Optimization of saturation‐recovery dynamic contrast‐enhanced MRI acquisition protocol: monte carlo simulation approach demonstrated with gadolinium MR renography

Dynamic contrast‐enhanced (DCE) MRI is widely used for the measurement of tissue perfusion and to assess organ function. MR renography, which is acquired using a DCE sequence, can measure renal perfusion, filtration and concentrating ability. Optimization of the DCE acquisition protocol is important for the minimization of the error propagation from the acquired signals to the estimated parameters, thus improving the precision of the parameters. Critical to the optimization of contrast‐enhanced T₁‐weighted protocols is the balance of the T₁‐shortening effect across the range of gadolinium (Gd) contrast concentration in the tissue of interest. In this study, we demonstrate a Monte Carlo simulation approach for the optimization of DCE MRI, in which a saturation‐recovery T₁‐weighted gradient echo sequence is simulated and the impact of injected dose (D) and time delay (TD, for saturation recovery) is tested. The results show that high D and/or high TD cause saturation of the peak arterial signals and lead to an overestimation of renal plasma flow (RPF) and glomerular filtration rate (GFR). However, the use of low TD (e.g. 100 ms) and low D leads to similar errors in RPF and GFR, because of the Rician bias in the pre‐contrast arterial signals. Our patient study including 22 human subjects compared TD values of 100 and 300 ms after the injection of 4 mL of Gd contrast for MR renography. At TD = 100 ms, we computed an RPF value of 157.2 ± 51.7 mL/min and a GFR of 33.3 ± 11.6 mL/min. These results were all significantly higher than the parameter estimates at TD = 300 ms: RPF = 143.4 ± 48.8 mL/min (p = 0.0006) and GFR = 30.2 ± 11.5 mL/min (p = 0.0015). In conclusion, appropriate optimization of the DCE MRI protocol using simulation can effectively improve the precision and, potentially, the accuracy of the measured parameters. Copyright © 2016 John Wiley & Sons, Ltd.     

A comparison of arterial spin labeling perfusion MRI and DCE‐MRI in human prostate cancer

Perfusion MRI has the potential to provide pathophysiological biomarkers for the evaluating, staging and therapy monitoring of prostate cancer. The objective of this study was to explore the feasibility of noninvasive arterial spin labeling (ASL) to detect prostate cancer in the peripheral zone and to investigate the correlation between the blood flow (BF) measured by ASL and the pharmacokinetic parameters K^trans (forward volume transfer constant), k_ep (reverse reflux rate constant between extracellular space and plasma) and v_e (the fractional volume of extracellular space per unit volume of tissue) measured by dynamic contrast‐enhanced (DCE) MRI in patients with prostate cancer. Forty‐three consecutive patients (ages ranging from 49 to 86 years, with a median age of 74 years) with pathologically confirmed prostate cancer were recruited. An ASL scan with four different inversion times (TI = 1000, 1200, 1400 and 1600 ms) and a DCE‐MRI scan were performed on a clinical 3.0 T GE scanner. BF, K^trans, k_ep and v_e maps were calculated. In order to determine whether the BF values in the cancerous area were statistically different from those in the noncancerous area, an independent t‐test was performed. Spearman's bivariate correlation was used to assess the relationship between BF and the pharmacokinetic parameters K^trans, k_ep and v_e. The mean BF values in the cancerous areas (97.1 ± 30.7, 114.7 ± 28.7, 102.3 ± 22.5, 91.2 ± 24.2 ml/100 g/min, respectively, for TI = 1000, 1200, 1400, 1600 ms) were significantly higher (p < 0.01 for all cases) than those in the noncancerous regions (35.8 ± 12.5, 42.2 ± 13.7, 53.5 ± 19.1, 48.5 ± 13.5 ml/100 g/min, respectively). Significant positive correlations (p < 0.01 for all cases) between BF and the pharmacokinetic parameters K^trans, k_ep and v_e were also observed for all four TI values (r = 0.671, 0.407, 0.666 for TI = 1000 ms; 0.713, 0.424, 0.698 for TI = 1200 ms; 0.604, 0.402, 0.595 for TI = 1400 ms; 0.605, 0.422, 0.548 for TI = 1600 ms). It can be seen that the quantitative ASL measurements show significant differences between cancerous and benign tissues, and exhibit strong to moderate correlations with the parameters obtained using DCE‐MRI. These results show the promise of ASL as a noninvasive alternative to DCE‐MRI. Copyright © 2014 John Wiley & Sons, Ltd.     

