MRI and T(1) relaxation time, the image intensity was converted into the concentration of manganese. Assuming a simple diffusion process, the apparent diffusion coefficient (D (ap)) of manganese (4.2×10(-5)mm(2)s(-1)) is much lower than that of water (6×10(-4)mm(2)s(-1)), and the D (ap) tended to decrease when the distance from the third ventricle increased. These results suggest (1) the Mn(2+) ion is trapped by neural cells during diffusion and (2) the manganese efflux is discharged from the brain via veins.

S-Gal, a novel 1H MRI reporter for beta-galactosidase.

Reporter genes and associated enzyme activity are becoming increasingly significant for research in vivo. The lacZ gene and beta-galactosidase (beta-gal) expression have long been exploited as reporters of biologic manipulation at the molecular level, and a noninvasive detection strategy based on proton MRI is particularly attractive. 3,4-Cyclohexenoesculetin beta-D-galactopyranoside (S-Gal) is a commercial histologic stain, which forms a black precipitate in the presence of beta-gal and ferric ions, suggesting potential detectability by MRI. Generation of the precipitate is now shown to cause strong T(2)* relaxation, revealing beta-gal activity. A series of tests with the enzyme in vitro and with tumor cells shows that this approach can be used as an assay for beta-gal activity. Proof of principle is shown in human breast tumor xenografts in mice. Upon direct injection of a mixture of 3,4-cyclohexenoesculetin beta-D-galactopyranoside and ferric ammonium citrate, intense contrast was observed immediately in MCF7-lacZ tumors, but not in wild-type tumors. 3,4-Cyclohexenoesculetin beta-D-galactopyranoside activation in combination with ferric ions introduces a novel approach for assaying enzyme activity by MRI in vivo.

TH‐D‐201C‐05: Monitoring Response of Liver Cancer to Targeted Radiation Therapy with a Novel 31P/1H MRS Coil

Purpose: To present a novel multi‐channel dual‐tuned 31P/1H MRS coil which allows for non‐invasive acquisition of in‐vivo phosphorus (31P) spectroscopy data from the whole liver. We hypothesize MRS data collected with this coil can improve the assessment of early tumor response to targeted radiation therapy. Method and Materials: A novel dual‐tuned 8‐channel 31P/1H coil for a Siemens 3T Tim Trio whole Body MRI scanner was designed and validated. The coil consists of two plates placed anterior and posterior of the patient's torso with four 31P receive elements (24×20 cm2) each. Furthermore each plate has one 31P transmit element and one 1H transmit‐receive element. Thus the coil allows for 31P MRS conventional MRI and 1H MRS during the same scan session. For our clinical study the 31P MRS data was acquired with a 2D slice selective free‐induction‐decay (FID) sequence using the following parameters: TE 2.3 ms TR 1 s field of view (FOV) 400×400×30 mm3 nominal voxel size 25×25×30 mm3 30 weighted averages. Each free‐induction‐decay (FID) was acquired with 2048 points over a bandwidth of 5000 Hz. The resulting scan time was about 25 min. Results: In vivo 31P liver spectra and 1H MRI images of the entire liver were successfully acquired in healthy volunteers and patients undergoing targeted radiation therapy. The optimized 31P MRS sequence allowed for identification and quantification of ATP phosphomonoesters (PME) phosphodiesters (PDE) and inorganic phosphate (Pi) metabolites throughout the liver on an axial slice. Metabolic differences between healthy and malignant liver tissue were clearly identified. Conclusions: We have shown that our novel 31P/1H MRS coil allows for assessing 31P metabolites in lesions located in deep tissue while being able to run conventional MRI imaging scans during the same scan session.

High Relaxivity Trimetallic Nitride (Gd3N) Metallofullerene MRI Contrast Agents with Optimized Functionality

Water-soluble poly(ethylene glycol) (PEG) functionalized and hydroxylated endohedral trimetallic nitride metallofullerene derivatives, Gd(3)N@C(80)[DiPEG(OH)(x)], have been synthesized and characterized. The (1)H MRI relaxivities in aqueous solution were measured for the derivatives with four different molecular weights of PEG (350-5000 Da) at 0.35, 2.4, and 9.4 T. The 350/750 Da PEG derivatives have the highest relaxivities among the derivatives, 237/232 mM(-1) s(-1) for r(1) and 460/398 mM(-1) s(-1) for r(2) (79/77 mM(-1) s(-1) and 153/133 mM(-1) s(-1) based on Gd(3+) ion), respectively, at a clinical-range magnetic field of 2.4 T. These represent some of the highest relaxivities reported for commercial or investigational MRI contrast agents. Dynamic light scattering results confirm a larger average size for 350/750 Da PEGs derivatives (95/96 nm) relative to longer chain length derivatives, 5000 Da PEG derivatives (37 nm). Direct infusion of the optimized 350 Da PEG derivatives into live tumor-bearing rat brains demonstrated an initial uniform distribution, and hence, the potential for effective brachytherapy applications when the encapsulated Gd(3+) ions are replaced with radioactive (177)Lu.

