Simultaneous multi‐slice spin‐ and gradient‐echo dynamic susceptibility‐contrast perfusion‐weighted MRI of gliomas

Although combined spin‐ and gradient‐echo (SAGE) dynamic susceptibility‐contrast (DSC) MRI can provide perfusion quantification that is sensitive to both macrovessels and microvessels while correcting for T₁‐shortening effects, spatial coverage is often limited in order to maintain a high temporal resolution for DSC quantification. In this work, we combined a SAGE echo‐planar imaging (EPI) sequence with simultaneous multi‐slice (SMS) excitation and blipped controlled aliasing in parallel imaging (blipped CAIPI) at 3 T to achieve both high temporal resolution and whole brain coverage. Two protocols using this sequence with multi‐band (MB) acceleration factors of 2 and 3 were evaluated in 20 patients with treated gliomas to determine the optimal scan parameters for clinical use. ΔR₂*(t) and ΔR₂(t) curves were derived to calculate dynamic signal‐to‐noise ratio (dSNR), ΔR₂*‐ and ΔR₂‐based relative cerebral blood volume (rCBV), and mean vessel diameter (mVD) for each voxel. The resulting SAGE DSC images acquired using MB acceleration of 3 versus 2 appeared visually similar in terms of image distortion and contrast. The difference in the mean dSNR from normal‐appearing white matter (NAWM) and that in the mean dSNR between NAWM and normal‐appearing gray matter were not statistically significant between the two protocols. ΔR₂*‐ and ΔR₂‐rCBV maps and mVD maps provided unique contrast and spatial heterogeneity within tumors.     

Water signal attenuation by D2O infusion as a novel contrast mechanism for 1H perfusion MRI

Deuterium oxide (D₂O), which is commercially available and nonradioactive, was proposed as a perfusion tracer before the clinical usage of conventional gadolinium‐based MRI contrast agents. However, the sensitivity of direct deuterium detection is the major challenge for its application. In this study, we propose a contrast‐enhanced strategy to indirectly trace administered D₂O by monitoring the signal attenuation of ¹H MRI. Experiments on D₂O concentration phantoms and in vivo rat brains were conducted to prove the concept of the proposed contrast mechanism. An average maximum signal drop ratio of 5.25 ± 0.91% was detected on ¹H MR images of rat brains with 2 mL of D₂O administered per 100 g of body weight. As a diffusible tracer for perfusion, D₂O infusion is a practicable method for the assessment of tissue perfusion and has the potential to provide different information from gadolinium‐based contrast agents, which have limited permeability for blood vessels. Furthermore, the observed negative relaxivities of D₂O reveal the ¹H–D exchange effect. Therefore, applications of perfusion MRI with D₂O as a contrast agent are worthy of further investigation. Copyright © 2013 John Wiley & Sons, Ltd.     

Evaluation of renal oxygenation change under the influence of carbogen breathing using a dynamic R2, R2′ and R2* quantification approach

The purpose of this study is to demonstrate the feasibility of dynamic renal R₂/R₂′/R₂* measurements based on a method, denoted psMASE‐ME, in which a periodic 180° pulse‐shifting multi‐echo asymmetric spin echo (psMASE) sequence, combined with a moving estimation (ME) strategy, is adopted. Following approval by the institutional animal care and use committee, a block design of respiratory challenge with interleaved air and carbogen (97% O₂, 3% CO₂) breathing was employed in nine rabbits. Parametrical R₂/R₂′/R₂* maps were computed and average R₂/R₂′/R₂* values were measured in regions of interest in the renal medulla and cortex. Bland–Altman plots showed good agreement between the proposed method and reference standards of multi‐echo spin echo and multi‐echo gradient echo sequences. Renal R₂, R₂′ and R₂* decreased significantly from 16.2 ± 4.4 s^?1, 9.8 ± 5.2 s^?1 and 25.9 ± 5.0 s^?1 to 14.9 ± 4.4 s^?1 (p < 0.05), 8.5 ± 4.1 s^?1 (p < 0.05) and 23.4 ± 4.8 s^?1 (p < 0.05) in the cortex when switching the gas mixture from room air to carbogen. In the renal medulla, R₂, R₂′ and R₂* also decreased significantly from 12.9 ± 4.7 s^?1, 15.1 ± 5.8 s^?1 and 27.9 ± 5.3 s^?1 to 11.8 ± 4.5 s^?1 (p < 0.05), 14.2 ± 4.2 s^?1 (p < 0.05) and 25.8 ± 5.1 s^?1 (p < 0.05). No statistically significant differences in relative R₂, R₂′ and R₂* changes were observed between the cortex and medulla (p = 0.72 for R₂, p = 0.39 for R₂′ and p = 0.61 for R₂*). The psMASE‐ME method for dynamic renal R₂/R₂′/R₂* measurements, together with the respiratory challenge, has potential use in the evaluation of renal oxygenation in many renal diseases     