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.     

In vivo chlorine‐35, sodium‐23 and proton magnetic resonance imaging of the rat brain

In this study we demonstrate the feasibility of combined chlorine‐35, sodium‐23 and proton magnetic resonance imaging (MRI) at 9.4 Tesla, and present the first in vivo chlorine‐35 images obtained by means of MRI. With the experimental setup used in this study all measurements could be done in one session without changing the setup or moving the subject. The multinuclear measurement requires a total measurement time of 2 h and provides morphological (protons) and physiological (sodium‐23, chlorine‐35) information in one scanning session. Chlorine‐35, sodium‐23 and high resolution proton images were acquired from a phantom, a healthy rat and from a rat displaying a focal cerebral infarction. Compared to the healthy tissue a signal enhancement of a factor of 2.2 ± 0.2 in the chlorine‐35 and a factor of 2.9 ± 0.6 in the sodium‐23 images is observed in the areas of infarction. Exemplary unlocalized measurement of the in vivo longitudinal and transversal relaxation time of chlorine‐35 in a healthy rat showed multi‐exponential behaviour. A biexponential fit revealed a fast and a slow relaxing component with T_1,a = (1.7 ± 0.4) ms, T_1,b = (25.1 ± 1.4) ms, amplitudes of A = 0.26 ± 0.02, (1–A) = 0.74 ± 0.02 and T_2,a = (1.3 ± 0.1) ms, T_2,b = (11.8 ± 1.1) ms, A = 0.64 ± 0.02, (1–A) = 0.36 ± 0.02. Combined proton, sodium‐23 and chlorine‐35 MRI may provide a new approach for non‐invasive studies of ionic regulatory processes under physiological and pathological conditions in vivo. Copyright © 2010 John Wiley & Sons, Ltd.     

Effects of transcytolemmal water exchange on the assessment of myocardial extracellular volume with cardiovascular MRI

Quantitative analysis of the myocardial interstitial space is gaining increased interest as a biomarker in the MRI and clinical cardiovascular communities. To investigate the effect of water exchange on the calculation of myocardial extracellular volume (ECV), we employed two tissue models: the standard ECV two‐point model (SM) and the shutter speed model (SSM). Twenty individuals (18 men and two women; age 61.9 ± 10.3 years) underwent MRI at 1.5 T with pre‐contrast and post‐contrast dynamic T₁ quantification. Means, standard deviations and ranges for SM and SSM model parameters were calculated. Infarct and viable myocardial model parameters as well as apparent ECV values calculated with the SM and SSM were statistically compared. Viable ECV^SM remained temporally constant (27.3–28.0%: P = 0.5) and infarcted myocardial ECV^SM changed significantly (49.3–58.8%; P < 0.001), reaching a steady‐state value after 15 min. The intracellular lifetime of water was three times greater in infarcted myocardium when compared with viable myocardium (τ_i: 66.6 ± 115 versus 208.7 ± 72.7 ms) and accompanied a twofold increase in ECV (ECV^SSM: 30.3 ± 11.1 versus 71.0 ± 13.1%; P < 0.001). There was a consistent significant difference in ECV values of infarcted myocardium at different timepoints between the SM and SSM, but not viable myocardium, presumably due to slower water exchange. In summary, we found a significant change in apparent ECV and water exchange in infarcted myocardium when compared with viable myocardium. This was visualized by changes in dynamic contrast enhanced curve shapes and quantified using the SSM as not only an increase in apparent ECV but also a decrease in water exchange. Copyright © 2016 John Wiley & Sons, Ltd.     

Classification of prostatic diseases by means of multivariate analysis on in vivo proton MRSI and DCE‐MRI data

Multivariate analysis has been applied on proton magnetic resonance spectroscopic imaging (¹H‐MRSI) and dynamic contrast enhanced MRI (DCE‐MRI) data of patients with different prostatic diseases such as chronic inflammation, fibrosis and adenocarcinoma. Multivariate analysis offers a global view of the entire range of information coming from both the imaging and spectroscopic side of NMR technology, leading to an integrated picture of the system relying upon the entire metabolic and dynamic profile of the studied samples. In this study, we show how this approach, applied to ¹H‐MRSI/DCE‐MRI results, allows us to differentiate among the various prostatic diseases in a non‐invasive way with a 100% accuracy. These findings suggest that multivariate analysis of ¹H‐MRSI/DCE‐MRI can significantly improve the diagnostic accuracy for these pathological entities. From a more theoretical point of view, the complementation of a single biomarker approach with an integrated picture of the entire metabolic and dynamic profile allows for a more realistic appreciation of pathological entities. Copyright © 2009 John Wiley & Sons, Ltd.     

