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The goal of the current study is to include transcytolemmal water exchange in MR cell size imaging using the IMPULSED model for more accurate characterization of tissue cellular properties (e.g., apparent volume fraction of intracellular spacemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miv/mml:mimml:mtextin/mml:mtext/mml:msub/mml:math) and quantification of indicators of transcytolemmal water exchange. We propose a heuristic model that incorporates transcytolemmal water exchange into a multicompartment diffusion-based method (IMPULSED) that was developed previously to extract microstructural parameters (e.g., mean cell sizemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:mid/mml:mi/mml:mathand apparent volume fraction of intracellular spacemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miv/mml:mimml:mtextin/mml:mtext/mml:msub/mml:math) assuming no water exchange. Formml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:mit/mml:mimml:mtextdiff/mml:mtext/mml:msub/mml:math≤ 5 ms, the water exchange can be ignored, and the signal model is the same as the IMPULSED model. Formml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:mit/mml:mimml:mtextdiff/mml:mtext/mml:msub/mml:math≥ 30 ms, we incorporated the modified Kärger model that includes both restricted diffusion and exchange between compartments. Using simulations and previously published in vitro cell data, we evaluated the accuracy and precision of model-derived parameters and determined how they are dependent on SNR and imaging parameters. The joint model provides more accuratemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:mid/mml:mi/mml:mathvalues for cell sizes ranging from 10 to 12 microns when water exchange is fast (e.g., intracellular water pre-exchange lifetimemml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miτ/mml:mimml:mtextin/mml:mtext/mml:msubmml:mspace//mml:math≤ 100 ms) than IMPULSED, and reduces the bias of IMPULSED-derived estimates ofmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miv/mml:mimml:mtextin/mml:mtext/mml:msub/mml:math, especially when water exchange is relatively slow (e.g.,mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miτ/mml:mimml:mtextin/mml:mtext/mml:msubmml:mspace//mml:mathgt; 200 ms). Indicators of transcytolemmal water exchange derived from the proposed joint model are linearly correlated with ground truthmml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"mml:msubmml:miτ/mml:mimml:mtextin/mml:mtext/mml:msub/mml:mathvalues and can detect changes in cell membrane permeability induced by saponin treatment in murine erythroleukemia cancer cells. Our results suggest this joint model not only improves the accuracy of IMPULSED-derived microstructural parameters, but also provides indicators of water exchange that are usually ignored in diffusion models of tissues.

Tubular atrophy and fibrosis are pathological changes that determine the prognosis of kidney disease induced by acute kidney injury (AKI). We aimed to evaluate multiple magnetic resonance imaging (MRI) parameters, including pool size ratio (PSR) from quantitative magnetization transfer, relaxation rates, and measures from spin-lock imaging (

Spinal cord injuries (SCIs) are a leading cause of disability and can severely impact the quality of life. However, to date, the processes of spontaneous repair of damaged spinal cord remain incompletely understood, partly due to a lack of appropriate longitudinal tracking methods. Non-invasive, multi-parametric magnetic resonance imaging (MRI) provides potential biomarkers for the comprehensive evaluation of spontaneous repair after SCI. In this study in rats, a clinically relevant contusion injury was introduced at the lumbar level that impairs both hindlimb motor and sensory functions. Quantitative MRI measurements were acquired at baseline and serially post-SCI for up to two weeks. The progressions of injury and spontaneous recovery in both white and gray matter were tracked longitudinally using pool-size ratio (PSR) measurements derived from quantitative magnetization transfer (qMT) methods, measurements of water diffusion parameters using diffusion tensor imaging (DTI), and intra-segment functional connectivity derived from resting state functional MRI. Changes in these quantitative imaging measurements were correlated with behavioral readouts. We found (1) a progressive decrease in PSR values within two weeks post-SCI, indicating a progressive demyelination at the center of the injury that was validated with histological staining; (2) PSR correlated closely with fractional anisotropy and transverse relaxation of free water, but did not show significant correlations with behavioral recovery; (3) preliminary evidence that SCI induced a decrease in functional connectivity between dorsal horns below the injury site at 24 hours. Findings from this study not only confirm the value of qMT and DTI methods for assessing the myelination state of injured spinal cord but indicate that they may also have further implications on whether therapies targeted towards remyelination may be appropriate. Additionally, a better understanding of changes after SCI provides valuable information to guide and assess interventions.

