Magnetization exchange observed in human skeletal muscle by non‐water‐suppressed proton magnetic resonance spectroscopy

Many metabolites in the proton magnetic resonance spectrum undergo magnetization exchange with water, such as those in the downfield region (6.0–8.5 ppm) and the upfield peaks of creatine, which can be measured to reveal additional information about the molecular environment. In addition, these resonances are attenuated by conventional water suppression techniques complicating detection and quantification. To characterize these metabolites in human skeletal muscle in vivo at 3 T, metabolite cycled non‐water‐suppressed spectroscopy was used to conduct a water inversion transfer experiment in both the soleus and tibialis anterior muscles. Resulting median exchange‐independent T₁ times for the creatine methylene resonances were 1.26 and 1.15 s, and for the methyl resonances were 1.57 and 1.74 s, for soleus and tibialis anterior muscles, respectively. Magnetization transfer rates from water to the creatine methylene resonances were 0.56 and 0.28 s^?1, and for the methyl resonances were 0.39 and 0.30 s^?1, with the soleus exhibiting faster transfer rates for both resonances, allowing speculation about possible influences of either muscle fibre orientation or muscle composition on the magnetization transfer process. These water magnetization transfer rates observed without water suppression are in good agreement with earlier reports that used either postexcitation water suppression in rats, or short CHESS sequences in human brain and skeletal muscle. Magn Reson Med, 70:916–924, 2013. © 2012 Wiley Periodicals, Inc.     

T2 exchange agents: A new class of paramagnetic MRI contrast agent that shortens water T2 by chemical exchange rather than relaxation

Exchange of water molecules between the frequency‐shifted inner‐sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T₂ of bulk water protons. The magnitude of the line‐broadening T₂ exchange (T_2exch) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T_2exch contribution to the water linewidth was initially observed in experiments involving Eu³⁺‐based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu³⁺ complexes having water exchange rates ranging from zero (no exchange) to 5 × 10⁶ s^?1 (fast exchange) were performed. The results showed that the exchange relaxivity (r_2exch) is small for complexes having either very fast or very slow exchange, but reaches a well‐defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T_2exch agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.     

1H MRS of intramyocellular lipids in soleus muscle at 7 T: Spectral simplification by using long echo times without water suppression

The popular short echo time ¹H MR spectroscopy acquisition method for detection of intramyocellular lipids suffers from spectral overlap due to the large, broad, and asymmetric extramyocellular lipid signals, the time‐consuming practice of selecting “lean” voxels for spectroscopy, and the overlap of the extramyocellular lipid signal with the creatine methyl ¹H signal at ～3 parts per million (ppm), commonly used as an internal standard. Using an alternative acquisition strategy, spectra with well‐resolved intramyocellular lipids resonances were acquired from large volumes (10 to 15 mL) of human soleus muscle in less than 5 min by single‐voxel 7‐T ¹H MR spectroscopy, using an echo time of 280 ms. From the high‐resolution spectra, an average intramyocellular lipid concentration of 7.7 ± 3.5 mmol/kg muscle was found for 25 healthy subjects (male/female 17/8; age 29.4 ± 6.6 years). Since water suppression was not required, the ¹H signals from unsaturated intracellular triglycerides at about 5.3 ppm were easily detected, which, in combination with the well‐determined ? (CH₂)_n? /CH₃ intensity ratio at long echo time, enabled assessment of the composition of triglycerides in the intramyocellular lipids compartment. Long‐echo single‐voxel spectroscopy at 7 T offers rapid and convenient acquisition of high‐resolution spectra from human soleus muscle. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Noninvasive quantification of hepatic steatosis inrats using 3.0 T 1H‐magnetic resonance spectroscopy

Purpose:

To assess the accuracy of noninvasive 3.0 T ¹H‐magnetic resonance spectroscopy (¹H‐MRS) in an experimental steatosis model for the discrimination of clinically relevant macrovesicular steatosis degrees and to evaluate three different ¹H‐MR spectrum‐based fat quantification methods.

Materials and Methods:

Steatosis was induced in rats by a methionine/choline‐deficient diet for 0–5 weeks. ¹H‐MRS measurements of hepatic fat content were compared with histopathological and biochemical steatosis degree. In ¹H‐MR spectra, areas under the curve (AUC) of fat (1.3 ppm), water (4.7 ppm), total fat (0.5–5.3 ppm), and total spectrum peaks (0.5–5.3 ppm) were determined and hepatic fat content calculated as follows: [AUC_{total fat peaks}/AUC_{total peaks}], [AUC_fat/AUC_fat + (AUC_water/0.7)], and [AUC_fat/AUC_water].