Accurate identification of myocardial viability after myocardial infarction with novel manganese chelate‐based MR imaging

We developed a novel manganese (Mn²⁺) chelate for magnetic resonance imaging (MRI) assessment of myocardial viability in acute and chronic myocardial infarct (MI) models, and compared it with Gadolinium‐based delay enhancement MRI (Gd³⁺‐DEMRI) and histology. MI was induced in 14 rabbits by permanent occlusion of the left circumflex coronary artery. Gd³⁺‐DEMRI and Mn²⁺ chelate‐based delayed enhancement MRI (Mn²⁺ chelate‐DEMRI) were performed at 7 days (acute MI, n = 8) or 8 weeks (chronic MI, n = 6) after surgery with sequential injection of 0.15 mmol/kg Gd³⁺ and Mn²⁺ chelate. The biodistribution of Mn²⁺ in tissues and blood was measured at 1.5 and 24 h. Blood pressure, heart rate (HR), left ventricular (LV) function, and infarct fraction (IF) were analyzed, and IF was compared with the histology. The Mn²⁺ chelate group maintained a stable hemodynamic status during experiment. For acute and chronic MI, all rabbits survived without significant differences in HR or LV function before and after injection of Mn²⁺ chelate or Gd³⁺ (p > 0.05). Mn²⁺ chelate mainly accumulated in the kidney, liver, spleen, and heart at 1.5 h, with low tissue uptake and urine residue at 24 h after injection. In the acute MI group, there was no significant difference in IF between Mn²⁺ chelate‐DEMRI and histology (22.92 ± 2.21% vs. 21.79 ± 2.25%, respectively, p = 0.87), while Gd³⁺‐DEMRI overestimated IF, as compared with histology (24.54 ± 1.73%, p = 0.04). In the chronic MI group, there was no significant difference in IF between the Mn²⁺ chelate‐DEMRI, Gd³⁺‐DEMRI, and histology (29.50 ± 11.39%, 29.95 ± 9.40%, and 29.00 ± 10.44%, respectively, p > 0.05), and all three were well correlated (r = 0.92–0.96, p < 0.01). We conclude that the use of Mn²⁺ chelate‐DEMRI is reliable for MI visualization and identifies acute MI more accurately than Gd³⁺‐DEMRI.     

Intratumor mapping of intracellular water lifetime: metabolic images of breast cancer?

Shutter‐speed pharmacokinetic analysis of dynamic‐contrast‐enhanced (DCE)‐MRI data allows evaluation of equilibrium inter‐compartmental water interchange kinetics. The process measured here – transcytolemmal water exchange – is characterized by the mean intracellular water molecule lifetime (τ_i). The τ_i biomarker is a true intensive property not accessible by any formulation of the tracer pharmacokinetic paradigm, which inherently assumes it is effectively zero when applied to DCE‐MRI. We present population‐averaged in vivo human breast whole tumor τ_i changes induced by therapy, along with those of other pharmacokinetic parameters. In responding patients, the DCE parameters change significantly after only one neoadjuvant chemotherapy cycle: while K^trans (measuring mostly contrast agent (CA) extravasation) and k_ep (CA intravasation rate constant) decrease, τ_i increases. However, high‐resolution, (1 mm)², parametric maps exhibit significant intratumor heterogeneity, which is lost by averaging. A typical 400 ms τ_i value means a trans‐membrane water cycling flux of 10¹³ H₂O molecules s^?1/cell for a 12 µm diameter cell. Analyses of intratumor variations (and therapy‐induced changes) of τ_i in combination with concomitant changes of v_e (extracellular volume fraction) indicate that the former are dominated by alterations of the equilibrium cell membrane water permeability coefficient, P_W, not of cell size. These can be interpreted in light of literature results showing that τ_i changes are dominated by a P_W(active) component that reciprocally reflects the membrane driving P‐type ATPase ion pump turnover. For mammalian cells, this is the Na⁺,K⁺‐ATPase pump. These results promise the potential to discriminate metabolic and microenvironmental states of regions within tumors in vivo, and their changes with therapy. © 2014 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.     