Nuclear magnetic relaxation dispersion of murine tissue for development of T1 (R1) dispersion contrast imaging

This study quantified the spin–lattice relaxation rate (R₁) dispersion of murine tissues from 0.24 mT to 3 T. A combination of ex vivo and in vivo spin–lattice relaxation rate measurements were acquired for murine tissue. Selected brain, liver, kidney, muscle, and fat tissues were excised and R₁ dispersion profiles were acquired from 0.24 mT to 1.0 T at 37 °C, using a fast field‐cycling MR (FFC‐MR) relaxometer. In vivo R₁ dispersion profiles of mice were acquired from 1.26 T to 1.74 T at 37 °C, using FFC‐MRI on a 1.5 T scanner outfitted with a field‐cycling insert electromagnet to dynamically control B₀ prior to imaging. Images at five field strengths (1.26, 1.39, 1.5, 1.61, 1.74 T) were acquired using a field‐cycling pulse sequence, where B₀ was modulated for varying relaxation durations prior to imaging. R₁ maps and R₁ dispersion (ΔR₁/ΔB₀) were calculated at 1.5 T on a pixel‐by‐pixel basis. In addition, in vivo R₁ maps of mice were acquired at 3 T. At fields less than 1 T, a large R₁ magnetic field dependence was observed for tissues. ROI analysis of the tissues showed little relaxation dispersion for magnetic fields from 1.26 T to 3 T. Our tissue measurements show strong R₁ dispersion at field strengths less than 1 T and limited R₁ dispersion at field strengths greater than 1 T. These findings emphasize the inherent weak R₁ magnetic field dependence of healthy tissues at clinical field strengths. This characteristic of tissues can be exploited by a combination of FFC‐MRI and T₁ contrast agents that exhibit strong relaxivity magnetic field dependences (inherent or by binding to a protein), thereby increasing the agents' specificity and sensitivity. This development can provide potential insights into protein‐based biomarkers using FFC‐MRI to assess early changes in tumour development, which are not easily measureable with conventional MRI.     

Increased brain perfusion contrast with T2‐prepared intravoxel incoherent motion (T2prep IVIM) MRI

The feasibility to measure brain perfusion using intravoxel incoherent motion (IVIM) MRI has been reported recently with currently clinically available technology. The method is intrinsically local and quantitative, but is contaminated by partial volume effects with cerebrospinal fluid (CSF). Signal from CSF can be suppressed by a 180° inversion recovery (180°‐IR) magnetization preparation, but this also leads to strong suppression of blood and brain tissue signal. Here, we take advantage of the different T₂ relaxations of blood and brain relative to CSF, and implement a T₂‐prepared IVIM (T2prep IVIM) inversion recovery acquisition, which permits a recovery of between 43% and 57% of arterial and venous blood magnetization at excitation time compared with the theoretical recovery of between 27% and 30% with a standard 180°‐IR. We acquired standard IVIM (IVIM), T2prep IVIM and dynamic susceptibility contrast (DSC) images at 3 T using a 32‐multichannel receiver head coil in eight patients with known large high‐grade brain tumors. We compared the contrast and contrast‐to‐noise ratio obtained in the corresponding cerebral blood volume images quantitatively, as well as subjectively by two neuroradiologists. Our findings suggest that quantitative cerebral blood volume contrast and contrast‐to‐noise ratio, as well as subjective lesion detection, contrast quality and diagnostic confidence, are increased with T2prep IVIM relative to IVIM and DSC. Copyright © 2014 John Wiley & Sons, Ltd.     