Results:

A significant correlation was found between ¹H‐MRS and macrovesicular steatosis (r = 0.932, P < 0.0001) and between ¹H‐MRS and total fatty acids (r = 0.935, P < 0.0001). ¹H‐MRS accurately distinguished mild from moderate and moderate from severe steatosis. Calculations using [AUC_fat/AUC_water] ratio in severe steatotic livers resulted in higher hepatic fat percentages as compared to the other methods due to a decrease in hepatic water content.

Conclusion:

¹H‐MRS quantification of hepatic fat content showed high correlations with histological and biochemical steatosis determination in an experimental steatosis rat model and accurately discriminated between clinically relevant steatosis degrees. These results encourage further application of ¹H‐MRS in patients for accurate steatosis assessment. J. Magn. Reson. Imaging 2010;32:148–154. © 2010 Wiley‐Liss, Inc.     

Tracer kinetic analysis of dynamic contrast‐enhanced MRI and CT bladder cancer data: A preliminary comparison to assess the magnitude of water exchange effects

The purpose of this study was to determine the impact of water exchange on tracer kinetic parameter estimates derived from T₁‐weighted dynamic contrast‐enhanced (DCE)‐MRI data using a direct quantitative comparison with DCE‐CT. Data were acquired from 12 patients with bladder cancer who underwent DCE‐CT followed by DCE‐MRI within a week. A two‐compartment tracer kinetic model was fitted to the CT data, and two versions of the same model with modifications to account for the fast exchange and no exchange limits of water exchange were fitted to the MR data. The two‐compartment tracer kinetic model provided estimates of the fractional plasma volume (v_p), the extravascular extracellular space fraction (v_e), plasma perfusion (F_p), and the microvascular permeability surface area product. Our findings suggest that DCE‐CT is an appropriate reference for DCE‐MRI in bladder cancers as the only significant difference found between CT and MR parameter estimates were the no exchange limit estimates of v_p (P = 0.002). These results suggest that although water exchange between the intracellular and extravascular‐extracellular space has a negligible effect on DCE‐MRI, vascular–extravascular‐extracellular space water exchange may be more important. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Detection of lactate with a hadamard slice selected,selective multiple quantum coherence,chemical shift imaging sequence (HDMD‐SelMQC‐CSI) on a clinical MRI scanner: Application to tumors and muscle ischemia

Lactate is an important metabolite in normal and malignant tissues detectable by NMR spectroscopy; however, it has been difficult to clinically detect the lactate methyl resonance because it is obscured by lipid resonances. The selective homonuclear multiple quantum coherence transfer technique offers a method for distinguishing lipid and lactate resonances. We implemented a three‐dimensional selective homonuclear multiple quantum coherence transfer version with Hadamard slice selection and two‐dimensional phase encoding (Hadamard encoded–selective homonuclear multiple quantum coherence transfer–chemical shift imaging) on a conventional clinical MR scanner. Hadamard slice selection is explained and demonstrated in vivo. This is followed by 1‐cm³ resolution lactate imaging with detection to 5‐mM concentration in 20 min on a 3‐T clinical scanner. An analysis of QSel gradient duration and amplitude effects on lactate and lipid signal is presented. To demonstrate clinical feasibility, a 5‐min lactate scan of a patient with a non‐Hodgkin's lymphoma in the superficial thigh is reported. The elevated lactate signal coincides with the T₂‐weighted image of this tumor. As a test of selective homonuclear multiple quantum coherence transfer sensitivity, a thigh tourniquet was applied to a normal volunteer and an increase in lactate was detected immediately after tourniquet flow constriction. In conclusion, the Hadamard encoded–selective homonuclear multiple quantum coherence transfer–chemical shift imaging sequence is demonstrated on a phantom and in two lipid‐rich, clinically relevant, in vivo conditions. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Metabolite proton T2 mapping in the healthy rhesus macaque brain at 3 T