Three‐dimensional dynamic contrast‐enhanced MRI for the accurate,extensive quantification of microvascular permeability in atherosclerotic plaques

Atherosclerotic plaques that cause stroke and myocardial infarction are characterized by increased microvascular permeability and inflammation. Dynamic contrast‐enhanced MRI (DCE‐MRI) has been proposed as a method to quantify vessel wall microvascular permeability in vivo. Until now, most DCE‐MRI studies of atherosclerosis have been limited to two‐dimensional (2D) multi‐slice imaging. Although providing the high spatial resolution required to image the arterial vessel wall, these approaches do not allow the quantification of plaque permeability with extensive anatomical coverage, an essential feature when imaging heterogeneous diseases, such as atherosclerosis. To our knowledge, we present the first systematic evaluation of three‐dimensional (3D), high‐resolution, DCE‐MRI for the extensive quantification of plaque permeability along an entire vascular bed, with validation in atherosclerotic rabbits. We compare two acquisitions: 3D turbo field echo (TFE) with motion‐sensitized‐driven equilibrium (MSDE) preparation and 3D turbo spin echo (TSE). We find 3D TFE DCE‐MRI to be superior to 3D TSE DCE‐MRI in terms of temporal stability metrics. Both sequences show good intra‐ and inter‐observer reliability, and significant correlation with ex vivo permeability measurements by Evans Blue near‐infrared fluorescence (NIRF). In addition, we explore the feasibility of using compressed sensing to accelerate 3D DCE‐MRI of atherosclerosis, to improve its temporal resolution and therefore the accuracy of permeability quantification. Using retrospective under‐sampling and reconstructions, we show that compressed sensing alone may allow the acceleration of 3D DCE‐MRI by up to four‐fold. We anticipate that the development of high‐spatial‐resolution 3D DCE‐MRI with prospective compressed sensing acceleration may allow for the more accurate and extensive quantification of atherosclerotic plaque permeability along an entire vascular bed. We foresee that this approach may allow for the comprehensive and accurate evaluation of plaque permeability in patients, and may be a useful tool to assess the therapeutic response to approved and novel drugs for cardiovascular disease. Copyright © 2015 John Wiley & Sons, Ltd.     

Diffusion tensor imaging MRI of sickle cell kidney disease: initial results and comparison with iron deposition

Chronic kidney disease (CKD) occurs in over one‐third of patients with sickle cell disease (SCD) and can progress to end‐stage renal disease. Unfortunately, current clinical assessments of kidney function are insensitive to early‐stage CKD. Previous studies have shown that diffusion magnetic resonance imaging (MRI) can sensitively detect regional renal microstructural changes associated with early‐stage CKD. However, previous MRI studies in patients with SCD have been largely limited to the detection of renal iron deposition assessed by T₂* relaxometry. In this pilot imaging study, we compare MRI assessments of renal microstructure (diffusion) and iron deposition (T₂*) in patients with SCD and in non‐SCD control subjects. Diffusion tensor imaging (DTI) and T₂* relaxometry MRI data were obtained for pediatric (n = 5) and adult (n = 4) patients with SCD, as well as for non‐SCD control subjects (n = 10), on a Siemens Espree 1.5‐T MRI scanner. A region‐of‐interest analysis was used to calculate mean medullary and cortical values for each MRI metric. MRI findings were also compared with clinical assessments of renal function and hemolysis. Patients with SCD showed a significant decrease in medullary fractional anisotropy (FA, p = 0.0001) in comparison with non‐SCD subjects, indicative of microstructural alterations in the renal medulla of patients with SCD. Cortical and medullary reductions in T₂* (increased iron deposition, p = ≤0.0001) were also observed. Significant correlations were also observed between kidney T₂* assessments and multiple measures of hemolysis. This is the first DTI MRI study of patients with SCD to demonstrate reductions in medullary FA despite no overt CKD [estimated glomerular filtration rate (eGFR) > 100 mL/min/1.73 m²]. These medullary FA changes are consistent with previous studies in patients with CKD, and suggest that DTI MRI can provide a useful measure of kidney injury to complement MRI assessments of iron deposition.     