Myelin water imaging and R2* mapping in neonates: Investigating R2* dependence on myelin and fibre orientation in whole brain white matter

R₂^* relaxation provides a semiquantitative method of detecting myelin, iron and white matter fibre orientation angles. Compared with standard histogram‐based analyses, angle‐resolved analysis of R₂^* has previously been shown to substantially improve the detection of subtle differences in the brain between healthy siblings of subjects with multiple sclerosis and unrelated healthy controls. Neonates, who are born with very little myelin and iron, and an underdeveloped connectome, provide researchers with an opportunity to investigate whether R₂^* is intimately linked with fibre‐angle or myelin content as it is in adults, which may in future studies be explored as a potential white matter developmental biomarker. Five healthy adult volunteers (mean age [±SD] = 31.2 [±8.3] years; three males) were recruited from Vancouver, Canada. Eight term neonates (mean age = 38.6 ± 1.2 weeks; five males) were recruited from the Children's Hospital of Chongqing Medical University neonatal ward. All subjects were scanned on identical 3 T Philips Achieva scanners equipped with an eight‐channel SENSE head coil and underwent a multiecho gradient echo scan, a 32‐direction DTI scan and a myelin water imaging scan. For both neonates and adults, bin‐averaged R₂^* variation across the brain's white matter was found to be best explained by fibre orientation. For adults, this represented a difference in R₂^* values of 3.5 Hz from parallel to perpendicular fibres with respect to the main magnetic field. In neonates, the fibre orientation dependency displayed a cosine wave shape, with a small R₂^* range of 0.4 Hz. This minor relationship in neonates provides further evidence for the key role myelin probably plays in creating this fibre orientation dependence later in life, but suggests limited clinical application in newborn populations. Future studies should investigate fibre‐orientation dependency in infants in the first 5 years, when substantial myelin development occurs.     

MRI and quantitative autoradiographic studies following bolus injections of unlabeled and (14)C-labeled gadolinium-diethylenetriaminepentaacetic acid in a rat model of stroke yield similar distribution volumes and blood-to-brain influx rate constants

In previous studies on a rat model of transient cerebral ischemia, the blood and brain concentrations of gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DTPA) following intravenous bolus injection were repeatedly assessed by dynamic contrast‐enhanced (DCE)‐MRI, and blood‐to‐brain influx rate constants (K_i) were calculated from Patlak plots of the data in areas with blood–brain barrier (BBB) opening. For concurrent validation of these findings, after completing the DCE‐MRI study, radiolabeled sucrose or α‐aminoisobutyric acid was injected intravenously, and the brain disposition and K_i values were calculated by quantitative autoradiography (QAR) assay employing the single‐time equation. To overcome two of the shortcomings of this comparison, the present experiments were carried out with a radiotracer virtually identical to Gd‐DTPA, Gd‐[¹⁴C]DTPA, and K_i was calculated from both sets of data by the single‐time equation. The protocol included 3 h of middle cerebral artery occlusion and 2.5 h of reperfusion in male Wistar rats (n = 15) preceding the DCE‐MRI Gd‐DTPA and QAR Gd‐[¹⁴C]DTPA measurements. In addition to K_i, the tissue‐to‐blood concentration ratios, or volumes of distribution (V_R), were calculated. The regions of BBB opening were similar on the MRI maps and autoradiograms. Within them, V_R was nearly identical for Gd‐DTPA and Gd‐[¹⁴C]DTPA, and K_i was slightly, but not significantly, higher for Gd‐DTPA than for Gd‐[¹⁴C]DTPA. The K_i values were well correlated (r = 0.67; p = 0.001). When the arterial concentration–time curve of Gd‐DTPA was adjusted to match that of Gd‐[¹⁴C]DTPA, the two sets of K_i values were equal and statistically comparable with those obtained previously by Patlak plots (the preferred, less model‐dependent, approach) of the same data (p = 0.2–0.5). These findings demonstrate that this DCE‐MRI technique accurately measures the Gd‐DTPA concentration in blood and brain, and that K_i estimates based on such data are good quantitative indicators of BBB injury. Copyright © 2010 John Wiley & Sons, Ltd.     

Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume

The susceptibility differences at the gas–liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd‐DTPA (rCBV_Gd) and the MB‐induced susceptibility effect (ΔR₂*_MB) by conventional dynamic susceptibility contrast MRI (DSC‐MRI). Custom‐made MBs had a mean diameter of 0.92 µm and were capable of inducing 4.68 ± 3.02% of the maximum signal change (MSC). The MB‐associated ΔR₂*_MB was compared with rCBV_Gd in 16 rats on 4.7‐T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between ΔR₂*_MB and rCBV_Gd, and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC‐MRI, and emphasize the critical effect of TTP on MB‐based contrast MRI. Copyright © 2013 John Wiley & Sons, Ltd.     