Excessive tissue scarring, or fibrosis, is a critical contributor to end stage renal disease, but current clinical tests are not sufficient for assessing renal fibrosis. Quantitative magnetization transfer (qMT) MRI provides indirect information about the macromolecular composition of tissues. We evaluated measurements of the pool size ratio (PSR, the ratio of immobilized macromolecular to free water protons) obtained by qMT as a biomarker of tubulointerstitial fibrosis in a well-established murine model with progressive renal disease. MR images were acquired from 16-week-old fibrotic hHB-EGFTg/Tg mice and normal wild-type (WT) mice (N = 12) at 7 T. QMT parameters were derived using a two-pool five-parameter fitting model. A normal range of PSR values in the cortex and outer stripe of outer medulla (CR + OSOM) was determined by averaging across voxels within WT kidneys (mean ± 2SD). Regions in diseased mice whose PSR values exceeded the normal range above a threshold value (tPSR) were identified and measured. The spatial distribution of fibrosis was confirmed using picrosirius red stains. Compared with normal WT mice, scattered clusters of high PSR regions were observed in the OSOM of hHB-EGFTg/Tg mouse kidneys. Moderate increases in mean PSR (mPSR) of CR + OSOM regions were observed across fibrotic kidneys. The abnormally high PSR regions (% area) detected by the tPSR were significantly increased in hHB-EGFTg/Tg mice, and were highly correlated with regions of fibrosis detected by histological fibrosis indices measured from picrosirius red staining. Renal tubulointerstitial fibrosis in OSOM can thus be assessed by qMT MRI using an appropriate analysis of PSR. This technique may be used as an imaging biomarker for chronic kidney diseases.

Measurements of spin-lock relaxation rates in the rotating frame (R1ρ ) at high magnetic fields afford the ability to probe not only relatively slow molecular motions, but also other dynamic processes, such as chemical exchange and diffusion. In particular, measurements of the variation (or dispersion) of R1ρ with locking field allow the derivation of quantitative parameters that describe these processes. Measurements in deuterated solutions demonstrate the manner and degree to which exchange dominates relaxation at high fields (4.7 T, 7 T) in simple solutions, whereas temperature and pH are shown to be very influential factors affecting the rates of proton exchange. Simulations and experiments show that multiple exchanging pools of protons in realistic tissues can be assumed to behave independently of each other. R1ρ measurements can be combined to derive an exchange rate contrast (ERC) that produces images whose intensities emphasize protons with specific exchange rates rather than chemical shifts. In addition, water diffusion in the presence of intrinsic susceptibility gradients may produce significant effects on R1ρ dispersions at high fields. The exchange and diffusion effects act independently of each other, as confirmed by simulation and experimentally in studies of red blood cells at different levels of oxygenation. Collectively, R1ρ measurements provide an ability to quantify exchange processes, to provide images that depict protons with specific exchange rates and to describe the microstructure of tissues containing magnetic inhomogeneities. As such, they complement traditional T1 or T2 measurements and provide additional insights from measurements of R1ρ at a single locking field. Copyright © 2016 John Wiley & Sons, Ltd.

Mapping axon diameter is of interest for the potential diagnosis and monitoring of various neuronal pathologies. Advanced diffusion-weighted MRI methods have been developed to measure mean axon diameters non-invasively, but suffer major drawbacks that prevent their direct translation into clinical practice, such as complex non-linear data fitting and, more importantly, long scanning times that are usually not tolerable for most human subjects. In the current study, temporal diffusion spectroscopy using oscillating diffusion gradients was used to measure mean axon diameters with high sensitivity to small axons in the central nervous system. Axon diameters have been found to be correlated with a novel metric, DDR⊥ (the rate of dispersion of the perpendicular diffusion coefficient with gradient frequency), which is a model-free quantity that does not require complex data analyses and can be obtained from two diffusion coefficient measurements in clinically relevant times with conventional MRI machines. A comprehensive investigation including computer simulations and animal experiments ex vivo showed that measurements of DDR⊥ agree closely with histological data. In humans in vivo, DDR⊥ was also found to correlate well with reported mean axon diameters in human corpus callosum, and the total scan time was only about 8 min. In conclusion, DDR⊥ may have potential to serve as a fast, simple and model-free approach to map the mean axon diameter of white matter in clinics for assessing axon diameter changes.

