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.     

Predominant neuronal B-cell loss in L5 DRG of p75 receptor-deficient mice

The significance of the p75 low‐affinity neurotrophin receptor, for the maintenance and survival of DRG cells, was studied in p75‐deficient mice. Perikarya of the L5 DRG of 12‐week‐old p75 receptor‐deficient mice and healthy Balb C mice were compared using stereological techniques. Following systematic sampling, the optical fractionator and the planar vertical rotator were used to estimate the number and mean volume of the cell bodies of the two neuronal subpopulations. The loss of B‐cells was 57% (P < 0.00001), numbers being 7300 (CV = 0.12) in controls and 3100 in p75 receptor‐deficient mice (CV = 0.18). Also, A‐cells showed a significant loss of 39% (P < 0.0001), numbers being 2600 (CV = 0.12) in control mice and 1500 (CV = 0.16) in p75 receptor‐deficient mice. The volume of A‐cells was reduced by 30% (P < 0.01), from 24.700 µm³ (CV = 0.17) perikarya in p75 knock‐out mice to 15.100 µm³ (CV = 0.17) in controls. B‐cell volume did not change significantly. It is concluded that the p75 receptor plays a major role in the survival of DRG cells. The predominant loss of small B‐cells indicates that the effect of neurotrophins is dependent upon the presence of the p75 low‐affinity receptor.     

Dynamic contrast‐enhanced MRI in mouse tumors at 11.7 T: comparison of three contrast agents with different molecular weights to assess the early effects of combretastatin A4

Dynamic contrast‐enhanced (DCE)‐MRI is useful to assess the early effects of drugs acting on tumor vasculature, namely anti‐angiogenic and vascular disrupting agents. Ultra‐high‐field MRI allows higher‐resolution scanning for DCE‐MRI while maintaining an adequate signal‐to‐noise ratio. However, increases in susceptibility effects, combined with decreases in longitudinal relaxivity of gadolinium‐based contrast agents (GdCAs), make DCE‐MRI more challenging at high field. The aim of this work was to explore the feasibility of using DCE‐MRI at 11.7 T to assess the tumor hemodynamics of mice. Three GdCAs possessing different molecular weights (gadoterate: 560 Da, 0.29 mmol Gd/kg; p846: 3.5 kDa, 0.10 mmol Gd/kg; and p792: 6.47 kDa, 0.15 mmol Gd/kg) were compared to see the influence of the molecular weight in the highlight of the biologic effects induced by combretastatin A4 (CA4). Mice bearing transplantable liver tumor (TLT) hepatocarcinoma were divided into two groups (n = 5–6 per group and per GdCA): a treated group receiving 100 mg/kg CA4, and a control group receiving vehicle. The mice were imaged at 11.7 T with a T₁‐weighted FLASH sequence 2 h after the treatment. Individual arterial input functions (AIFs) were computed using phase imaging. These AIFs were used in the Extended Tofts Model to determine K^trans and v_p values. A separate immunohistochemistry study was performed to assess the vascular perfusion and the vascular density. Phase imaging was used successfully to measure the AIF for the three GdCAs. In control groups, an inverse relationship between the molecular weight of the GdCA and K^trans and v_p values was observed. K^trans was significantly decreased in the treated group compared with the control group for each GdCA. DCE‐MRI at 11.7 T is feasible to assess tumor hemodynamics in mice. With K^trans, the three GdCAs were able to track the early vascular effects induced by CA4 treatment. Copyright © 2014 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.     

Assessment of vessel permeability by combining dynamic contrast‐enhanced and arterial spin labeling MRI

The forward volumetric transfer constant (K^trans), a physiological parameter extracted from dynamic contrast‐enhanced (DCE) MRI, is weighted by vessel permeability and tissue blood flow. The permeability × surface area product per unit mass of tissue (PS) in brain tumors was estimated in this study by combining the blood flow obtained through pseudo‐continuous arterial spin labeling (PCASL) and K^trans obtained through DCE MRI. An analytical analysis and a numerical simulation were conducted to understand how errors in the flow and K^trans estimates would propagate to the resulting PS. Fourteen pediatric patients with brain tumors were scanned on a clinical 3‐T MRI scanner. PCASL perfusion imaging was performed using a three‐dimensional (3D) fast‐spin‐echo readout module to determine blood flow. DCE imaging was performed using a 3D spoiled gradient‐echo sequence, and the K^trans map was obtained with the extended Tofts model. The numerical analysis demonstrated that the uncertainty of PS was predominantly dependent on that of K^trans and was relatively insensitive to the flow. The average PS values of the whole tumors ranged from 0.006 to 0.217 min^?1, with a mean of 0.050 min^?1 among the patients. The mean K^trans value was 18% lower than the PS value, with a maximum discrepancy of 25%. When the parametric maps were compared on a voxel‐by‐voxel basis, the discrepancies between PS and K^trans appeared to be heterogeneous within the tumors. The PS values could be more than two‐fold higher than the K^trans values for voxels with high K^trans levels. This study proposes a method that is easy to implement in clinical practice and has the potential to improve the quantification of the microvascular properties of brain tumors. Copyright © 2015 John Wiley & Sons, Ltd.     