Accuracy of fully automated,quantitative, volumetric measurement of the amount of fibroglandular breast tissue using MRI: correlation with anthropomorphic breast phantoms

To demonstrate the accuracy of fully automated, quantitative, volumetric measurement of the amount of fibroglandular breast tissue (FGT), using MRI, and to investigate the impact of different MRI sequences using anthropomorphic breast phantoms as the ground truth. In this study, 10 anthropomorphic breast phantoms that consisted of different known fractions of adipose and protein tissue, which closely resembled normal breast parenchyma, were developed. Anthropomorphic breast phantoms were imaged with a 1.5 T unit (Siemens, Avantofit) using an 18‐channel breast coil. The sequence protocol consisted of an isotropic Dixon sequence (Di), an anisotropic Dixon sequence (Da), and T₁ 3D FLASH sequences with and without fat saturation (T1). Fully automated, quantitative, volumetric measurement of FGT for all anthropomorphic phantoms and sequences was performed and correlated with the amounts of fatty and protein components in the phantoms as the ground truth. Fully automated, quantitative, volumetric measurements of FGT with MRI for all sequences ranged from 5.86 to 61.05% (mean 33.36%). The isotropic Dixon sequence yielded the highest accuracy (median 0.51%–0.78%) and precision (median range 0.19%) compared with anisotropic Dixon (median 1.92%–2.09%; median range 0.55%) and T₁‐weighted sequences (median 2.54%–2.46%; median range 0.82%). All sequences yielded good correlation with the FGT content of the anthropomorphic phantoms. The best correlation of FGT measurements was identified for Dixon sequences (Di, R² = 0.999; Da, R² = 0.998) compared with conventional T₁‐weighted sequences (R² = 0.971). MRI yields accurate, fully automated, quantitative, volumetric measurements of FGT, an increasingly important and sensitive imaging biomarker for breast cancer risk. Compared with conventional T₁ sequences, Dixon‐type sequences show the highest correlation and reproducibility for automated, quantitative, volumetric FGT measurements using anthropomorphic breast phantoms as the ground truth.     

Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination

A model of dysmyelination, the Long Evans Shaker (les) rat, was used to study the contribution of myelin to MR tissue properties in white matter. A large region of white matter was identified in the deep cerebellum and was used for measurements of the MR relaxation rate constants, R₁ = 1/T₁ and R₂ = 1/T₂, at 7 T. In this study, R₁ of the les deep cerebellar white matter was found to be 0.55 ± 0.08 s ^–1 and R₂ was found to be 15 ± 1 s^–1, revealing significantly lower R₁ and R₂ in les white matter relative to wild‐type (wt: R₁ = 0.69 ± 0.05 s^–1 and R₂ = 18 ± 1 s^–1). These deviated from the expected ΔR₁ and ΔR₂ values, given a complete lack of myelin in the les white matter, derived from the literature using values of myelin relaxivity, and we suspect that metals could play a significant role. The absolute concentrations of the paramagnetic transition metals iron (Fe) and manganese (Mn) were measured by a micro‐synchrotron radiation X‐ray fluorescence (μSRXRF) technique, with significantly greater Fe and Mn in les white matter than in wt (in units of μg [metal]/g [wet weight tissue]: les: Fe concentration,19 ± 1; Mn concentration, 0.71 ± 0.04; wt: Fe concentration,10 ± 1; Mn concentration, 0.47 ± 0.04). These changes in Fe and Mn could explain the deviations in R₁ and R₂ from the expected values in white matter. Although it was found that the influence of myelin still dominates R₁ and R₂ in wt rats, there were non‐negligible changes in the contribution of the metals to relaxation. Although there are already problems with the estimation of myelin from R₁ and R₂ changes in disease models with pathology that also affects the relaxation rate constants, this study points to a specific pitfall in the estimation of changes in myelin in diseases or models with disrupted concentrations of paramagnetic transition metals. Copyright © 2016 John Wiley & Sons, Ltd.     

