magnetization transfer (MT) measurements were performed in vitro at 3 T and 37°C on a variety of tissues: mouse liver, muscle, and heart; rat spinal cord and kidney; bovine optic nerve, cartilage, and white and gray matter; and human blood. The MR parameters were compared to those at 1.5 T. As expected, the T 2 relaxation time constants and quantitative MT parameters (MT exchange rate, R, macromolecular pool fraction, M 0B , and macromolecular T 2 relaxation time, T 2B ) at 3 T were similar to those at 1.5 T. Longitudinal, T 1 , and transverse, T 2 , relaxation time measurements are relevant in understanding water molecular dynamics in biologic systems. T 1 , T 2 relaxation times and MT depend on the chemical and physical environments of water protons in tissue. MRI contrast between normal and pathologic tissue is often based on differences in tissue microstructure and, therefore, different T 1 and T 2 relaxation times. Moreover, T 1 , T 2 , and MT provide quantitative assessment of tissue pathology. In particular, they offer additional information about the processes of demyelination and axonal loss (1-4), inflammation (5), infarction (6), white matter edema (7), tumor malignancy (8), and ischemia (9). Both tissue relaxation and MT parameter estimates are important in designing MRI pulse sequences that aim to accentuate contrast between normal and pathologic tissue. Since MRI at higher fields (particularly 3 T) has become more common, it is important to evaluate MR parameters of tissue quantitatively to determine MRI sequence parameters, such as TE (echo time), TR (repetition time), or MT saturation schemes, that provide an optimal contrast. The literature data regarding MR parameters at high fields (such as 3 T) is surprisingly limited. The goal of this study is to provide a comprehensive evaluation of MR parameters at 3 T to serve as reference for further MRI pulse sequence optimization. Therefore, T 1 and T 2 relaxation, and MT parameters at 3 T and 37°C for a wide range of tissues: liver, muscle, optic nerve, spinal cord, heart, kidney, white (corpus callosum) and gray matter (brain cortex), cartilage, and blood were measured and compared to those at 1.5 T. EXPERIMENTAL METHODS MR MeasurementsAll 3 T, MR measurements were performed at 37°C using a research-dedicated, whole body GE SIGNA magnet. MR pulse sequences and data acquisition were controlled by an NMR spectroscopy console (SMIS, Surrey, England). Rectangular radiofrequency (RF) pulses were transmitted by an RF amplifier (American Microwave Technology, Brea, CA; model 3205) and solenoid RF coil designed to accommodate in vitro tissue measurements in test tubes (9 turns, 8 mm in diameter, 15 mm length). Immediately after tissue excision, the samples (approximately 300 L by volume) were immersed in non-protonated, MR-compatible fluid (Fluorinert; 3M, London, Canada) to avoid dehydration and reduce magnetic susceptibility effects. Temperature was controlled by an air-flow mechanism with MR-compatible thermocouple (Luxtron) inserted into the measured sam...

Magnetization transfer contrast (MTC) experiments using off-resonance irradiation have been performed with an agar gel model by systematically varying offset frequency, amplitude of the RF irradiation and gel concentration. The experimental results are shown to be quantitatively modelled by a two-pool system consisting of a liquid pool with a Lorentzian line shape and a small semisolid pool with a Gaussian lineshape. The fitted model yields physically realistic fundamental parameters with a T2 of the semisolid pool of 13 microseconds. Further analysis shows that the off-resonance irradiation MTC experiment had significant limitations in its ability to saturate the semisolid pool without directly affecting the liquid component.

This review describes magnetization transfer (MT) contrast in magnetic resonance imaging. A qualitative description of how MT works is provided along with experimental evidence that leads to a quantitative model for MT in tissues. The implementation of MT saturation in imaging sequences and the interpretation of the MT-induced signal change in terms of exchange processes and direct effects are presented. Finally, highlights of clinical uses of MT are outlined and future directions for investigation proposed.

An analytical model of restricted diffusion in bovine optic nerve is presented. The nerve tissue model is composed of two different objects: prolate ellipsoids (axons) and spheres (glial cells) surrounded by partially permeable membranes. The free diffusion coefficients of intracellular and extracellular water may differ. Analytical formulas for signal loss due to diffusion in the pulsed gradient spin echo (PGSE) experiment for this tissue model are derived. The model is fitted to experimental data for bovine optic nerve. The obtained model parameters are shown to be reasonable. The model describes all of the characteristics of the PGSE data: anisotropy, upward curvature of decay curves, and diffusion time dependence. The validity and sensitivity of the model are also discussed.