The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and ¹H‐MR spectroscopy. Due to the shorter transverse relaxation time (T₂) at the higher magnetic fields these studies favor, the echo times used in ¹H‐MR spectroscopy subject the metabolites to unknown T₂ weighting, decreasing the accuracy of quantification which is key for inter‐ and intra‐animal comparisons. To establish the “baseline” (healthy animal) T₂ values, we mapped them for the three main metabolites' T₂s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three‐dimensional multivoxel ¹H‐MR spectroscopy at (0.6 × 0.6 × 0.5 cm)³ = 180 μL spatial resolution over a 4.2 × 3.0 × 2.0 = 25 cm³ (～30%) of the macaque brain in a two‐point protocol that optimizes T₂ precision per unit time. The estimated T₂s in several gray and white matter regions are all within 10% of those reported in the human brain (mean ± standard error of the mean): N‐acetylaspartate = 316 ± 7, creatine = 177 ± 3, and choline = 264 ± 9 ms, with no statistically significant gray versus white matter differences. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Insight into in vivo magnetization exchange in human white matter regions

Water exchange can play an important role in interpreting compartment‐specific magnetic resonance imaging data in brain. For example, an MR method of myelin measurement, known as myelin water fraction imaging, assumes that water exchange processes are slow compared with the measurement time scale. In this article, we examined whether water exchange processes have an effect on myelin water fraction values. A previously established four pool model of white matter was used to simulate the interactions between two aqueous compartments (myelin water and intra/extracellular water) and nonaqueous compartments (myelin and nonmyelin tissues). To extract the water exchange cross relaxation times, the Bloch equations were solved analytically. As the water exchange time scales are dependent on the spin‐lattice T₁ relaxation of each of these four pools and due to the current uncertainties regarding the T₁ associated with each pool, exchange cross relaxation times for three different T₁ scenarios were calculated. The corrections that need to be considered in order for myelin water fraction to be an accurate marker for myelin were found to be less than 15%. This work indicates that regional variations in white matter myelin water fraction values are most likely due to variations in myelin content rather than regional differences in exchange rates. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Brain metabolites B1‐corrected proton T1 mapping in the rhesus macaque at 3 T

The accuracy of metabolic quantification in MR spectroscopy is limited by the unknown radiofrequency field and T₁. To address both issues in proton (¹H) MR spectroscopy, we obtained radiofrequency field–corrected T₁ maps of N‐acetylaspartate, choline, and creatine in five healthy rhesus macaques at 3 T. For efficient use of the 4 hour experiment, we used a new three‐point protocol that optimizes the precision of T₁ in three‐dimensional ¹H‐MR spectroscopy localization for extensive, ～30%, brain coverage at 0.6 × 0.6 × 0.5 cm³ = 180‐μL spatial resolution. The resulting mean T₁s in 700 voxels were N‐acetylaspartate = 1232 ± 44, creatine = 1238 ± 23 and choline = 1107 ± 56 ms (mean ± standard error of the mean). Their histograms from all 140 voxels in each animal were similar in position and shape, characterized by standard errors of the mean of the full width at half maximum divided by their means of better than 8%. Regional gray matter N‐acetylaspartate, choline, and creatine T₁s (1333 ± 43, 1265 ± 52, and 1131 ± 28 ms) were 5–10% longer than white matter: 1188 ± 34, 1201 ± 24, and 1082 ± 50 ms (statistically significant for the N‐acetylaspartate only), all within 10% of the corresponding published values in the human brain. Magn Reson Med 63:865–871, 2010. © 2010 Wiley‐Liss, Inc.     

Quantitative spectroscopic imaging with in situ measurements of tissue water T1, T2, and density

The use of tissue water as a concentration standard in proton magnetic resonance spectroscopy (¹H‐MRS) of the brain requires that the water proton signal be adjusted for relaxation and partial volume effects. While single voxel ¹H‐MRS studies have often included measurements of water proton T₁, T₂, and density based on additional ¹H‐MRS acquisitions (e.g., at multiple echo or repetition times), this approach is not practical for ¹H‐MRS imaging (¹H‐MRSI). In this report we demonstrate a method for using in situ measurements of water T₁, T₂, and density to calculate metabolite concentrations from ¹H‐MRSI data. The relaxation and density data are coregistered with the ¹H‐MRSI data and provide detailed information on the water signal appropriate to the individual subject and tissue region. We present data from both healthy subjects and a subject with brain lesions, underscoring the importance of water parameter measurements on a subject‐by‐subject and voxel‐by‐voxel basis. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Fast acquisition scheme for achieving high‐resolution MRS with J‐scaling under inhomogeneous fields

