Quantitative imaging of magnetization transfer using an inversion recovery sequence.

A new imaging method has been developed for quantitatively measuring magnetization transfer (MT). It uses a simple inversion recovery sequence, although one with very short (milliseconds) inversion times, and thus can be implemented on clinical imaging systems with little modification to existing pulse sequences. The sequence requires an inversion pulse with a length much longer than T(2m) (typically 10 micros) and much shorter than T(2f) (typically tens of ms) and 1/k(mf) (typically tens of ms), where T(2m) and T(2f) are the transverse relaxation times of the immobile macromolecular and free water protons, respectively, and k(mf) is the rate of MT between these populations. The resultant NMR signal is sensitive to MT when this inversion pulse affects the mobile and immobile proton pools to different degrees and by appropriate analysis of the signals obtained for different inversion times, quantitative information can be derived on the macromolecular content and exchange rates within the sample. The method has been used in conjunction with echo planar imaging to produce maps of the spatial distribution of the macromolecular content and MT rate in cross-linked bovine serum albumin. Comparisons between this method and other quantitative MT techniques are discussed.     

Pulsed magnetization transfer spin-echo MR imaging

Cross relaxation between macromolecular protons and water protons is known to be important in biologic tissue. In magnetic resonance (MR) imaging sequences, selective saturation of the characteristically short T2 macromolecular proton pool can produce contrast called magnetization transfer contrast, based on the cross-relaxation process. Selective saturation can be achieved with continuous wave irradiation several kilohertz off resonance or short, intense 0° pulses on resonance. The authors analyze 0° binomial pulses for T2 selective saturation, present design guidelines, and demonstrate the use of these pulses in spin-echo imaging sequences in healthy volunteers and patients. Using the phenomenologic Bloch equations modified for two-site exchange, the authors derive the analytic expressions for water proton relaxation under periodic pulsed saturation of the macromolecular protons. This relaxation is shown to be monoexpo-nential, with a rate constant dependent on the saturation pulse repetition rate and the individual and cross-relaxation rates.     

Magnetic coupling of creatine/phosphocreatine protons in rat skeletal muscle, as studied by (1)H-magnetization transfer MRS.

Off-resonance saturation caused a reduction of the 3.04 ppm NMR signal from the methyl protons of creatine in rat hindleg skeletal muscle. (1)H-NMR spectra were recorded over a 200 kHz range of off-resonance saturation frequencies. The span of frequencies over which the creatine signal was reduced greatly exceeded that expected for direct saturation by the off-resonance RF-field. This suggests that there is a motionally restricted proton pool which exchanges magnetization with the free creatine pool. The experimental data were fitted to characterize the immobilized proton pool and the exchange kinetics, using a two-pool exchange model. The immobile pool was estimated to amount to ca. 2.5% of the mobile pool of free creatine, while the rate of exchange between the mobile and immobile configurations is ca. 2.3 sec(-1). After depletion of phosphocreatine by termination of the animal, the MT effect on the creatine methyl protons remained unchanged. This indicates that phosphocreatine and creatine both contribute to the MT phenomenon. Selective saturation of the mobile water pool also led to a reduction in the intensity of the total creatine methyl signal, suggesting that water and creatine are magnetically coupled via a macromolecular interface. The precise mechanism responsible for and the biological significance of the pronounced creatine magnetization transfer effect in rat skeletal muscle remains to be established. Magn Reson Med 42:665-672, 1999.     

Synergistic enhancement of MRI with Gd-DTPA and magnetization transfer.

Magnetization transfer (MT) between protons of macromolecules and protons of water molecules is a recently introduced mechanism for tissue contrast in MR imaging. The MT effect is strong in tissues where there is an efficient cross relaxation between macromolecular protons and water protons and where this interaction is the dominant source of relaxation. Paramagnetic ions shorten relaxation times and decrease the MT effect. These two facts led to the assumption that, in the case of contrast enhanced MRI, the combination of the T1-weighted imaging method and the MT technique may yield increased contrast, compared with standard methods. The synergistic effect is demonstrated in this work with studies of egg white samples and by imaging three patients with different brain pathologies. The lesion-to-white matter contrasts, with standard T1-weighted sequences with and without the MT effect, were compared before and after the introduction of Gd-DTPA. In each case the synergistic effect of T1 weighting and MT improved the contrast enhancement provided with Gd-diethylenetriamine pentaacetic acid.     