Amide proton transfer (APT) imaging may potentially detect mobile proteins/peptides non-invasively in vivo, but its specificity may be reduced by contamination from other confounding effects such as asymmetry of non-specific magnetization transfer (MT) effects and spin-lattice relaxation with rate R1 (=1/T1). Previously reported spillover, MT and R1 correction methods were based on a two-pool model, in which the existence of multiple water compartments with heterogeneous relaxation properties in real tissues was ignored. Such simple models may not adequately represent real tissues, and thus such corrections may be unreliable. The current study investigated the effectiveness and accuracy of correcting for R1 in APT imaging via simulations and in vivo experiments using tumor-bearing rats subjected to serial injections of Gd-DTPA that produced different tissue R1 values in regions of blood-brain-barrier breakdown. The results suggest that conventional measurements of APT contrast (such as APT* and MTRasym ) may be significantly contaminated by R1 variations, while the R1 -corrected metric AREX* was found to be relatively unaffected by R1 changes over a broad range (0.4-1 Hz). Our results confirm the importance of correcting for spin-lattice relaxation effects in quantitative APT imaging, and demonstrate the reliability of using the observed tissue R1 for corrections to obtain more specific and accurate measurements of APT contrast in vivo. The results also indicate that, due to relatively fast transcytolemmal water exchange, the influence of intra- and extracellular water compartments on CEST measurements with seconds long saturation time may be ignored in tumors.

Off-resonant RF irradiation in tissue indirectly lowers the water signal by saturation transfer processes: on the one hand, there are selective chemical exchange saturation transfer (CEST) effects originating from exchanging endogenous protons resonating a few parts per million from water; on the other hand, there is the broad semi-solid magnetization transfer (MT) originating from immobile protons associated with the tissue matrix with kilohertz linewidths. Recently it was shown that endogenous CEST contrasts can be strongly affected by the MT background, so corrections are needed to derive accurate estimates of CEST effects. Herein we show that a full analytical solution of the underlying Bloch-McConnell equations for both MT and CEST provides insights into their interaction and suggests a simple means to isolate their effects. The presented analytical solution, based on the eigenspace solution of the Bloch-McConnell equations, extends previous treatments by allowing arbitrary lineshapes for the semi-solid MT effects and simultaneously describing multiple CEST pools in the presence of a large MT pool for arbitrary irradiation. The structure of the model indicates that semi-solid MT and CEST effects basically add up inversely in determining the steady-state Z-spectrum, as previously shown for direct saturation and CEST effects. Implications for existing previous CEST analyses in the presence of a semi-solid MT are studied and discussed. It turns out that, to accurately quantify CEST contrast, a good reference Z-value, the observed longitudinal relaxation rate of water, and the semi-solid MT pool size fraction must all be known.

Chemical exchange saturation transfer (CEST) potentially provides the ability to detect small solute pools through indirect measurements of attenuated water signals. However, CEST effects may be diluted by various competing effects, such as non-specific magnetization transfer (MT) and asymmetric MT effects, water longitudinal relaxation (T1) and direct water saturation (radiofrequency spillover). In the current study, CEST images were acquired in rats following ischemic stroke and analyzed by comparing the reciprocals of the CEST signals at three different saturation offsets. This combined approach corrects the above competing effects and provides a more robust signal metric sensitive specifically to the proton exchange rate constant. The corrected amide proton transfer (APT) data show greater differences between the ischemic and contralateral (non-ischemic) hemispheres. By contrast, corrected nuclear Overhauser enhancements (NOEs) around −3.5 ppm from water change over time in both hemispheres, indicating whole-brain changes that have not been reported previously. This study may help us to better understand the contrast mechanisms of APT and NOE imaging in ischemic stroke, and may also establish a framework for future stroke measurements using CEST imaging with spillover, MT and T1 corrections. Copyright © 2014 John Wiley & Sons, Ltd.

Diffusion measurements derived from breast MRI can be adversely affected by unwanted signals from abundant fatty tissues if they are not suppressed adequately. To minimize this undesired contribution, we designed and optimized a water-selective diffusion-weighted imaging (DWI) sequence, which relies on spectrally selective excitation on the water resonance,obviatingthe needfor fat suppression.AsthismethodismorecomplexthanstandardDWImethods,we also report a test–retest study to evaluate its reproducibility.In this study, a spectrally selective Gaussianpulse on water resonance was combined with a pair of slice-selective adiabatic refocusing pulses for water-only DWI. Field map-based shimming and manual determination of the center frequency were used for water selection. The selectivity of the excitation pulse was optimized by a spectrally selective spectroscopy sequence based on the same principles. A test–retest study of 10 volunteers in two separate visits was used to evaluate its reproducibility. Our results from all subjects showed high-quality diffusion-weighted images of the breast without fat contamination. Mean apparent diffusion coefficients for b=0, 600s/mm 2 and b=50, 600s/mm 2 all showed good reproducibility, as 95% confidence intervals of the apparent diffusion coefficients were 4×10 –5 mm 2 /s and 5×10 –5 mm 2 /s and repeatability values were 1.09×10 –4 and 1.31×10 –4 , respectively. In conclusion, water-selective DWI is a feasible alternative to standard methods of DWI based on fat suppression. The added complexity of the method does not compromise the reproducibility of diffusion measurements in the breast. Copyright © 2014 John Wiley & Sons, Ltd.