Effect of anesthesia on renal R2* measured by blood oxygen level‐dependent MRI

Blood oxygen level‐dependent (BOLD) MRI is increasingly being used to assess renal tissue oxygenation during disease based on the transverse relaxation rate (R₂*). In preclinical small animal models, the requisite use of anesthesia during imaging may lead to functional changes which influence R₂* and confound results. The purpose of this study was to evaluate the effects of four common anesthetic compounds on renal R₂* in healthy mice. Five female ICR mice were imaged with BOLD MRI approximately 25 min after induction with isoflurane (Iso; 1% or 1.5%, delivered in 100% O₂), ketamine/xylazine (KX), sodium pentobarbital (PB) or 2,2,2‐tribromoethanol (TBE). A significant effect of anesthetic agent on R₂* was observed in all tissue layers of the kidney, including the cortex, outer stripe of the outer medulla (OSOM), inner stripe of the outer medulla (ISOM) and inner medulla (IM). Pairwise significant differences in R₂* between specific agents were found in the cortex, OSOM and ISOM, with the largest difference observed in the ISOM between 1.5% Iso (26.6 ± 1.7 s^–1) and KX (66.0 ± 7.1 s^–1). The difference between 1% Iso and KX in the ISOM was not abolished when KX was administered with supplemental 100% O₂ or when 1% Iso was delivered in 21% O₂, indicating that the fraction of inspired oxygen did not account for the observed differences. Our results indicate that the choice of anesthesia has a large influence on the observed R₂* in mouse kidney, and anesthetic effects must be considered in the design and interpretation of renal BOLD MRI studies. Copyright © 2015 John Wiley & Sons, Ltd.     

UTE–ΔR2–ΔR2* combined MR whole‐brain angiogram using dual‐contrast superparamagnetic iron oxide nanoparticles

The ability to visualize whole‐brain vasculature is important for quantitative in vivo investigation of vascular malfunctions in cerebral small vessel diseases, including cancer, stroke and neurodegeneration. Transverse relaxation‐based ΔR₂ and ΔR₂* MR angiography (MRA) provides improved vessel–tissue contrast in animal deep brain with the aid of intravascular contrast agents; however, it is susceptible to orientation dependence, air–tissue interface artifacts and vessel size overestimation. Dual‐mode MRA acquisition with superparamagnetic iron oxide nanoparticles (SPION) provides a unique opportunity to systematically compare and synergistically combine both longitudinal (R₁) and transverse (ΔR₂ and ΔR₂*) relaxation‐based MRA. Through Monte Carlo (MC) simulation and MRA experiments in normal and tumor‐bearing animals with intravascular SPION, we show that ultrashort TE (UTE) MRA acquires well‐defined vascularization on the brain surface, minimizing air–tissue artifacts, and combined ΔR₂ and ΔR₂* MRA simultaneously improves the sensitivity to intracortical penetrating vessels and reduces vessel size overestimation. Consequently, UTE–ΔR₂–ΔR₂* combined MRA complements the shortcomings of individual angiograms and provides a strategy to synergistically merge longitudinal and transverse relaxation effects to generate more robust in vivo whole‐brain micro‐MRA. Copyright © 2016 John Wiley & Sons, Ltd.     

Pseudo‐extravasation rate constant of dynamic susceptibility contrast‐MRI determined from pharmacokinetic first principles

Dynamic susceptibility contrast‐magnetic resonance imaging (DSC‐MRI) is widely used to obtain informative perfusion imaging biomarkers, such as the relative cerebral blood volume (rCBV). The related post‐processing software packages for DSC‐MRI are available from major MRI instrument manufacturers and third‐party vendors. One unique aspect of DSC‐MRI with low‐molecular‐weight gadolinium (Gd)‐based contrast reagent (CR) is that CR molecules leak into the interstitium space and therefore confound the DSC signal detected. Several approaches to correct this leakage effect have been proposed throughout the years. Amongst the most popular is the Boxerman–Schmainda–Weisskoff (BSW) K₂ leakage correction approach, in which the K₂ pseudo‐first‐order rate constant quantifies the leakage. In this work, we propose a new method for the BSW leakage correction approach. Based on the pharmacokinetic interpretation of the data, the commonly adopted R₂* expression accounting for contributions from both intravascular and extravasating CR components is transformed using a method mathematically similar to Gjedde–Patlak linearization. Then, the leakage rate constant (K_L) can be determined as the slope of the linear portion of a plot of the transformed data. Using the DSC data of high‐molecular‐weight (~750 kDa), iron‐based, intravascular Ferumoxytol (FeO), the pharmacokinetic interpretation of the new paradigm is empirically validated. The primary objective of this work is to empirically demonstrate that a linear portion often exists in the graph of the transformed data. This linear portion provides a clear definition of the Gd CR pseudo‐leakage rate constant, which equals the slope derived from the linear segment. A secondary objective is to demonstrate that transformed points from the initial transient period during the CR wash‐in often deviate from the linear trend of the linearized graph. The inclusion of these points will have a negative impact on the accuracy of the leakage rate constant, and even make it time dependent.     