Quantitative magnetization transfer imaging via selective inversion recovery with short repetition times.

Quantitative magnetization transfer imaging (qMTI) methods are able to estimate fundamental sample parameters, such as the relative size of the solid-like macromolecular proton pool and the spin exchange rate between this pool and the directly measured free water protons. One such method is selective inversion recovery (SIR), in which the free water protons are selectively inverted and the signal is fit to a biexponential function of the inversion time (TI). SIR uses only low-power pulses and requires no separate RF (B1) or static field (B0) field maps, and the analysis is largely independent of the macromolecular pool lineshape. These are all advantages over steady-state off-resonance saturation qMTI methods. However, up to now, SIR has been implemented only with repetition times TR>T1. This paper describes a modification of SIR with smaller TR values and a greater signal-to-noise ratio (SNR) efficiency.     

Optimum setting of binomial pulses for magnetization transfer contrast

Investigation of the cause of image artifacts generated by a magnetization transfer (MT) sequence using binomial-pulse trains led to findings of imperfections in the pulses. These imperfections caused anomalous direct saturation of the free water, which was localized due to the static magnetic field inhomogeneity. In the case of single binomial pulses a loss of overall MT response across the field of view results. Two methods of correcting the imperfections and removing the artifact have been established using interactive adjustment of sub-pulse lobes and phase swapping of pulse trains. These imperfections may be present in many systems and may have led to erroneous judgements of the value of binomial pulses for MT imaging. A technique for interrogating the frequency spectrum of the binomial-pulse train has been utilized, allowing its optimization. The use of accurate and optimized binomial pulses may yet prove to be preferable to pulsed off-resonance methods for quantitative, clinical MT imaging.     

Efficiency of inversion pulses for background suppressed arterial spin labeling.

Background suppression strategies for arterial spin labeling (ASL) MRI offer reduced noise from motion and other system instabilities. However, the inversion pulses used for suppression can also attenuate the ASL signal, which may offset the advantages of background suppression. Numerical simulations were used to optimize the inversion efficiency of four candidate pulses over a range of radiofrequency (RF) and static magnetic field variations typical of in vivo imaging. Optimized pulses were then used within a pulsed ASL sequence to assess the pulses' in vivo inversion efficiencies for ASL. The measured in vivo inversion efficiency was significantly lower than theoretical predictions (e.g., 93% experimental compared to 99% theoretical) for the tangent hyperbolic pulse applied in a background suppression scheme. This inefficiency was supported by an in vitro study of human blood. These results suggest that slow magnetization transfer (MT) in blood, either with bound water or macromolecular protons, dominates the inversion inefficiency in blood. Despite the attenuated signal relative to unsuppressed ASL, the signal-to-noise ratio (SNR) with suppression was improved by 23-110% depending on the size of the region measured. Knowledge of efficiency will aid optimization of the number of suppression pulses and provide more accurate quantification of blood flow.     

Quantitative studies of magnetization transfer by selective excitation and T1 recovery

Water proton longitudinal relaxation has been measured in agar and cross-linked bovine serum albumin (BSA) using modified selective excitation (Goldman-Shen and Edzes-Samulski) pulse sequences. The resulting recovery curves are fit to biexponentials. The fast recovery rate gives magnetization transfer (MT) information, which is complementary to that given by steady-state saturation methods. This rate provides an estimate of the strength of the coupling of the immobile proton pool to the mobile proton pool. Near their optimal pulse power values, the Goldman-Shen and Edzes-Samulski sequences give fast recovery rates that agree with each other. However, these measured fast recovery rates are dependent on the pulse power, an effect not predicted by the coupled two-pool model. For 8% agar and 17% BSA, both methods (at optimal pulse powers) give rates in the neighborhoods of 210 and 64 Hz, respectively. The Goldman-Shen and Edzes-Samulski pulse sequences have several advantages over those techniques based on steady state saturation: no long saturating pulses, shorter measurement time, and reduced necessity for making lineshape or fitting technique assumptions. The principle disadvantages are smaller effects on the NMR signal, less complete characterization of the MT system, and, in the case of the Goldman-Shen sequence, greater pulse power.     