Chemical exchange saturation transfer (CEST) provides an indirect means to detect exchangeable protons within tissues through their effects on the water signal. Previous studies have suggested that amide proton transfer (APT) imaging, a specific form of CEST, detects endogenous amide protons with a resonance frequency offset 3.5 ppm downfield from water, and thus may be sensitive to variations of mobile proteins/peptides in tumors. However, since CEST measurements are influenced by various confounding effects, such as spillover saturation, magnetization transfer (MT) and MT asymmetry, the mechanism or degree of increased APT signal in tumors are not certain. In addition to APT, nuclear Overhauser enhancement (NOE) effects upfield from water may also provide distinct information about tissue composition. In the current study, APT, NOE and several other magnetic resonance parameters were measured and compared comprehensively in order to elucidate the origins of APT and NOE contrasts in tumors at 9.4T. In addition to conventional CEST methods, a new intrinsic inverse metric was applied to correct for relaxation and other effects. After corrections for spillover, MT and T1 effects, corrected APT in tumors was found not significantly different from normal tissues, but corrected NOE effects in tumors showed significant decreases compared with normal tissues. Biochemical measurements verified that there is no significant enhancement of protein contents in the tumors studied, consistent with corrected APT measurements and previous literature while qMT data showed decreases in the fractions of immobile macromolecules in tumors. Our results may assist better understanding the contrast depicted by CEST imaging in tumors, and the development of improved APT and NOE measurements for cancer imaging.

Endogenous chemical exchange saturation transfer (CEST) effects are always diluted by competing effects, such as direct water proton saturation (spillover) and semi-solid macromolecular magnetization transfer (MT). This leads to unwanted T2 and MT signal contributions that lessen the CEST signal specificity to the underlying biochemical exchange processes. A spillover correction is of special interest for clinical static field strengths and protons resonating near the water peak. This is the case for all endogenous CEST agents, such as amide proton transfer, -OH-CEST of glycosaminoglycans, glucose or myo-inositol, and amine exchange of creatine or glutamate. All CEST effects also appear to be scaled by the T1 relaxation time of water, as they are mediated by the water pool. This forms the motivation for simple metrics that correct the CEST signal. Based on eigenspace theory, we propose a novel magnetization transfer ratio (MTRRex ), employing the inverse Z-spectrum, which eliminates spillover and semi-solid MT effects. This metric can be simply related to Rex , the exchange-dependent relaxation rate in the rotating frame, and ka , the inherent exchange rate. Furthermore, it can be scaled by the duty cycle, allowing for simple translation to clinical protocols. For verification, the amine proton exchange of creatine in solutions with different agar concentrations was studied experimentally at a clinical field strength of 3 T, where spillover effects are large. We demonstrate that spillover can be properly corrected and that quantitative evaluation of pH and creatine concentration is possible. This proves that MTRRex is a quantitative and biophysically specific CEST-MRI metric. Applied to acute stroke induced in rat brain, the corrected CEST signal shows significantly higher contrast between the stroke area and normal tissue, as well as less B1 dependence, than conventional approaches.

Magnetization transfer (MT) provides an indirect means to detect noninvasively variations in macromolecular contents in biological tissues, but, so far, there have been only a few quantitative MT (qMT) studies reported in cancer, all of which used off-resonance pulsed saturation methods. This article describes the first implementation of a different qMT approach, selective inversion recovery (SIR), for the characterization of tumor in vivo using a rodent glioma model. The SIR method is an on-resonance method capable of fitting qMT parameters and T1 relaxation time simultaneously without mapping B0 and B1, which is very suitable for high-field qMT measurements because of the lower saturation absorption rate. The results show that the average pool size ratio (PSR, the macromolecular pool versus the free water pool) in rat 9L glioma (5.7%) is significantly lower than that in normal rat gray matter (9.2%) and white matter (17.4%), which suggests that PSR is potentially a sensitive imaging biomarker for the assessment of brain tumor. Despite being less robust, the estimated MT exchange rates also show cleardifferencesfromnormaltissues (19.7Hz for tumorsversus14.8and10.2Hz for grayand whitemater,respectively). In addition, the influence of confounding effects, e.g. B1 inhomogeneity, on qMT parameter estimates is investigated with numerical simulations. These findings not only help to better understand the changes in the macromolecular contents of tumors, but are also important for the interpretation of other imaging contrasts, such as chemical exchange saturation transfer of tumors. Copyright © 2013 John Wiley & Sons, Ltd.