Orientational anisotropy of T2 and T1 relaxation times, diffusion, and magnetization transfer has been investigated for six different tissues: tendon, cartilage, kidney, muscle, white matter, and optic nerve. Relaxation anisotropy was observed for tendon and cartilage, and diffusional anisotropy was measured in kidney, muscle, white matter, and optic nerve. All other NMR measurements of these tissues showed no orientational dependence. This pattern of NMR anisotropies can be interpreted from the underlying geometrical structures of the tissues.

Chemically-fixed nervous tissues are well-suited for high-resolution, time-intensive MRI acquisitions without motion artifacts, such as those required for brain atlas projects, but the aldehyde fixatives used may significantly alter tissue MRI properties. To test this hypothesis, this study characterized the impact of common aldehyde fixatives on the MRI properties of a rat brain slice model. Rat cortical slices immersion-fixed in 4% formaldehyde demonstrated 21% and 81% reductions in tissue T 1 and T 2 , respectively (P < 0.001). The T 2 reduction was reversed by washing slices with phosphate-buffered saline (PBS) for 12 h to remove free formaldehyde solution. Diffusion MRI of cortical slices analyzed with a two-compartment analytical model of water diffusion demonstrated 88% and 30% increases in extracellular apparent diffusion coefficient (ADC EX ) and apparent restriction size, respectively, when slices were chemically-fixed with 4% formaldehyde (P ≤ 0.021). Further, fixation with 4% formaldehyde increased the transmembrane water exchange rate 239% (P < 0.001), indicating increased membrane permeability. Karnovsky's and 4% glutaraldehyde fixative solutions also changed the MRI properties of cortical slices, but significant differences were noted between the different fixative treatments (P < 0.05). The observed water relaxation and diffusion changes help better define the validity and limitations of using chemically-fixed nervous tissue for MRI investigations. Magn Reson Med 62:26 -34, 2009.

b S Supporting Information ' INTRODUCTIONColloidal nanomaterials show unique properties and are widely explored for a variety of applications. 1À4 Lanthanidebased nanomaterials have versatile utility in biological applications, as they can be made either as luminescent, magnetic, or as dual probe by selective doping of lanthanide ions. 5 In particular, paramagnetic Gd 3+ -doped NPs show tremendous potential as contrast agents (CAs) for magnetic resonance imaging (MRI). 6,7 MRI is a powerful medical diagnostic tool, where the relaxation of water protons exposed to an external magnetic field is used to obtain morphological and anatomical information with unlimited tissue penetration and yet high spatial resolution. 8 CAs are used to improve the sensitivity, because they interact with the surrounding water protons and shorten their relaxation time to provide better contrast. Two types of CAs are clinically prevalent: (i) paramagnetic Gd 3+ chelates, which affect the longitudinal relaxivity (r 1 ), and are termed positive (T 1 ) CAs, because they enhance the contrast; 9 and (ii) superparamagnetic iron oxide (SPIO) NPs, which affect transverse relaxivity (r 2 ) and are referred to as negative (T 2 ) CAs, because they diminish the signal intensity at the region of interest. 7,10 T 1 contrast agents are preferred over the T 2 agents as their enhanced brightening effect can easily be used to differentiate the signal from other pathogenic or biological conditions. 7 Gd 3+ chelates that are used clinically have very low body circulation time, because of their low molecular weight and show limitations as molecular probes for long-term tracking. 6 They also provide very low local contrast, because each chelate has only one Gd 3+ ion. To increase the local contrast and relaxivity, second-generation agents have been developed by covalently anchoring Gd 3+ chelates to different nanostructure frameworks, 11 or bundling multiple Gd 3+ chelates together using polymers, dendrimers, liposomes, and viral capsids. 12 These structures have been shown to have high relaxivity and increased local contrast as multiple Gd 3+ ions are coupled to a single nanostructure. The main disadvantage of this class of agents concerns their functionalization, which is tedious, expensive, and the number of ions that can be loaded to a NP is further limited by the number of anchoring sites available. Moreover, some of these aggregates are too large to be clinically useful. 6,7 Recently,

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