Density of organic matrix of native mineralized bone measured by water- and fat-suppressed proton projection MRI.

Water- and fat-suppressed projection MR imaging (WASPI) utilizes the large difference between the proton T(2) (*)s of the solid organic matrix and the fluid constituents of bone to suppress the fluid signals while preserving solid matrix signals. The solid constituents include collagen and some molecularly immobile water and exhibit very short T(2) (*). The fluid constituents include mobile water and fat, with long T(2) (*). In WASPI, chemical shift selective low-power pi/2 pulses excite mobile water and fat magnetization which is subsequently dephased by gradient pulses, while the magnetization of collagen and immobile water remains mostly in the z-direction. Additional selective pi pulses in alternate scans further cancel the residual water and fat magnetization. Following water and fat suppression, the matrix signal is excited by a short hard pulse and the free induction decay acquired in the presence of a gradient in a 3D projection method. WASPI was implemented on a 4.7 T MR imaging system and tested on phantoms and bone specimens, enabling excellent visualization of bone matrix. The bone matrix signal per unit volume of bovine trabecular specimens was measured by this MR technique and compared with that determined by chemical analysis. This method could be used in combination with bone mineral density measurement by solid state (31)P projection MRI to determine the degree of bone mineralization.     

Method for quantitative imaging of the macromolecular 1H fraction in tissues.

A new method was developed for mapping the relative density of the macromolecular protons involved in magnetization transfer (MT). This method employs a stimulated echo preparation scheme in order to modulate the phase distribution within a spin ensemble. This labeled spin ensemble is then used as an intrinsic indicator, which is diluted due to magnetization exchange with macromolecular protons. A pulse sequence is presented which compensates for longitudinal relaxation, allows observation of the dilution effect only, and provides for calculation of parameter maps using indicator dilution theory. Compared to other quantitative MT techniques, neither additional relaxation time measurements nor knowledge regarding the lineshape of the macromolecular proton pool are required. Moreover, the inherent low specific absorption rate and the low sensitivity for B(1) errors make this method favorable in a clinical setting. This sequence was used to measure the macromolecular proton density in cross-linked bovine serum albumin. Using a navigated echo planar readout, the sequence was also employed to visualize the macromolecular content of human brain in vivo.     

MTR variations in normal adult brain structures using balanced steady-state free precession

Introduction  

Magnetization transfer (MT) is sensitive to the macromolecular environment of water protons and thereby provides information not obtainable from conventional magnetic resonance imaging (MRI). Compared to standard methods, MT-sensitized balanced steady-state free precession (bSSFP) offers high-resolution images with significantly reduced acquisition times. In this study, high-resolution magnetization transfer ratio (MTR) images from normal appearing brain structures were acquired with bSSFP.     

Correlation of apparent myelin measures obtained in multiple sclerosis patients and controls from magnetization transfer and multicompartmental T2 analysis.

Two relatively new techniques purport to give measures of the myelin content of brain tissue. These measures are the myelin water fraction from multicompartmental T(2) analysis, and the semisolid proton fraction from analysis of magnetization transfer (MT). The myelin water fraction is the fraction of signal with a T(2) of less than 50 ms measured from a 32-echo sequence. It is believed to originate from water trapped between the myelin bilayers. The semisolid proton fraction is thought to include protons within phospholipid bilayers and macromolecular protons, and may also be a measure of myelin content. Multicompartmental T(2) and MT imaging were carried out on controls and patients with multiple sclerosis (MS), and estimates of the semisolid proton and myelin water fractions were obtained from white matter (WM), gray matter (GM), and MS lesions. These were then correlated for each tissue and subject group. Positive correlations were seen for MS lesions (r approximately 0.2) and in WM in patients (r = 0.6). A negative correlation (r approximately -0.3) was seen for GM. These results indicate that the two techniques measure, to some extent, the same thing (most likely myelin content), but that other factors, such as inflammation, mean they may provide complementary information.     