Chemical exchange saturation transfer (CEST) can offer information about protons associated with mobile proteins through the amide proton transfer (APT) effect, which has been shown to discriminate tumor from healthy tissue and, more recently, has been suggested as a prognosticator of response to therapy. Despite this promise, APT effects are small (only a few percent of the total signal); and APT imaging is often prone to artifacts resulting from system instability. Here we present a procedure that enables the detection of APT effects in the human breast at 7 T while mitigating these issues. Adequate signal-to-noise ratio (SNR) was achieved via an optimized quadrature RF breast coil and 3D acquisitions. To reduce the influence of fat, effective fat suppression schemes were developed that did not degrade SNR. To reduce the levels of ghosting artifacts, dummy scans have been integrated into the scanning protocol. Compared to results obtained at 3 T, the standard deviation of the measured APT effect was reduced by a factor of four at 7 T, allowing for the detection of APT effects with a standard deviation of 1% in the human breast at 7 T. Together, these results demonstrate that the APT effect can be reliably detected in the healthy human breast with a high level of precision at 7 T.

Accurate quantification of chemical exchange saturation transfer (CEST) effects, including dipole-dipole mediated relayed nuclear Overhauser enhancements (rNOE) saturation transfer, is important for applications and studies of molecular concentration and transfer rate (and thereby pH or temperature). Although several quantification methods, such as Lorentzian difference (LD) analysis, multiple-pool Lorentzian fits, and the three-point method, have been extensively used in several preclinical and clinical applications, the accuracy of these methods has not been evaluated. Here we simulated multiple-pool Z-spectra containing the pools that contribute to the main CEST and rNOE saturation transfer signals in brain, and numerically fit them using the different methods, and then compared their derived CEST metrics with the known solute concentrations and exchange rates. Our results show that the LD analysis overestimates contributions from amide proton transfer (APT) and intermediate exchanging amine protons; the three-point method significantly underestimates both APT and rNOE saturation transfer at −3.5 ppm (NOE(−3.5)). In contrast, the multiple-pool Lorentzian fit is more accurate than the other two methods, but only at lower irradiation powers (< 1 μT at 9.4 T) within the range of our simulations. At higher irradiation powers, this method is also inaccurate because of the presence of a fast exchanging CEST signal that has a non-Lorentzian lineshape. Quantitative parameters derived from in vivo images of rodent brain tumor obtained using an irradiation power of 1 μT were also compared. Our results demonstrate that all three quantification methods show similar contrasts between tumor and contralateral normal tissue for both APT and the NOE(−3.5). However, the quantified values of the three methods are significantly different. Our work provides insight into the fitting accuracy obtainable in a complex tissue model and provides guidelines for evaluating other newly developed quantification methods.

Mapping axon diameter is of interest for the potential diagnosis and monitoring of various neuronal pathologies. Advanced diffusion-weighted MRI methods have been developed to measure mean axon diameters non-invasively, but suffer major drawbacks that prevent their direct translation into clinical practice, such as complex non-linear data fitting and, more importantly, long scanning times that are usually not tolerable for most human subjects. In the current study, temporal diffusion spectroscopy using oscillating diffusion gradients was used to measure mean axon diameters with high sensitivity to small axons in the central nervous system. Axon diameters have been found to be correlated with a novel metric, DDR⊥ (the rate of dispersion of the perpendicular diffusion coefficient with gradient frequency), which is a model-free quantity that does not require complex data analyses and can be obtained from two diffusion coefficient measurements in clinically relevant times with conventional MRI machines. A comprehensive investigation including computer simulations and animal experiments ex vivo showed that measurements of DDR⊥ agree closely with histological data. In humans in vivo, DDR⊥ was also found to correlate well with reported mean axon diameters in human corpus callosum, and the total scan time was only about 8 min. In conclusion, DDR⊥ may have potential to serve as a fast, simple and model-free approach to map the mean axon diameter of white matter in clinics for assessing axon diameter changes.