DCE‐MRI prediction of survival time for patients with glioblastoma multiforme: using an adaptive neuro‐fuzzy‐based model and nested model selection technique

This pilot study investigates the construction of an Adaptive Neuro‐Fuzzy Inference System (ANFIS) for the prediction of the survival time of patients with glioblastoma multiforme (GBM). ANFIS is trained by the pharmacokinetic (PK) parameters estimated by the model selection (MS) technique in dynamic contrast enhanced‐magnetic resonance imaging (DCE‐MRI) data analysis, and patient age. DCE‐MRI investigations of 33 treatment‐naïve patients with GBM were studied. Using the modified Tofts model and MS technique, the following physiologically nested models were constructed: Model 1, no vascular leakage (normal tissue); Model 2, leakage without efflux; Model 3, leakage with bidirectional exchange (influx and efflux). For each patient, the PK parameters of the three models were estimated as follows: blood plasma volume (v_p) for Model 1; v_p and volume transfer constant (K^trans) for Model 2; v_p, K^trans and rate constant (k_ep) for Model 3. Using Cox regression analysis, the best combination of the estimated PK parameters, together with patient age, was identified for the design and training of ANFIS. A K‐fold cross‐validation (K = 33) technique was employed for training, testing and optimization of ANFIS. Given the survival time distribution, three classes of survival were determined and a confusion matrix for the correct classification fraction (CCF) of the trained ANFIS was estimated as an accuracy index of ANFIS's performance. Patient age, k_ep and v_e (K^trans/k_ep) of Model 3, and K^trans of Model 2, were found to be the most effective parameters for training ANFIS. The CCF of the trained ANFIS was 84.8%. High diagonal elements of the confusion matrix (81.8%, 90.1% and 81.8% for Class 1, Class 2 and Class 3, respectively), with low off‐diagonal elements, strongly confirmed the robustness and high performance of the trained ANFIS for predicting the three survival classes. This study confirms that DCE‐MRI PK analysis, combined with the MS technique and ANFIS, allows the construction of a DCE‐MRI‐based fuzzy integrated predictor for the prediction of the survival of patients with GBM.     

Impact of contrast agent injection duration on dynamic contrast‐enhanced MRI quantification in prostate cancer

The volume transfer constant K^trans, which describes the leakage of contrast agent (CA) from vasculature into tissue, is the most commonly reported quantitative parameter for dynamic contrast‐enhanced (DCE‐) MRI. However, the variation in reported K^trans values between studies from different institutes is large. One of the primary sources of uncertainty is quantification of the arterial input function (AIF). The aim of this study is to determine the influence of the CA injection duration on the AIF and tracer kinetic analysis (TKA) parameters (i.e. K^trans, k_ep and v_e). Thirty‐one patients with prostate cancer received two DCE‐MRI examinations with an injection duration of 5 s in the first examination and a prolonged injection duration in the second examination, varying between 7.5 s and 30 s. The DCE examination was carried out on a 3.0 T MRI scanner using a transversal T₁‐weighted 3D spoiled gradient echo sequence (300 s duration, dynamic scan time of 2.5 s). Data of 29 of the 31 were further analysed. AIFs were determined from the phase signal in the left and right femoral arteries. K^trans, k_ep and v_e were estimated with the standard Tofts model for regions of healthy peripheral zone and tumour tissue. We observed a significantly smaller peak height and increased width in the AIF for injection durations of 15 s and longer. However, we did not find significant differences in K^trans, k_ep or v_e for the studied injection durations. The study demonstrates that the TKA parameters K^trans, k_ep and v_e, measured in the prostate, do not show a significant change as a function of injection duration.     