Quantification of myocardial fibrosis using noninvasive T2-mapping magnetic resonance imaging: Preclinical models of aging and pressure overload

Noninvasive imaging of cardiac fibrosis is important for early diagnosis and intervention in chronic heart diseases. Here, we investigated whether noninvasive, contrast agent-free MRI T₂-mapping can quantify myocardial fibrosis in preclinical models of aging and pressure overload. Myocardial fibrosis and remodeling were analyzed in two animal models: (i) aging (15-month-old male CF-1 mice vs. young 6- to 8-week-old mice), and (ii) pressure overload (PO; by transverse aortic constriction in 4- to 5-month-old male C57BL/6 mice vs. sham-operated for 14 days). In vivo T₂-mapping was performed by acquiring data during the isovolumic and early diastolic phases, with a modified respiratory and ECG-triggered multiecho TurboRARE sequence on a 7-T MRI. Cine MRI provided cardiac morphology and function. A quantitative segmentation method was developed to analyze the in vivo T₂-maps of hearts at midventricle, apex, and basal regions. The cardiac fibrosis area was analyzed ex vivo by picro sirius red (PSR) staining. Both aged and pressure-overloaded hearts developed significant myocardial contractile dysfunction, cardiac hypertrophy, and interstitial fibrosis. The aged mice had two phenotypes, fibrotic and mild-fibrotic. Notably, the aged fibrotic subgroup and the PO mice showed a marked decrease in T₂ relaxation times (25.3 ± 0.6 in aged vs. 29.9 ± 0.7 ms in young mice, p = 0.002; and 24.3 ± 1.7 in PO vs. 28.7 ± 0.7 ms in shams, p = 0.05). However, no significant difference in T₂ was detected between the aged mild-fibrotic subgroup and the young mice. Accordingly, an inverse correlation between myocardial fibrosis percentage (FP) and T₂ relaxation time was derived (R² = 0.98): T₂ (ms) = 30.45 – 1.05 × FP. Thus, these results demonstrate a statistical agreement between T₂-map–quantified fibrosis and PSR staining in two different clinically relevant animal models. In conclusion, T₂-mapping MRI is a promising noninvasive contrast agent-free quantitative technique to characterize myocardial fibrosis.     

Cardiac cine magnetic resonance fingerprinting for combined ejection fraction,T1 and T2 quantification

This study introduces a technique called cine magnetic resonance fingerprinting (cine‐MRF) for simultaneous T₁, T₂ and ejection fraction (EF) quantification. Data acquired with a free‐running MRF sequence are retrospectively sorted into different cardiac phases using an external electrocardiogram (ECG) signal. A low‐rank reconstruction with a finite difference sparsity constraint along the cardiac motion dimension yields images resolved by cardiac phase. To improve SNR and precision in the parameter maps, these images are nonrigidly registered to the same phase and matched to a dictionary to generate T₁ and T₂ maps. Cine images for computing left ventricular volumes and EF are also derived from the same data. Cine‐MRF was tested in simulations using a numerical relaxation phantom. Phantom and in vivo scans of 19 subjects were performed at 3 T during a 10.9 seconds breath‐hold with an in‐plane resolution of 1.6 x 1.6 mm² and 24 cardiac phases. Left ventricular EF values obtained with cine‐MRF agreed with the conventional cine images (mean bias ?1.0%). Average myocardial T₁ times in diastole/systole were 1398/1391 ms with cine‐MRF, 1394/1378 ms with ECG‐triggered cardiac MRF (cMRF) and 1234/1212 ms with MOLLI; and T₂ values were 30.7/30.3 ms with cine‐MRF, 32.6/32.9 ms with ECG‐triggered cMRF and 37.6/41.0 ms with T₂‐prepared FLASH. Cine‐MRF and ECG‐triggered cMRF relaxation times were in good agreement. Cine‐MRF T₁ values were significantly longer than MOLLI, and cine‐MRF T₂ values were significantly shorter than T₂‐prepared FLASH. In summary, cine‐MRF can potentially streamline cardiac MRI exams by combining left ventricle functional assessment and T₁‐T₂ mapping into one time‐efficient acquisition.     