The concepts, theoretical behavior and experimental applications of temporal diffusion spectroscopy are reviewed and illustrated. Temporal diffusion spectra are obtained using oscillating-gradient waveforms in diffusion-weighted measurements, and represent the manner in which various spectral components of molecular velocity correlations vary in different geometrical structures that restrict or hinder free movements. Measurements made at different gradient frequencies reveal information on the scale of restrictions or hindrances to free diffusion, and the shape of a spectrum reveals the relative contributions of spatial restrictions at different distance scales. Such spectra differ from other so-called diffusion spectra which depict spatial frequencies and are defined at a fixed diffusion time. Experimentally, oscillating gradients at moderate frequency are more feasible for exploring restrictions at very short distances which, in tissues, correspond to structures smaller than cells. We describe the underlying concepts of temporal diffusion spectra and provide analytical expressions for the behavior of the diffusion coefficient as a function of gradient frequency in simple geometries with different dimensions. Diffusion in more complex model media that mimic tissues has been simulated using numerical methods. Experimental measurements of diffusion spectra have been obtained in suspensions of particles and cells, as well as in vivo in intact animals. An observation of particular interest is the increased contrast and heterogeneity observed in tumors using oscillating gradients at moderate frequency compared with conventional pulse gradient methods, and the potential for detecting changes in tumors early in their response to treatment. Computer simulations suggest that diffusion spectral measurements may be sensitive to intracellular structures, such as nuclear size, and that changes in tissue diffusion properties may be measured before there are changes in cell density.

We have previously reported that the dispersion of spin lattice relaxation rates in the rotating frame (R(1)(ρ)) of tissue water protons at high field can be dominated by chemical exchange contributions. Ischemia in brain causes changes in tissue pH which in turn may affect proton exchange rates. Amide proton transfer (APT, a form of chemical exchange saturation transfer) has been shown to be sensitive to chemical exchange rates and able to detect pH changes non-invasively following ischemic stroke. However, the specificity of APT to pH changes is decreased because of the influence of several other factors that affect magnetization transfer. R(1)(ρ) is less influenced by such confounding factors and thus may be more specific for detecting variations in pH. Here, we applied a spin-locking sequence to detect ischemic stroke in animal models. Although R(1)(ρ) images acquired with a single spin-locking amplitude (ω(1)) have previously been used to assess stroke, here we use ΔR(1ρ), which is the difference in R(1)(ρ) values acquired with two different locking fields to emphasize selectively the contribution of chemical exchange effects. Numerical simulations with different exchange rates and measurements of tissue homogenates with different pH were performed to evaluate the specificity of ΔR(1ρ) to detect tissue acidosis. Spin-lock and APT data were acquired on five rat brains after ischemic strokes induced via middle cerebral artery occlusions (MCAO). Correlations between these data were analyzed at different time points after the onset of stroke. The results show that ΔR(1ρ), (but not R(1)(ρ) acquired with a single ω(1)) was significantly correlated with APT metrics consistent with ΔR(1ρ) varying with pH.

The aim of this study was to characterize multiexponential T2 (MET2) relaxation in a rat C6 glioblastoma tumor model. To do this, rats (n = 11) were inoculated with the C6 cells via stereotaxic injection into the brain. Ten days later, MET2 measurements were performed in vivo using a single-slice, multi-echo spin-echo sequence at 7.0 T. Tumor signal was biexponential in eight animals with a short-lived T2 component (T2 = 20.7 ± 5.4 ms across samples) representing 6.8 ± 6.2% of the total signal and a long-lived T2 component (T2 = 76.4 ± 9.3 ms) representing the remaining signal fraction. In contrast, signal from contralateral grey matter was consistently monoexponential (T2 = 48.8 ± 2.3 ms). Additional ex vivo studies (n = 3) and Monte Carlo simulations showed that the in vivo results were not significantly corrupted by partial volume averaging or noise. The underlying physiological origin of the observed MET2 components is unknown; however, MET2 analysis may hold promise as a non-invasive tool for characterizing tumor microenvironment in vivo on a sub-voxel scale. Copyright © 2009 John Wiley & Sons, Ltd.