Assessment of early docetaxel response in an experimental model of human breast cancer using DCE‐MRI,ex vivo HR MAS,and in vivo 1H MRS

The purpose of this study was to evaluate the use of dynamic contrast‐enhanced (DCE) MRI, in vivo ¹H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF‐7) in mice. MCF‐7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE‐MRI and in vivo ¹H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two‐compartment model, yielding the vascular parameters K^trans and v_e. HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki‐67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel‐treated mice compared to the controls. The anti‐tumor effect led to an increase in K^trans and v_e values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki‐67 stained sections. In this study DCE‐MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra‐tumoral treatment effects. Copyright © 2009 John Wiley & Sons, Ltd.     

Middle cerebral artery blood velocity during exercise with β‐1 adrenergic and unilateral stellate ganglion blockade in humans

A reduced ability to increase cardiac output (CO) during exercise limits blood flow by vasoconstriction even in active skeletal muscle. Such a flow limitation may also take place in the brain as an increase in the transcranial Doppler determined middle cerebral artery blood velocity (MCA V_mean) is attenuated during cycling with β‐1 adrenergic blockade and in patients with heart insufficiency. We studied whether sympathetic blockade at the level of the neck (0.1% lidocain; 8 mL; n=8) affects the attenuated exercise – MCA V_mean following cardio‐selective β‐1 adrenergic blockade (0.15 mg kg^?1 metoprolol i.v.) during cycling. Cardiac output determined by indocyanine green dye dilution, heart rate (HR), mean arterial pressure (MAP) and MCA V_mean were obtained during moderate intensity cycling before and after pharmacological intervention. During control cycling the right and left MCA V_mean increased to the same extent (11.4 ± 1.9 vs. 11.1 ± 1.9 cm s^?1). With the pharmacological intervention the exercise CO (10 ± 1 vs. 12 ± 1 L min^?1; n=5), HR (115 ± 4 vs. 134 ± 4 beats min^?1) and ΔMCA V_mean (8.7 ± 2.2 vs. 11.4 ± 1.9 cm s^?1) were reduced, and MAP was increased (100 ± 5 vs. 86 ± 2 mmHg; P < 0.05). However, sympathetic blockade at the level of the neck eliminated the β‐1 blockade induced attenuation in ΔMCA V_mean (10.2 ± 2.5 cm s^?1). These results indicate that a reduced ability to increase CO during exercise limits blood flow to a vital organ like the brain and that this flow limitation is likely to be by way of the sympathetic nervous system.     

Reduced respiratory motion artifacts using structural similarity in fast 2D dynamic contrast enhanced MRI of liver lesions

The purpose of this work was to improve dynamic contrast enhanced MRI (DCE‐MRI) of liver lesions by removing motion corrupted images as identified by a structural similarity (SSIM) algorithm, and to assess the effect of this correction on the pharmacokinetic parameter K^trans using automatically determined arterial input functions (AIFs). Fifteen patients with colorectal liver metastases were measured twice with a T₁ weighted multislice 2D FLASH sequence for DCE‐MRI (time resolution 1.2 s). AIFs were automatically derived from contrast inflow in the aorta of each patient. Thereafter, SSIM identified motion corrupted images of the liver were removed from the DCE dataset. From this corrected data set K^trans and its reproducibility were determined. Using the SSIM algorithm a median fraction of 46% (range 37–50%) of the liver images in DCE time series was labeled as motion distorted. Rejection of these images resulted in a significantly lower median K^trans (p < 0.05) and lower coefficient of repeatability of K^trans in liver metastases compared with an analysis without correction. SSIM correction improves the reproducibility of the DCE‐MRI parameter K^trans in liver metastasis and reduces contamination of K^trans values of lesions by that of surrounding normal liver tissue.     

Changes of vitamin D levels and bone turnover markers after CPAP therapy: a randomized sham‐controlled trial