Phase contrast MRI is an early marker of micrometastatic breast cancer development in the rat brain

The early growth of micrometastatic breast cancer in the brain often occurs through vessel co‐option and is independent of angiogenesis. Remodeling of the existing vasculature is an important step in the evolution of co‐opting micrometastases into angiogenesis‐dependent solid tumor masses. The purpose of this study was to determine whether phase contrast MRI, an intrinsic source of contrast exquisitely sensitive to the magnetic susceptibility properties of deoxygenated hemoglobin, could detect vascular changes occurring independent of angiogenesis in a rat model of breast cancer metastases to the brain. Twelve nude rats were administered 10⁶ MDA‐MB‐231BRL ‘brain‐seeking’ breast cancer cells through intracardiac injection. Serial, multiparametric MRI of the brain was performed weekly until metastatic disease was detected. The results demonstrated that images of the signal phase (area under the receiver operating characteristic curve, 0.97) were more sensitive than T₂* gradient echo magnitude images (area under the receiver operating characteristic curve, 0.73) to metastatic brain lesions. The difference between the two techniques was probably the result of the confounding effects of edema on the magnitude of the signal. A region of interest analysis revealed that vascular abnormalities detected with phase contrast MRI preceded tumor permeability measured with contrast‐enhanced MRI by 1–2 weeks. Tumor size was correlated with permeability (R² = 0.23, p < 0.01), but phase contrast was independent of tumor size (R² = 0.03). Histopathologic analysis demonstrated that capillary endothelial cells co‐opted by tumor cells were significantly enlarged, but less dense, relative to the normal brain vasculature. Although co‐opted vessels were vascular endothelial growth factor‐negative, vessels within larger tumor masses were vascular endothelial growth factor‐positive. In conclusion, phase contrast MRI is believed to be sensitive to vascular remodeling in co‐opting brain tumor metastases independent of sprouting angiogenesis, and may therefore aid in preclinical studies of angiogenic‐independent tumors or in the monitoring of continued tumor growth following anti‐angiogenic therapy. Published 2011. This article is a US Government work and is in the public domain in the USA.     

Vessel size index measurements in a rat model of glioma: comparison of the dynamic (Gd) and steady-state (iron-oxide) susceptibility contrast MRI approaches

Vessel size index (VSI), a parameter related to the distribution of vessel diameters, may be estimated using two MRI approaches: (i) dynamic susceptibility contrast (DSC) MRI following the injection of a bolus of Gd‐chelate. This technique is routinely applied in the clinic to assess intracranial tissue perfusion in patients; (ii) steady‐state susceptibility contrast with USPIO contrast agents, which is considered here as the standard method. Such agents are not available for human yet and the steady‐state approach is currently limited to animal studies. The aim is to compare VSI estimates obtained with these two approaches on rats bearing C6 glioma (n = 7). In a first session, VSI was estimated from two consecutive injections of Gd‐Chelate (Gd₁ and Gd₂). In a second session (4 hours later), VSI was estimated using USPIO. Our findings indicate that both approaches yield comparable VSI estimates both in contralateral (VSI{USPIO} = 7.5 ± 2.0 µm, VSI{Gd₁} = 6.5 ± 0.7 µm) and in brain tumour tissues (VSI{USPIO} = 19.4 ± 7.1 µm, VSI{Gd₁} = 16.6 ± 4.5 µm). We also observed that, in the presence of BBB leakage (as it occurs typically in brain tumours), applying a preload of Gd‐chelate improves the VSI estimate with the DSC approach both in contralateral (VSI{Gd₂} = 7.1 ± 0.4 µm) and in brain tumour tissues (VSI{Gd₂} = 18.5 ± 4.3 µm) but is not mandatory. VSI estimates do not appear to be sensitive to T₁ changes related to Gd extravasation. These results suggest that robust VSI estimates may be obtained in patients at 3 T or higher magnetic fields with the DSC approach. Copyright © 2011 John Wiley & Sons, Ltd.     