Amide proton transfer (APT) imaging may potentially detect mobile proteins/peptides non-invasively in vivo, but its specificity may be reduced by contamination from other confounding effects such as asymmetry of non-specific magnetization transfer (MT) effects and spin-lattice relaxation with rate R1 (=1/T1). Previously reported spillover, MT and R1 correction methods were based on a two-pool model, in which the existence of multiple water compartments with heterogeneous relaxation properties in real tissues was ignored. Such simple models may not adequately represent real tissues, and thus such corrections may be unreliable. The current study investigated the effectiveness and accuracy of correcting for R1 in APT imaging via simulations and in vivo experiments using tumor-bearing rats subjected to serial injections of Gd-DTPA that produced different tissue R1 values in regions of blood-brain-barrier breakdown. The results suggest that conventional measurements of APT contrast (such as APT* and MTRasym ) may be significantly contaminated by R1 variations, while the R1 -corrected metric AREX* was found to be relatively unaffected by R1 changes over a broad range (0.4-1 Hz). Our results confirm the importance of correcting for spin-lattice relaxation effects in quantitative APT imaging, and demonstrate the reliability of using the observed tissue R1 for corrections to obtain more specific and accurate measurements of APT contrast in vivo. The results also indicate that, due to relatively fast transcytolemmal water exchange, the influence of intra- and extracellular water compartments on CEST measurements with seconds long saturation time may be ignored in tumors.

Chemical exchange saturation transfer (CEST) imaging of fast exchanging amine protons at 3 ppm offset from the water resonant frequency is of practical interest, but quantification of fast exchanging pools by CEST is challenging. To effectively saturate fast exchanging protons, high irradiation powers need to be applied, but these may cause significant direct water saturation as well as non-specific semi-solid magnetization transfer (MT) effects, and thus decrease the specificity of the measured signal. In addition, the CEST signal may depend on the water longitudinal relaxation time (T1w ), which likely varies between tissues and with pathology, further reducing specificity. Previously, an analysis of the asymmetry of saturation effects (MTRasym ) has been commonly used to quantify fast exchanging amine CEST signals. However, our results show that MTRasym is greatly affected by the above factors, as well as asymmetric MT and nuclear Overhauser enhancement (NOE) effects. Here, we instead applied a relatively more specific inverse analysis method, named AREX (apparent exchange-dependent relaxation), that has previously been applied only to slow and intermediate exchanging solutes. Numerical simulations and controlled phantom experiments show that, although MTRasym depends on T1w and semi-solid content, AREX acquired in steady state does not, which suggests that AREX is more specific than MTRasym . By combining with a fitting approach instead of using the asymmetric analysis to obtain reference signals, AREX can also avoid contaminations from asymmetric MT and NOE effects. Animal experiments show that these two quantification methods produce differing contrasts between tumors and contralateral normal tissues in rat brain tumor models, suggesting that conventional MTRasym applied in vivo may be influenced by variations in T1w , semi-solid content, or NOE effect. Thus, the use of MTRasym may lead to misinterpretation, while AREX with corrections for competing effects likely enhances the specificity and accuracy of quantification to fast exchanging pools.

Diffusion measurements derived from breast MRI can be adversely affected by unwanted signals from abundant fatty tissues if they are not suppressed adequately. To minimize this undesired contribution, we designed and optimized a water-selective diffusion-weighted imaging (DWI) sequence, which relies on spectrally selective excitation on the water resonance, obviating the need for fat suppression. As this method is more complex than standard DWI methods, we also report a test-retest study to evaluate its reproducibility. In this study, a spectrally selective Gaussian pulse on water resonance was combined with a pair of slice-selective adiabatic refocusing pulses for water-only DWI. Field map-based shimming and manual determination of the center frequency were used for water selection. The selectivity of the excitation pulse was optimized by a spectrally selective spectroscopy sequence based on the same principles. A test-retest study of 10 volunteers in two separate visits was used to evaluate its reproducibility. Our results from all subjects showed high-quality diffusion-weighted images of the breast without fat contamination. Mean apparent diffusion coefficients for b = 0, 600 s/mm(2) and b = 50, 600 s/mm(2) all showed good reproducibility, as 95% confidence intervals of the apparent diffusion coefficients were 4 × 10(-5) mm(2) /s and 5 × 10(-5) mm(2) /s and repeatability values were 1.09 × 10(-4) and 1.31 × 10(-4) , respectively. In conclusion, water-selective DWI is a feasible alternative to standard methods of DWI based on fat suppression. The added complexity of the method does not compromise the reproducibility of diffusion measurements in the breast.