The aim was to investigate whether continuous positive airway pressure treatment could modulate serum vitamin D (25‐hydroxyvitamin D) and bone turnover markers (collagen‐type 1 cross‐linked C‐telopeptide, osteocalcin and N‐terminal propeptide of type 1 collagen) in secondary analysis from a randomized controlled trial. Sixty‐five continuous positive airway pressure‐naïve male patients with obstructive sleep apnea (age = 49 ± 12 years, apnea–hypopnea index = 39.9 ± 17.7 events h^?1, body mass index = 31.3 ± 5.2 kg m^?2) were randomized to receive either real (n  = 34) or sham (n  = 31) continuous positive airway pressure for 12 weeks. At 12 weeks, all participants received real continuous positive airway pressure for an additional 12 weeks. After 12 weeks of continuous positive airway pressure (real versus sham), there were no between‐group differences for any of the main outcomes [Δ25‐hydroxyvitamin D: ?0.80 ± 5.28 ng mL ^?1 (mean ± SE ) versus 3.08 ± 3.66 ng mL ^?1, P  = 0.42; Δcollagen‐type 1 cross‐linked C‐telopeptide: 0.011 ± 0.014 ng mL ^?1 versus ?0.004 ± 0.009 ng mL ^?1, P  = 0.48; Δosteocalcin: 1.13 ± 1.12 ng mL ^?1 versus 0.46 ± 0.75 ng mL ^?1, P  = 0.80; ΔN‐terminal propeptide of type 1 collagen: 2.07 ± 3.05 μ g L^?1 versus ?1.05 ± 2.13 μ g L^?1, P  = 0.48]. There were no further differences in subgroup analyses (continuous positive airway pressure‐compliant patients, patients with severe obstructive sleep apnea or sleepy patients). However, after 24 weeks irrespective of initial randomization, vitamin D increased in patients with severe obstructive sleep apnea (9.56 ± 5.51 ng mL ^?1, P  = 0.045) and in sleepy patients (14.0 ± 4.69 ng mL ^?1, P  = 0.007). Also, there was a significant increase in osteocalcin at 24 weeks (3.27 ± 1.06 ng mL ^?1, P  = 0.01) in compliant patients. We conclude that 12 weeks of continuous positive airway pressure did not modulate vitamin D or modulate any of the bone turnover markers compared with sham. However, it is plausible that continuous positive airway pressure may have late beneficial effects on vitamin D levels and bone turnover markers in selected groups of patients with obstructive sleep apnea.     

Assessing manganese efflux using SEA0400 and cardiac T1‐mapping manganese‐enhanced MRI in a murine model

The sodium–calcium exchanger (NCX) is one of the transporters contributing to the control of intracellular calcium (Ca²⁺) concentration by normally mediating net Ca²⁺ efflux. However, the reverse mode of the NCX can cause intracellular Ca²⁺ concentration overload, which exacerbates the myocardial tissue injury resulting from ischemia. Although the NCX inhibitor SEA0400 has been shown to therapeutically reduce myocardial injury, no in vivo technique exists to monitor intracellular Ca²⁺ fluctuations produced by this drug. Cardiac manganese‐enhanced MRI (MEMRI) may indirectly assess Ca²⁺ efflux by estimating changes in manganese (Mn²⁺) content in vivo, since Mn²⁺ has been suggested as a surrogate marker for Ca²⁺. This study used the MEMRI technique to examine the temporal features of cardiac Mn²⁺ efflux by implementing a T₁‐mapping method and inhibiting the NCX with SEA0400. The change in ¹H₂O longitudinal relaxation rate, ΔR₁, in the left ventricular free wall, was calculated at different time points following infusion of 190 nmol/g manganese chloride (MnCl₂) in healthy adult male mice. The results showed 50% MEMRI signal attenuation at 3.4 ± 0.6 h post‐MnCl₂ infusion without drug intervention. Furthermore, treatment with 50 ± 0.2 mg/kg of SEA0400 significantly reduced the rate of decrease in ΔR₁. At 4.9–5.9 h post‐MnCl₂ infusion, the average ΔR₁ values for the two groups treated with SEA0400 were 2.46 ± 0.29 and 1.72 ± 0.24 s^?1 for 50 and 20 mg/kg doses, respectively, as compared to the value of 1.27 ± 0.28 s^?1 for the control group. When this in vivo data were compared to ex vivo absolute manganese content data, the MEMRI T₁‐mapping technique was shown to effectively quantify Mn²⁺ efflux rates in the myocardium. Therefore, combining an NCX inhibitor with MEMRI may be a useful technique for assessing Mn²⁺ transport mechanisms and rates in vivo, which may reflect changes in Ca²⁺ transport. Copyright © 2009 John Wiley & Sons, Ltd.     