Intermolecular multiple‐quantum coherences (iMQCs) can refocus the phase dispersion caused by magnetic field inhomogeneities while preserving the chemical shift, so they have been applied to achieve high‐resolution MR spectroscopy free of line broadening caused by susceptibility gradients. However, previous iMQC high‐resolution methods all require two‐dimensional spectra sampling of the full range of chemical shifts of solute evolutions in both F₁ and F₂ dimensions, resulting in a prolonged scanning time for data acquisition. In this work, sparse sampling in the t₁ dimension and subsequent fold‐over correction are used to speed up the intermolecular zero‐quantum coherence spectroscopy by up to 50 times on high‐field MR systems. Furthermore, three types of spectra with homo‐decoupling, original J‐coupling constants, and doubled J‐coupling constants respectively are obtained with manipulation of the t₁ period. The water suppression is also improved by the combined use of intermolecular double‐quantum filter and excitation sculpting. The feasibilities of this group of new sequences are demonstrated by experiments using an agar gel phantom with an air bubble, in vitro pig brain tissues and an intact postmortem mudskipper. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

SWIFT‐CEST: A new MRI method to overcome T2 shortening caused by PARACEST contrast agents

The exchange of water molecules between the inner sphere of a paramagnetic chemical exchange saturation transfer (PARACEST) contrast agent and bulk water can shorten the bulk water T₂ through the T₂‐exchange (T_2ex) mechanism. The line‐broadening T_2ex effect is proportional to the agent concentration, the chemical shift of the exchanging water molecule, and is highly dependent on the water molecule exchange rate. A significant T_2ex contribution to the bulk water linewidth can make the regions of agent uptake appear dark when imaging with conventional sequences like gradient‐echo and fast spin‐echo. The minimum echo times for these sequences (1–10 ms) are not fast enough to capture signal from the regions of shortened T₂. This makes “Off” (saturation at ?Δω) minus “On” (saturation at +Δω) imaging of PARACEST agents difficult, because the regions of uptake are dark in both images. It is shown here that the loss of bulk water signal due to T_2ex can be reclaimed using the ultrashort echo times (<10 μs) achieved with the sweep imaging with Fourier transform pulse sequence. Modification of the sweep imaging with Fourier transform sequence for PARACEST imaging is first discussed, followed by parameter optimization using in vitro experiments. In vivo PARACEST studies comparing fast spin‐echo to sweep imaging with Fourier transform were performed using EuDOTA‐(gly) uptake in healthy mouse kidneys. The results show that the negative contrast caused by T_2ex can be overcome using the ultrashort echo time achieved with sweep imaging with Fourier transform, thereby enabling fast and sensitive in vivo PARACEST imaging. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.     

Cellular‐interstitial water exchange and its effect on the determination of contrast agent concentration in vivo: Dynamic contrast‐enhanced MRI of human internal obturator muscle

The purpose of this study was to assess the effects of cellular‐interstitial water exchange on estimates of tracer kinetics parameters obtained using rapid dynamic contrast‐enhanced (DCE) MRI. Data from the internal obturator muscle of six patients were examined using three models of water exchange: no exchange (NX), fast exchange limit (FXL), and intermediate rate (shutter‐speed [SS]). In combination with additional multiple flip angle (FA) data, a full two‐pool exchange model was also used. The results obtained using the NX model (transfer constant, K^trans = 0.049 ± 0.027 min^–1, apparent interstitial volume, v_e = 0.14 ± 0.04) were marginally higher than those obtained using the FXL model (K^trans = 0.045 ± 0.025 min^–1, v_e = 0.13 ± 0.04), but the error bars overlapped in two‐thirds of these parameter estimate pairs. Estimates of K^trans and v_e obtained using the SS model exceeded those obtained using the NX model in half the patients, and many estimates, including all those of intracellular residence time of water, t_i, were imprecise. Results obtained using the full two‐pool model fell between those obtained using FXL and NX models, and estimates of t_i were also imprecise. The results suggest that data obtained using clinically relevant DCE‐MRI are exchange‐insensitive and unsuitable for the assessment of cellular‐interstitial water exchange. Magn Reson Med 60:1011–1019, 2008. © 2008 Wiley‐Liss, Inc.     