Chemical exchange saturation transfer (CEST) provides an indirect means to detect exchangeable protons within tissues through their effects on the water signal. Previous studies have suggested that amide proton transfer (APT) imaging, a specific form of CEST, detects endogenous amide protons with a resonance frequency offset 3.5 ppm downfield from water, and thus may be sensitive to variations in mobile proteins/peptides in tumors. However, as CEST measurements are influenced by various confounding effects, such as spillover saturation, magnetization transfer (MT) and MT asymmetry, the mechanism or degree of increased APT signal in tumors is not certain. In addition to APT, nuclear Overhauser enhancement (NOE) effects upfield from water may also provide distinct information on tissue composition. In the current study, APT, NOE and several other MR parameters were measured and compared comprehensively in order to elucidate the origins of APT and NOE contrasts in tumors at 9.4 T. In addition to conventional CEST methods, a new intrinsic inverse metric was applied to correct for relaxation and other effects. After corrections for spillover, MT and T1 effects, corrected APT in tumors was found not to be significantly different from that in normal tissues, but corrected NOE effects in tumors showed significant decreases compared with those in normal tissues. Biochemical measurements verified that there was no significant enhancement of protein contents in the tumors studied, consistent with the corrected APT measurements and previous literature, whereas quantitative MT data showed decreases in the fractions of immobile macromolecules in tumors. Our results may assist in the better understanding of the contrast depicted by CEST imaging in tumors, and in the development of improved APT and NOE measurements for cancer imaging.

Typical diffusion measurements use Stejskal-Tanner pulsed gradient spin echo sequences to provide information about the average diffusion and displacement profiles of particles in a sample. To derive structural information, a measured displacement profile has to be related by means of a model to the physical and geometrical properties of the tissue, such as diffusion coefficients and shapes of semi-permeable membranes of compartments in the system. The behavior of the NMR signal and the measured ADC are greatly affected by the cellular architecture of a tissue, mainly because cellular membranes are relatively impermeable to water. For long diffusion times, and small signal attenuations, ADC is relatively insensitive to how it is measured. In general, however, ADC values are not readily interpreted unless the measuring conditions are specified in detail. For given measuring conditions, ADC depends on intra- and extracellular diffusion coefficients, membrane permeabilities, cell sizes and the cellular volume fraction. If intra- and extracellular T2 relaxation rates are different enough, ADC may also depend on the relaxation properties of the system and the echo time. An improved understanding of the precise influence of these factors has been obtained by detailed consideration of theoretical and computer models that can be related to experimental data in simple systems. Further refinements of such models should advance our understanding of water diffusion in tissues.

Manganese (Mn) and iron (Fe) are both paramagnetic species that can affect magnetic resonance relaxation rates. They also share common transport systems in vivo and thus in experimental models of metal exposure their effects on relaxation rates may interact in a complex fashion. Here we present a novel model to interpret the combined effects of Mn and Fe on MRI relaxation rates. To achieve varying levels of both metals, adult rats were separated into four groups; a control group and three groups treated with weekly intravenous injections of 3 mg Mn/kg body for 14 weeks. The three treated groups were fed either a normal diet, Fe deficient or Fe enriched diet. All rats were scanned using MRI at the 14th week to measure regional water relaxation rates. Rat brains were removed at the end of the study (14th week) and dissected into regions for measurement of Mn and Fe by atomic absorption spectroscopy. For the normal diet groups, R(1) was strongly correlated with tissue Mn concentrations. However, the slopes of the linear regression fits varied significantly among different brain regions, and a simple linear model failed to explain the changes in relaxation rate when both Mn and Fe contents changed. We propose a competition model, which is based on the ability of Mn and Fe to compete in vivo for common binding sites. The combined effect of Mn and Fe on the relaxation rates is complicated and additional studies will be necessary to explain how MRI signals are affected when the levels of both metals are varied.

The apparent diffusion coefficient of brain water was decreased by frontal cortical electroshock, usually but not always associated with brief epileptic afterdischarge detectable at the parietal cortex. Previous studies have shown that status epilepticus causes similar larger decreases, which are largely reversible by the termination of seizure discharge with pentobarbital. Cerebral blood flow is elevated in these conditions, and biochemical energy failure does not occur. The brain water diffusion coefficient also decreases in spreading depression, without depletion of energy stores. All of these findings may be due in part to the reduction of brain extracellular space caused by cell swelling, which occurs to some degree in all three conditions. However, major biological differences between brain activation and brain ischemia and new evidence for increased cytosolic viscosity in the latter both suggest that other mechanisms deserve further investigation. Use-dependent motility of dendritic spines and other phenomena that may allow direct detection of neural activity by diffusion-weighted NMR imaging are of special interest.