Measurement of parenchymal extravascular R2* and tissue oxygen extraction fraction using multi‐echo vascular space occupancy MRI at 7 T

Parenchymal extravascular R₂* is an important parameter for quantitative blood oxygenation level‐dependent (BOLD) studies. Total and intravascular R₂* values and changes in R₂* values during functional stimulations have been reported in a number of studies. The purpose of this study was to measure absolute extravascular R₂* values in human visual cortex and to estimate the intra‐ and extravascular contributions to the BOLD effect at 7 T. Vascular space occupancy (VASO) MRI was employed to separate out the extravascular tissue signal. Multi‐echo VASO and BOLD functional MRI (fMRI) with visual stimulation were performed at 7 T for R₂* measurement at a spatial resolution of 2.5 × 2.5 × 2.5 mm³ in healthy volunteers (n = 6). The ratio of changes in extravascular and total R₂* (ΔR₂*) was used to estimate the extravascular fraction of the BOLD effect. Extravascular R₂* values were found to be 44.66 ± 1.55 and 43.38 ± 1.51 s^–1 (mean ± standard error of the mean, n = 6) at rest and activation, respectively, in human visual cortex at 7 T. The extravascular BOLD fraction was estimated to be 91 ± 3%. The parenchymal oxygen extraction fraction (OEF) during activation was estimated to be 0.24 ± 0.01 based on the R₂* measurements, indicating an approximately 37% decrease compared with OEF at rest. Copyright © 2014 John Wiley & Sons, Ltd.     

MR fingerprinting ASL: Sequence characterization and comparison with dynamic susceptibility contrast (DSC) MRI

MR Fingerprinting (MRF)‐based Arterial‐Spin‐Labeling (ASL) has the potential to measure multiple parameters such as cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T₁ in a single scan. However, the previous reports have only demonstrated a proof‐of‐principle of the technique but have not examined the performance of the sequence in the context of key imaging parameters. Furthermore, there has not been a study to directly compare the technique to clinically used perfusion method of dynamic‐susceptibility‐contrast (DSC) MRI. The present report consists of two studies. In the first study (N = 8), we examined the dependence of MRF‐ASL sequence on TR time pattern. Ten different TR patterns with a range of temporal characteristics were examined by both simulations and experiments. The results revealed that there was a significance dependence of the sequence performance on TR pattern (p < 0.001), although there was not a single pattern that provided dramatically improvements. Among the TR patterns tested, a sinusoidal pattern with a period of 125 TRs provided an overall best estimation in terms of spatial consistency. These experimental observations were consistent with those of numerical simulations. In the second study (N = 8), we compared MRF‐ASL results with those of DSC MRI. It was found that MRF‐ASL and DSC MRI provided highly comparable maps of cerebral blood flow (CBF) and bolus‐arrival‐time (BAT), with spatial correlation coefficients of 0.79 and 0.91, respectively. However, in terms of quantitative values, BAT obtained with MRF‐ASL was considerably lower than that from DSC (p < 0.001), presumably because of the differences in tracer characteristics in terms of diffusible versus intravascular tracers. Test–retest assessment of MRF‐ASL MRI revealed that the spatial correlations of parametric maps were 0.997, 0.962, 0.746 and 0.863 for B₁⁺, T₁, CBF, and BAT, respectively. MRF‐ASL is a promising technique for assessing multiple perfusion parameters simultaneously without contrast agent.     