Reproducibility of tract‐specific magnetization transfer and diffusion tensor imaging in the cervical spinal cord at 3 tesla

Damage to specific white matter tracts within the spinal cord can often result in the particular neurological syndromes that characterize myelopathies such as traumatic spinal cord injury. Noninvasive visualization of these tracts with imaging techniques that are sensitive to microstructural integrity is an important clinical goal. Diffusion tensor imaging (DTI)‐ and magnetization transfer (MT)‐derived quantities have shown promise in assessing tissue health in the central nervous system. In this paper, we demonstrate that DTI of the cervical spinal cord can reliably discriminate sensory (dorsal) and motor (lateral) columns. From data derived from nine healthy volunteers, two raters quantified column‐specific parallel (λ_||) and perpendicular (λ_?) diffusivity, fractional anisotropy (FA), mean diffusivity (MD), and MT‐weighted signal intensity relative to cerebrospinal fluid (MTCSF) over two time‐points separated by more than 1 week. Cross‐sectional means and standard deviations of these measures in the lateral and dorsal columns were as follows: λ_||: 2.13 ± 0.14 and 2.14 ± 0.11 μm²/ms; λ_?: 0.67 ± 0.16 and 0.61 ± 0.09 μm²/ms; MD: 1.15 ± 0.15 and 1.12 ± 0.08 μm²/ms; FA: 0.68 ± 0.06 and 0.68 ± 0.05; MTCSF: 0.52 ± 0.05 and 0.50 ± 0.05. We examined the variability and interrater and test‐retest reliability for each metric. These column‐specific MR measurements are expected to enhance understanding of the intimate structure‐function relationship in the cervical spinal cord and may be useful for the assessment of disease progression. Copyright © 2009 John Wiley & Sons, Ltd.     

Dynamic contrast‐enhanced MRI model selection for predicting tumor aggressiveness in papillary thyroid cancers

The purpose of this study was to identify the optimal tracer kinetic model from T₁‐weighted dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) data and evaluate whether parameters estimated from the optimal model predict tumor aggressiveness determined from histopathology in patients with papillary thyroid carcinoma (PTC) prior to surgery. In this prospective study, 18 PTC patients underwent pretreatment DCE‐MRI on a 3 T MR scanner prior to thyroidectomy. This study was approved by the institutional review board and informed consent was obtained from all patients. The two‐compartment exchange model, compartmental tissue uptake model, extended Tofts model (ETM) and standard Tofts model were compared on a voxel‐wise basis to determine the optimal model using the corrected Akaike information criterion (AICc) for PTC. The optimal model is the one with the lowest AICc. Statistical analysis included paired and unpaired t‐tests and a one‐way analysis of variance. Bonferroni correction was applied for multiple comparisons. Receiver operating characteristic (ROC) curves were generated from the optimal model parameters to differentiate PTC with and without aggressive features, and AUCs were compared. ETM performed best with the lowest AICc and the highest Akaike weight (0.44) among the four models. ETM was preferred in 44% of all 3419 voxels. The ETM estimates of K^trans in PTCs with the aggressive feature extrathyroidal extension (ETE) were significantly higher than those without ETE (0.78 ± 0.29 vs. 0.34 ± 0.18 min^?1, P = 0.005). From ROC analysis, cut‐off values of K^trans, v_e and v_p, which discriminated between PTCs with and without ETE, were determined at 0.45 min^?1, 0.28 and 0.014 respectively. The sensitivities and specificities were 86 and 82% (K^trans), 71 and 82% (v_e), and 86 and 55% (v_p), respectively. Their respective AUCs were 0.90, 0.71 and 0.71. We conclude that ETM K^trans has shown potential to classify tumors with and without aggressive ETE in patients with PTC.     

Diffusion‐weighted MRI monitoring of pancreatic cancer response to radiofrequency heat‐enhanced intratumor chemotherapy