Selective resonance suppression 1H‐[13C] NMR spectroscopy with asymmetric adiabatic RF pulses

Despite obvious improvements in spectral resolution at high magnetic field, the detection of ¹³C labeling by ¹H‐[¹³C] NMR spectroscopy remains hampered by spectral overlap, such as in the spectral region of ¹H resonances bound to C3 of glutamate (Glu) and glutamine (Gln), and C6 of N‐acetylaspartate (NAA). The aim of this study was to develop, implement, and apply a novel ¹H‐[¹³C] NMR spectroscopic editing scheme, dubbed “selective Resonance suppression by Adiabatic Carbon Editing and Decoupling single‐voxel STimulated Echo Acquisition Mode” (RACED‐STEAM). The sequence is based on the application of two asymmetric narrow‐transition‐band adiabatic RF inversion pulses at the resonance frequency of the ¹³C coupled to the protons that need to be suppressed during the mixing time (TM) period, alternating the inversion band downfield and upfield from the ¹³C resonance on odd and even scans, respectively, thus suppressing the detection of ¹H resonances bound to ¹³C within the transition band of the inversion pulse. The results demonstrate the efficient suppression of ¹H resonances bound to C3 of Glu and Gln, and C4 of Glu, which allows the ¹H resonances bound to C6 of NAA and C4 of Gln to be revealed. The measured time course of the resolved labeling into NAA C6 with the new scheme was consistent with the slow turnover of NAA. Magn Reson Med 61:260–266, 2009. © 2009 Wiley‐Liss, Inc.     

Contributions of chemical and diffusive exchange to T1ρ dispersion

Variations in local magnetic susceptibility may induce magnetic field gradients that affect the signals acquired for MR imaging. Under appropriate diffusion conditions, such fields produce effects similar to slow chemical exchange. These effects may also be found in combination with other chemical exchange processes at multiple time scales. We investigate these effects with simulations and measurements to determine their contributions to rotating frame (R_1ρ) relaxation in model systems. Simulations of diffusive and chemical exchange effects on R_1ρ dispersion were performed using the Bloch equations. Additionally, R_1ρ dispersion was measured in suspensions of Sephadex and latex beads with varying spin locking fields at 9.4 T. A novel analysis method was used to iteratively fit for apparent chemical and diffusive exchange rates with a model by Chopra et al. Single‐ and double‐inflection points in R_1ρ dispersion profiles were observed, respectively, in simulations of slow diffusive exchange alone and when combined with rapid chemical exchange. These simulations were consistent with measurements of R_1ρ in latex bead suspensions and small‐diameter Sephadex beads that showed single‐ and double‐inflection points, respectively. These observations, along with measurements following changes in temperature and pH, are consistent with the combined effects of slow diffusion and rapid ^?OH exchange processes. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Homocarnosine and the measurement of neuronal pH in patients with epilepsy

Homocarnosine is a dipeptide of gamma-aminobutyric acid (GABA) and histidine found uniquely in the brain, most likely in a subclass of GABAergic neurons. By comparison of spectra from the occipital lobe of patients receiving a homocarnosine elevation drug to normal subjects we have assigned two elevated resonances in the short TE ¹H MRS spectrum to homocarnosine. These resonances are partially resolved at 7.05 and 8.02 ppm in a short TE spectrum at 2.1 T when macromolecule resonances are removed by subtraction of a spectrum in which the metabolite resonances are nulled by inversion recovery. The chemical shift of both of these resonances is sensitive to pH_i. By comparison with a titration curve the pH_i was calculated from the downfield resonance to be 7.06 in the patient group which is similar to values reported using the P_i resonance. Based on the in vivo results and theoretical considerations the potential sensitivity for using nonelevated homocarnosine to measure pH is similar to that of P_i under physiological conditions.     

In vivo detection of MRI‐PARACEST agents in mouse brain tumors at 9.4 T

Paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents are under development for biological target identification by magnetic resonance imaging. Image contrast associated with PARACEST agents can be generated by radiofrequency irradiation of the chemically shifted protons bound to a PARACEST contrast agent molecule or by direct irradiation of the on‐resonance bulk water protons. The observed signal change in a magnetic resonance image after the administration of a PARACEST contrast agent is due to both altered relaxation time constants and the CEST effect. Despite high sensitivity in vitro, PARACEST agents have had limited success in vivo where sensitivity is reduced by the magnetization transfer effect from endogenous macromolecules. The purpose of this study was to demonstrate the in vivo detection of a PARACEST contrast agent using the on‐resonance paramagnetic chemical exchange effect (OPARACHEE) in a mouse glioblastoma multiforme tumor model and to isolate the OPARACHEE effect from the changes in relaxation induced by the PARACEST agent. Three mice with tumors were imaged on a 9.4 T MRI scanner following tail vein injection of 150 μL 50 mM Tm³⁺‐DOTAM‐glycine‐lysine. A fast low angle shot pulse sequence with a low power radiofrequency pulse train (WALTZ‐16) as the preparation pulse was used to generate OPARACHEE contrast. To study the dynamics of agent uptake, reference images (without the preparation pulse) and OPARACHEE images were acquired continuously in an alternating fashion before, during and after agent injection. Signal intensity decreased by more than 10% in tumor in the control images after agent administration. Despite these changes, a clear OPARACHEE contrast of 1–5% was also observed in brain tumors after contrast agent injection and maintained in the hour following injection. This result is the first in vivo observation of OPARACHEE contrast in brain tumors with correction of T₁ and T₂ relaxation effects. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Determination of the optimal first‐order gradient moment for flow‐sensitive dephasing magnetization‐prepared 3D noncontrast MR angiography