Manipulation of cortical gray matter oxygenation by hyperoxic respiratory challenge: field dependence of R(2) * and MR signal response

The aim of this study was to quantitatively assess the field strength dependence of the transverse relaxation rate (R₂*) change in cortical gray matter induced by hyperoxia and hyperoxic hypercapnia versus normoxia in an intra‐individual comparison of young healthy volunteers. Medical air (21% O₂), pure oxygen and carbogen (95% O₂, 5% CO₂) were alternatively administered in a block‐design temporal pattern to induce normoxia, hyperoxia and hyperoxic hypercapnia, respectively. Local R₂* values were determined from three‐dimensional, multiple, radiofrequency‐spoiled, fast field echo data acquired at 1.5, 3 and 7 T. Image quality was good at all field strengths. Under normoxia, the mean gray matter R₂* values were 13.3 ± 2.7 s^–1 (1.5 T), 16.9 ± 0.9 s^–1 (3 T) and 29.0 ± 2.6 s^–1 (7 T). Both hyperoxic gases induced relaxation rate decreases ΔR₂*, whose magnitudes increased quadratically with the field strength [carbogen: –0.69 ± 0.20 s^–1 (1.5 T), –1.49 ± 0.49 s^–1 (3 T), –5.64 ± 0.67 s^–1 (7 T); oxygen: –0.39 ± 0.20 s^–1 (1.5 T), –0.78 ± 0.48 s^–1 (3 T), –3.86 ± 1.00 s^–1 (7 T)]. Carbogen produced larger R₂* changes than oxygen at all field strengths. The relative change ΔR₂*/R₂* also increased with the field strength with a power between 1 and 2 for both carbogen and oxygen. The statistical significance of the R₂* response improved with increasing B₀ and was higher for carbogen than for oxygen. For a sequence with pure T₂* weighting of the signal response to respiratory challenge, the results suggested a maximum carbogen‐induced signal difference of 19.3% of the baseline signal at 7 T and TE = 38 ms, but a maximum oxygen‐induced signal difference of only 3.0% at 1.5 T and TE = 76 ms. For 3 T, maximum signal changes of 4.7% (oxygen) and 8.9% (carbogen) were computed. In conclusion, the R₂* response to hyperoxic respiratory challenge was stronger for carbogen than for oxygen, and increased quadratically with the static magnetic field strength for both challenges, which highlights the importance of high field strengths for future studies aimed at probing oxygen physiology in clinical settings. Copyright © 2012 John Wiley & Sons, Ltd.     

Bi‐component T2* analysis of bound and pore bone water fractions fails at high field strengths

Osteoporosis involves the degradation of the bone's trabecular architecture, cortical thinning and enlargement of cortical pores. Increased cortical porosity is a major cause of the decreased strength of osteoporotic bone. The majority of cortical pores, however, are below the resolution limit of MRI. Recent work has shown that porosity can be evaluated by MRI‐based quantification of bone water. Bi‐exponential T₂* fitting and adiabatic inversion preparation are the two most common methods purported to distinguish bound and pore water in order to quantify matrix density and porosity. To assess the viability of T₂* bi‐component analysis as a method for the quantification of bound and pore water fractions, we applied this method to human cortical bone at 1.5, 3, 7 and 9.4 T, and validated the resulting pool fractions against micro‐computed tomography‐derived porosity and gravimetrically determined bone densities. We also investigated alternative methods: two‐dimensional T₁–T₂* bi‐component fitting by incorporation of saturation recovery, one‐ and two‐dimensional fitting of Carr–Purcell–Meiboom–Gill (CPMG) echo amplitudes, and deuterium inversion recovery. The short‐T₂* pool fraction was moderately correlated with porosity (R² = 0.70) and matrix density (R² = 0.63) at 1.5 T, but the strengths of these associations were found to diminish rapidly as the field strength increased, falling below R² = 0.5 at 3 T. The addition of the T₁ dimension to bi‐component analysis only slightly improved the strengths of these correlations. T₂*‐based bi‐component analysis should therefore be used with caution. The performance of deuterium inversion recovery at 9.4 T was also poor (R² = 0.50 vs porosity and R² = 0.46 vs matrix density). The CPMG‐derived short‐T₂ fraction at 9.4 T, however, was highly correlated with porosity (R² = 0.87) and matrix density (R² = 0.88), confirming the utility of this method for independent validation of bone water pools. Copyright © 2015 John Wiley & Sons, Ltd.     

Inverse Z‐spectrum analysis for spillover‐, MT‐, and T1‐corrected steady‐state pulsed CEST‐MRI – application to pH‐weighted MRI of acute stroke

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 (MTR_Rex), employing the inverse Z‐spectrum, which eliminates spillover and semi‐solid MT effects. This metric can be simply related to R_ex, the exchange‐dependent relaxation rate in the rotating frame, and k_a, 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 MTR_Rex 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. Copyright © 2014 John Wiley & Sons, Ltd.