The aim of this study was to evaluate the feasibility of using diffusion‐weighted MRI to monitor the early response of pancreatic cancers to radiofrequency heat (RFH)‐enhanced chemotherapy. Human pancreatic carcinoma cells (PANC‐1) in different groups and 24 mice with pancreatic cancer xenografts in four groups were treated with phosphate‐buffered saline (PBS) as a control, RFH at 42 °C, gemcitabine and gemcitabine plus RFH at 42 °C. One day before and 1, 7 and 14 days after treatment, diffusion‐weighted MRI and T₂‐weighted imaging were applied to monitor the apparent diffusion coefficients (ADCs) of tumors and tumor growth. MRI findings were correlated with the results of tumor apoptosis analysis. In the in vitro experiments, the quantitative viability assay showed lower relative cell viabilities for treatment with gemcitabine plus RFH at 42 °C relative to treatment with RFH only and gemcitabine only (37 ± 5% versus 65 ± 4% and 58 ± 8%, respectively, p < 0.05). In the in vivo experiments, the combination therapy resulted in smaller relative tumor volumes than RFH only and chemotherapy only (0.82 ± 0.17 versus 2.23 ± 0.90 and 1.64 ± 0.44, respectively, p = 0.003). In vivo, 14‐T MRI demonstrated a remarkable decrease in ADCs at day 1 and increased ADCs at days 7 and 14 in the combination therapy group. The apoptosis index in the combination therapy group was significantly higher than those in the chemotherapy‐only, RFH‐only and PBS treatment groups (37 ± 6% versus 20 ± 5%, 8 ± 2% and 3 ± 1%, respectively, p < 0.05). This study confirms that it is feasible to use MRI to monitor RFH‐enhanced chemotherapy in pancreatic cancers, which may present new options for the efficient treatment of pancreatic malignancies using MRI/RFH‐integrated local chemotherapy. Copyright © 2013 John Wiley & Sons, Ltd.     

Effect of glycogen loading on skeletal muscle cross‐sectional area and T2 relaxation time

This study was performed to investigate if glycogen loading of skeletal muscles, by binding water, would effect the cross‐sectional area (CSA) and if an altered water content would alter the transverse relaxation time (T2) measured by magnetic resonance imaging (MRI). Five healthy volunteers participated in a programme with 4 days of extremely carbohydrate‐restricted meals followed by 4 days of extremely high carbohydrate intake. The CSA and T2 of thigh and calf muscles were related to the intramuscular glycogen content evaluated at days 4 and 8. An increase in glycogen content from 281 to 634 mmol kg^–1 dry wt increased the CSA of the vastus muscles by 3.5% from 78 ± 11 to 80 ± 12 cm² and the thigh circumference by 2.5% from 146 ± 20 to 150 ± 23 cm². Calf circumference increased non‐significantly by 4% from 78 ± 15 to 82 ± 19 cm². Mono‐exponential T2 decreased in m tibialis anterior from 27.8 ± 1.2 to 26.9 ± 1.7 ms, did not change in m. vastus lateralis 26.5 ± 1.9 ms/26.6 ± 1.3 ms or in m. gastrocnemius 29.5 ± 1.0 ms/29.8 ± 1.9 ms. Glycogen loading increased the signal intensity mainly at different echo times (TE) 15 and 30 ms. The study shows that increased glycogen filling in the muscles increases muscle CSA and that this can be detected by MRI. The signal intensity increased the most at shorter TEs suggesting a more tight intracellular binding of water in glycogen loaded muscles.     

Direct comparison of high‐temporal‐resolution CINE MRI with Doppler ultrasound for assessment of diastolic dysfunction in mice

Diastolic dysfunction is a sensitive early indicator of heart failure and can provide additional data to conventional measures of systolic function. Transmitral Doppler ultrasound, which measures the one‐dimensional flow of blood through the mitral valve, is currently the preferred method for the measurement of diastolic function, but the measurement of the left ventricular volume changes using high‐temporal‐resolution cinematic magnetic resonance imaging (CINE MRI) is an alternative approach which is emerging as a potentially more robust and user‐independent technique. Here, we investigated the performance of high‐temporal‐resolution CINE MRI and compared it with ultrasound for the detection of diastolic dysfunction in a mouse model of myocardial infarction. An in‐house, high‐temporal‐resolution, retrospectively gated CINE sequence was developed with a temporal resolution of 1 ms. Diastolic function in mice was assessed using a custom‐made, open‐source reconstruction package. Early (E) and late (A) left ventricular filling phases were easily identifiable, and these measurements were compared directly with high‐frequency, pulsed‐wave, Doppler ultrasound measurements of mitral valve inflow. A repeatability study established that high‐temporal‐resolution CINE MRI and Doppler ultrasound showed comparable accuracy when measuring E/A in normal control mice. However, when applied in a mouse model of myocardial infarction, high‐temporal‐resolution CINE MRI indicated diastolic heart failure (E/A = 0.94 ± 0.11), whereas ultrasound falsely detected normal cardiac function (E/A = 1.21 ± 0.11). The addition of high‐temporal‐resolution CINE MRI to preclinical imaging studies enhances the library of sequences available to cardiac researchers and potentially identifies diastolic heart failure early in disease progression.     