A multislice gradient echo pulse sequence for CEST imaging

Chemical exchange–dependent saturation transfer and paramagnetic chemical exchange–dependent saturation transfer are agent‐mediated contrast mechanisms that depend on saturating spins at the resonant frequency of the exchangeable protons on the agent, thereby indirectly saturating the bulk water. In general, longer saturating pulses produce stronger chemical and paramagnetic exchange–dependent saturation transfer effects, with returns diminishing for pulses longer than T₁. This could make imaging slow, so one approach to chemical exchange–dependent saturation transfer imaging has been to follow a long, frequency‐selective saturation period by a fast imaging method. A new approach is to insert a short frequency‐selective saturation pulse before each spatially selective observation pulse in a standard, two‐dimensional, gradient‐echo pulse sequence. Being much less than T₁ apart, the saturation pulses have a cumulative effect. Interleaved, multislice imaging is straightforward. Observation pulses directed at one slice did not produce observable, unintended chemical exchange–dependent saturation transfer effects in another slice. Pulse repetition time and signal‐to noise ratio increase in the normal way as more slices are imaged simultaneously. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Direct observation of the magnetization exchange dynamics responsible for magnetization transfer contrast in human cartilage in vitro.

Saturating irradiation far off-resonance can lead to diminution in the water signal seen in MRI, giving rise to magnetization transfer contrast. This results from transfer of magnetization between "solid" protons with restricted motion, which give rise to a band some tens of kilohertz wide, and the narrow signal from mobile protons. In the work reported here a high-power pulse spectrometer, which can detect signals from both mobile and immobile protons, was used to investigate the dynamics of magnetization transfer in cartilage in vitro. Magnetization transfer in modified Hoffman-Forsén inversion transfer experiments was well-described by a single rate constant model; full analytical solutions are offered for the resultant biexponential magnetization recovery curves. The use of pulsed methods to generate magnetization contrast may in some circumstances offer advantages over the steady-state saturation methods used hitherto.     

Modeling pulsed magnetization transfer.

Modeling the effects of clinical magnetization transfer (MT) scans, which generate contrast using short, shaped radiofrequency (RF) pulses (pulsed MT), is complex and time-consuming. As a result, several studies have proposed approximate methods for a simplified analysis of the experimental data. However, potential differences in the MT parameters estimated by each method may complicate the comparison of reported results. In this study we evaluated three approximate methods currently used in quantitative MT (qMT) studies. In the first part of the investigation, an MT modeling technique that makes minimal approximations, other than the use of a two-pool tissue representation, was developed and validated. Subsequently, this technique served as a standard against which to evaluate the other, more approximate models. Each model was used to fit experimental data from samples of wild-type (WT) and shiverer mouse spinal cord, as well as simulated data generated by our minimal approximation modeling technique. The results of this study demonstrate that the approximations used in pulsed MT modeling are quite robust. In particular, it was shown that the semisolid pool fraction, M(0)(B), which is known to correlate strongly with myelin content, and the transverse relaxation time of macromolecular protons, T(2)(B), could be evaluated with reasonable accuracy regardless of the model used.     

Proton magnetization transfer effect in rat liver lactate.

Off-resonance lactate magnetization transfer (MT) experiments were performed on the in situ rat liver under perfused and ischemic conditions. A significant MT effect for lactate methyl protons was observed. The effect was larger for the ischemic condition than for the perfused condition, and was largest in the blood-filled ischemic livers. The size of the motionally restricted lactate pool, determined using a two-pool model fit, was estimated to be about 1% in perfused livers and about 1.8-2.5% after more than 1 hr of onset of ischemia, suggesting that lactate in liver is almost fully NMR-visible. The MT data for both the perfused and the ischemic condition appeared to be better approximated when assuming a superLorentzian lineshape for the immobile pool rather than a Gaussian lineshape. Finally, the experiments demonstrated a coupling between the lactate methyl and water protons, which may be mediated by macromolecules.     