Flow‐sensitive dephasing (FSD) magnetization preparation has been developed for black‐blood vessel wall MRI and noncontrast MR angiography. The first‐order gradient moment, m₁, is a measure of the flow‐sensitization imparted by an FSD preparative module. Determination of the optimal m₁ for each individual is highly desirable for FSD‐prepared MR angiography. This work developed a 2D m₁‐scouting method that evaluates a range of m₁ values for their effectiveness in blood signal suppression in a single scan. The feasibility of using the 2D method to predict blood signal suppression in 3D FSD‐prepared imaging was validated on a flow phantom and the popliteal arteries of 5 healthy volunteers. Excellent correlation of the blood signal measurements between the 2D scouting and 3D FSD imaging was obtained. Therefore, the optimal m₁ determined from the 2D m₁‐scouting scan may be directly translated to 3D FSD‐prepared imaging. In vivo studies of additional 10 healthy volunteers and 2 patients have demonstrated the proposed method can help significantly improve the signal performance of FSD MR angiography, indicating its potential to enhance diagnostic confidence. Further systematic studies in patients are warranted to evaluate its clinical value. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

Three‐compartment T1 relaxation model for intracellular paramagnetic contrast agents

The goal of this work was to elaborate a model describing the effective longitudinal relaxation rate constant R₁ for ¹H₂O in three cellular compartments experiencing possible equilibrium water exchange, and to apply this model to explain the effective R₁ dependence on the overall concentration of a cell‐internalized Gd³⁺‐based contrast agent (CA). The model voxel comprises three compartments representing extracellular, cytoplasmic, and vesicular (e.g., endosomal, lysosomal) subcellular spaces. Relaxation parameters were simulated using a modified Bloch–McConnell equation including magnetization exchange between the three compartments. With the model, several possible scenarios for internalized CA distribution were evaluated. Relaxation parameters were calculated for contrast agent restricted to the cytoplasmic or vesicular compartments. The size or the number of CA‐loaded vesicles was varied. The simulated data were then separately fitted with empirical mono‐ and biexponential inversion recovery expressions. The voxel CA‐concentration dependencies of R₁ can be used to qualitatively and quantitatively understand a number of different experimental observations reported in the literature. Most important, the simulations reproduced the relaxivity “quenching” for cell‐internalized contrast agent that has been observed. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Detection of apoptotic cell death in vitro in the presence of Gd‐DTPA‐BMA

Due to variability in patient response to cancer therapy, there is a growing interest in monitoring patient progress during treatment. Apoptotic cell death is one early marker of tumor response to treatment. Using known extracellular concentrations of gadolinium diethylenetriamine pentaacetic acid bismethylamide (Gd‐DTPA‐BMA) to vary the exchange regime, T₁ and T₂ relaxation data for acute myeloid leukemia (AML) cell samples were obtained and then analyzed using a two‐pool model of relaxation with exchange. Leukemia cells treated with cisplatin to induce apoptosis exhibited a statistically significant (P < 0.05) decrease in intracellular longitudinal relaxation time, T_1I, from 1030 ms to 940 ms, a decrease (P < 0.001) in the intracellular water fraction, M_0I, from 0.86 to 0.68 and a statistically significant increase (P < 0.01) in transmembrane water exchange rate, k_IE, from 1.4 s^?1 to 6.8 s^?1. The changes in MR parameters correlated with quantitative histology, such as cellular cross‐sectional area and average nuclear area measurements. The results of this study emphasize the importance of accounting for water exchange in dynamic contrast‐enhanced MRI (DCE‐MRI) studies, particularly those that examine tumor response to therapies in which apoptotic changes occur. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.