In vivo observation of quadrupolar splitting in 39K magnetic resonance spectroscopy of human muscle tissue

The purpose of this work was to explore the origin of oscillations of the T^*₂ decay curve of ³⁹K observed in studies of ³⁹K magnetic resonance imaging of the human thigh. In addition to their magnetic dipole moment, spin‐³/₂ nuclei possess an electric quadrupole moment. Its interaction with non‐vanishing electrical field gradients leads to oscillations in the free induction decay and to splitting of the resonance. All measurements were performed on a 7T whole‐body MRI scanner (MAGNETOM 7T, Siemens AG, Erlangen, Germany) with customer‐built coils. According to the theory of quadrupolar splitting, a model with three Lorentzian‐shaped peaks is appropriate for ³⁹K NMR spectra of the thigh and calf. The frequency shifts of the satellites depend on the angle between the calf and the static magnetic field. When the leg is oriented parallel to the static magnetic field, the satellites are shifted by about 200 Hz. In the thigh, rank‐2 double quantum coherences arising from anisotropic quadrupolar interaction are observed by double‐quantum filtration with magic‐angle excitation. In addition to the spectra, an image of the thigh with a nominal resolution of (16 × 16 × 32) mm³ was acquired with this filtering technique in 1:17 h. From the line width of the resonances, ³⁹K transverse relaxation time constants T^*_{2, fast} = (0.51 ± 0.01) ms and T^*_{2, slow} = (6.21 ± 0.05) ms for the head were determined. In the thigh, the left and right satellite, both corresponding to the short component of the transverse relaxation time constant, take the following values: T^*_{2, fast} = (1.56 ± 0.03) ms and T^*_{2, fast} = (1.42 ± 0.03) ms. The centre line, which corresponds to the slow component, is T^*₂, _slow = (9.67 ± 0.04) ms. The acquisition time of the spectra was approximately 10 min. Our results agree well with a non‐vanishing electrical field gradient interacting with ³⁹K nuclei in the intracellular space of muscle tissue. Copyright © 2016 John Wiley & Sons, Ltd.     

Cardiac phenotyping in ex vivo murine embryos using µMRI

Microscopic MRI (µMRI) is an emerging technique for high‐throughput phenotyping of transgenic mouse embryos, and is capable of visualising abnormalities in cardiac development. To identify cardiac defects in embryos, we have optimised embryo preparation and MR acquisition parameters to maximise image quality and assess the phenotypic changes in chromodomain helicase DNA‐binding protein 7 (Chd7) transgenic mice. µMRI methods rely on tissue penetration with a gadolinium chelate contrast agent to reduce tissue T₁, thus improving signal‐to‐noise ratio (SNR) in rapid gradient echo sequences. We investigated 15.5 days post coitum (dpc) wild‐type CD‐1 embryos fixed in gadolinium‐diethylene triamine pentaacetic acid (Gd‐DTPA) solutions for either 3 days (2 and 4 mM) or 2 weeks (2, 4, 8 and 16 mM). To assess penetration of the contrast agent into heart tissue and enable image contrast simulations, T₁ and T were measured in heart and background agarose. Compared to 3‐day, 2‐week fixation showed reduced mean T₁ in the heart at both 2 and 4 mM concentrations (p < 0.0001), resulting in calculated signal gains of 23% (2 mM) and 29% (4 mM). Using T₁ and T values from 2‐week concentrations, computer simulation of heart and background signal, and ex vivo 3D gradient echo imaging, we demonstrated that 2‐week fixed embryos in 8 mM Gd‐DTPA in combination with optimised parameters (TE/TR/α/number of averages: 9 ms/20 ms/60°/7) produced the largest SNR in the heart (23.2 ± 1.0) and heart chamber contrast‐to‐noise ratio (CNR) (27.1 ± 1.6). These optimised parameters were then applied to an MRI screen of embryos heterozygous for the gene Chd7, implicated in coloboma of the eye, heart defects, atresia of the choanae, retardation of growth, genital/urinary abnormalities, ear abnormalities and deafness (CHARGE) syndrome (a condition partly characterised by cardiovascular birth defects in humans). A ventricular septal defect was readily identified in the screen, consistent with the human phenotype. Copyright © 2009 John Wiley & Sons, Ltd.