Analysis of on- and off-resonance magnetization transfer techniques

Three methods of performing magnetization transfer (MT) MR imaging ere emlyzed: (a) off-resonance continuous wave, (b) off-rceonance shaped pulses, end (c) on-resonance binomial pulses. With two-pool Bloch-model simulations., signal levels from “MT active” spin systems were calculated. with reference to direct saturation of “MT inactive” systems. allowing calculation of contrast due to MT. Simulations demonstrate several trends with variation of excitation amplitude and Offret fiequency for the off-resoname methods and with variation of excitation emplitude end pulse shape ?order”? for binomial pulses. The simulations show that nominally optimized versions of each of these approaches provide essentially equivalent contrast at a given level of applied MT power, contrary to previous claims. Experiments with an MT-inactive phentom, with a whole-body syetem, show results with off- rewnence pulses to be in good agreement with simulations. whereas binomiel- pulse experiments show anomalously large direct saturation.     

Using frequency-labeled exchange transfer to separate out conventional magnetization transfer effects from exchange transfer effects when detecting ParaCEST agents

Paramagnetic chemical exchange saturation transfer agents combine the benefits of a large chemical shift difference and a fast exchange rate for sensitive MRI detection. However, the in vivo detection of these agents is hampered by the need for high B(1) fields to allow sufficiently fast saturation before exchange occurs, thus causing interference of large magnetization transfer effects from semisolid macromolecules. A recently developed approach named frequency-labeled exchange transfer utilizes excitation pulses instead of saturation pulses for detecting the exchanging protons. Using solutions and gel phantoms containing the europium (III) complex of DOTA tetraglycinate (EuDOTA-(gly)(-) (4) ), it is shown that frequency-labeled exchange transfer allows the separation of chemical exchange effects and magnetization transfer (MT) effects in the time domain, therefore allowing the study of the individual resonance of rapidly exchanging water molecules (k(ex) >10(4) s(-1) ) without interference from conventional broad-band MT.     

Mechanism of magnetization transfer during on-resonance water saturation. A new approach to detect mobile proteins, peptides, and lipids.

The mechanism of magnetization transfer (MT) between water and components of the proton spectrum was studied ex vivo in a perfused cell system and in vivo in the rat brain (n = 5). Water was selectively labeled and spectral buildup consequential to transfer of longitudinal magnetization was followed as a function of time. At short mixing time (T(m)), nitrogen-bound solvent-exchangeable protons were observed, predominantly assigned to amide groups of proteins and peptides. At longer T(m), intramolecular nuclear Overhauser enhancement (NOE) was observed in the aliphatic proton region, leading to a mobile-macromolecule-weighted spectrum that resembles typical protein spectra described in the literature. This effect on the proton spectrum is distinct from that of classical off-resonance MT, which has been shown to be due to the immobile solid-like proton pool. When studying a solution of major brain metabolites under physiological concentrations and conditions (pH), no transfer effects were observed, in line with expectations based on reduced NOE effects in rapidly tumbling molecules and the fast proton exchange rates of amino, amine, SH, and OH groups. The spectral intensities of the amide protons may serve as indicators for pH and cellular levels of mobile proteins and peptides, while the aliphatic components are representative of several types of mobile macromolecules, including proteins, peptides, and lipids.     

Gd-DTPA relaxivity depends on macromolecular content.

Gd-DTPA T(1) relaxivity of water protons was measured at 1.5 T and room temperature as a function of macromolecular content in model systems. Gd-DTPA relaxivity was found to increase with macromolecular concentration. The results of this study indicate that the Gd-DTPA relaxivity in tissue extracellular compartment could be as much as 30-70% higher than that of Gd-DTPA in saline. Quantitative MR analyses that use T(1) as an estimation of local Gd-DTPA concentration require a priori determination of the Gd relaxivity in tissue.