Quantitative 31P NMR spectroscopy and 1H MRI measurements of bone mineral and matrix density differentiate metabolic bone diseases in rat models

In this study, bone mineral density (BMD) of normal (CON), ovariectomized (OVX), and partially nephrectomized (NFR) rats was measured by 31P NMR spectroscopy; bone matrix density was measured by 1H water- and fat-suppressed projection imaging (WASPI); and the extent of bone mineralization (EBM) was obtained by the ratio of BMD/bone matrix density. The capability of these MR methods to distinguish the bone composition of the CON, OVX, and NFR groups was evaluated against chemical analysis (gravimetry). For cortical bone specimens, BMD of the CON and OVX groups was not significantly different; BMD of the NFR group was 22.1% (by 31P NMR) and 17.5% (by gravimetry) lower than CON. For trabecular bone specimens, BMD of the OVX group was 40.5% (by 31P NMR) and 24.6% (by gravimetry) lower than CON; BMD of the NFR group was 26.8% (by 31P NMR) and 21.5% (by gravimetry) lower than CON. No significant change of cortical bone matrix density between CON and OVX was observed by WASPI or gravimetry; NFR cortical bone matrix density was 10.3% (by WASPI) and 13.9% (by gravimetry) lower than CON. OVX trabecular bone matrix density was 38.0% (by WASPI) and 30.8% (by gravimetry) lower than CON, while no significant change in NFR trabecular bone matrix density was observed by either method. The EBMs of OVX cortical and trabecular specimens were slightly higher than CON but not significantly different from CON. Importantly, EBMs of NFR cortical and trabecular specimens were 12.4% and 26.3% lower than CON by 31P NMR/WASPI, respectively, and 4.0% and 11.9% lower by gravimetry. Histopathology showed evidence of osteoporosis in the OVX group and severe secondary hyperparathyroidism (renal osteodystrophy) in the NFR group. These results demonstrate that the combined 31P NMR/WASPI method is capable of discerning the difference in EBM between animals with osteoporosis and those with impaired bone mineralization.

Flexible magnetoinductive ring MRI detector: Design for invariant nearest-neighbour coupling

A flexible birdcage-type resonant RF detector for magnetic resonance imaging is described. The circuit consists of a polygonal ring of magnetically coupled L– C resonators, a periodic structure supporting backward magnetoinductive waves. The elements are mechanically linked to allow relative rotation, and the pivot point is optimised to hold the nearest-neighbour coupling coefficient invariant to small changes in the angle of an undistorted joint. Simple theory based on a parallel wire approximation to rectangular inductors is developed to allow the variation of the coupling coefficient with angle and radius to be estimated, and hence determine the location of the pivot. The optimised pivot is shown to reduce resonance splitting in octagonal rings. However, second-neighbour interactions degrade performance. The theory is verified experimentally using printed circuit board elements coupled by flexible hinges, and the invariance of the nearest-neighbour coupling coefficient is confirmed. Octagonal ring resonators are constructed for operation at 63.8 MHz frequency and the mode spectra of regular and distorted rings are measured. Magnetic resonance imaging properties are investigated using 1H MRI of simple objects in a 1.5 T field. Images are obtained from undistorted and distorted resonators and the effect of distortion on SNR is quantified.

Water properties and salt uptake in Atlantic salmon fillets as affected by ante-mortem stress, rigor mortis, and brine salting: A low-field 1H NMR and 1H/ 23Na MRI study

A low-field (LF) 1H NMR T 2 relaxation and 23Na/ 1H MRI study was performed on Atlantic salmon to study the effect of ante-mortem handling stress and rigor mortis on muscle water properties and subsequent post-rigor salting. Compared to rested fish, exhausted fish exhibited a more rapid and stronger development of rigor mortis. This resulted in significant differences in post-rigor water-holding capacity and salt uptake. By LF NMR T 2 relaxation analysis significant differences in water distribution according to (1) ante-mortem handling, (2) fillet location, and (3) brine salting were detected. Furthermore, 23Na MRI revealed differences between the two treatments in fillet salt distribution, where the salt penetration in exhausted fillets was more pronounced. By combining 1H and 23Na MR images, the salt diffusion and distribution seemed to be highly affected by the distribution of fat.