Estimating B1+ in the breast at 7 T using a generic template

Dynamic contrast‐enhanced MRI is the workhorse of breast MRI, where the diagnosis of lesions is largely based on the enhancement curve shape. However, this curve shape is biased by RF transmit (B₁⁺) field inhomogeneities. B₁⁺ field information is required in order to correct these. The use of a generic, coil‐specific B₁⁺ template is proposed and tested. Finite‐difference time‐domain simulations for B₁⁺ were performed for healthy female volunteers with a wide range of breast anatomies. A generic B₁⁺ template was constructed by averaging simulations based on four volunteers. Three‐dimensional B₁⁺ maps were acquired in 15 other volunteers. Root mean square error (RMSE) metrics were calculated between individual simulations and the template, and between individual measurements and the template. The agreement between the proposed template approach and a B₁⁺ mapping method was compared against the agreement between acquisition and reacquisition using the same mapping protocol. RMSE values (% of nominal flip angle) comparing individual simulations with the template were in the range 2.00‐4.01%, with mean 2.68%. RMSE values comparing individual measurements with the template were in the range8.1‐16%, with mean 11.7%. The agreement between the proposed template approach and a B₁⁺ mapping method was only slightly worse than the agreement between two consecutive acquisitions using the same mapping protocol in one volunteer: the range of agreement increased from ±16% of the nominal angle for repeated measurement to ±22% for the B₁⁺ template. With local RF transmit coils, intersubject differences in B₁⁺ fields of the breast are comparable to the accuracy of B₁⁺ mapping methods, even at 7 T. Consequently, a single generic B₁⁺ template suits subjects over a wide range of breast anatomies, eliminating the need for a time‐consuming B₁⁺ mapping protocol.     

Quantitative MRI in murine radiation‐induced rectocolitis: comparison with histopathological inflammation score

Murine radiation‐induced rectocolitis is considered to be a relevant animal model of gastrointestinal inflammation. The purpose of our study was to compare quantitative MRI and histopathological features in this gastrointestinal inflammation model. Radiation rectocolitis was induced by localized single‐dose radiation (27 Gy) in Sprague‐Dawley rats. T₂‐weighted, T₁‐weighted and diffusion‐weighted MRI was performed at 7 T in 16 rats between 2 and 4 weeks after irradiation and in 10 control rats. Rats were sacrificed and the histopathological inflammation score of the colorectal samples was assessed. The irradiated rats showed significant increase in colorectal wall thickness (2.1 ± 0.3 mm versus 0.8 ± 0.3 mm in control rats, P < 0.0001), normalized T₂ signal intensity (4 ± 0.8 versus 2 ± 0.4 AU, P < 0.0001), normalized T₁ signal intensity (1.4 ± 0.1 versus 1.1 ± 0.2 AU, P = 0.0009) and apparent and pure diffusion coefficients (ADC and D) (2.06 × 10^?3 ± 0.34 versus 1.51 × 10^?3 ± 0.23 mm²/s, P = 0.0004, and 1.97 × 10^?3 ± 0.43 mm²/s versus 1.48 × 10^?3 ± 0.29 mm²/s, P = 0.008, respectively). Colorectal wall thickness (r = 0.84, P < 0.0001), normalized T₂ signal intensity (r = 0.85, P < 0.0001) and ADC (r = 0.80, P < 0.0001) were strongly correlated with the histopathological inflammation score, whereas normalized T₁ signal intensity and D were moderately correlated (r = 0.64, P = 0.0006, and r = 0.65, P = 0.0003, respectively). High‐field MRI features of single‐dose radiation‐induced rectocolitis in rats differ significantly from those of control rats. Quantitative MRI characteristics, especially wall thickness, normalized T₂ signal intensity, ADC and D, are potential markers of the histopathological inflammation score.     

Cluster analysis of DCE‐MRI data identifies regional tracer‐kinetic changes after tumor treatment with high intensity focused ultrasound

Evaluation of high intensity focused ultrasound (HIFU) treatment with MRI is generally based on assessment of the non‐perfused volume from contrast‐enhanced T₁‐weighted images. However, the vascular status of tissue surrounding the non‐perfused volume has not been extensively investigated with MRI. In this study, cluster analysis of the transfer constant K^trans and extravascular extracellular volume fraction v_e, derived from dynamic contrast‐enhanced MRI (DCE‐MRI) data, was performed in tumor tissue surrounding the non‐perfused volume to identify tumor subregions with distinct contrast agent uptake kinetics. DCE‐MRI was performed in CT26.WT colon carcinoma‐bearing BALB/c mice before (n = 12), directly after (n = 12) and 3 days after (n = 6) partial tumor treatment with HIFU. In addition, a non‐treated control group (n = 6) was included. The non‐perfused volume was identified based on the level of contrast enhancement. Quantitative comparison between non‐perfused tumor fractions and non‐viable tumor fractions derived from NADH‐diaphorase histology showed a stronger agreement between these fractions 3 days after treatment (R² to line of identity = 0.91) compared with directly after treatment (R² = 0.74). Next, k‐means clustering with four clusters was applied to K^trans and v_e parameter values of all significantly enhanced pixels. The fraction of pixels within two clusters, characterized by a low K^trans and either a low or high v_e, significantly increased after HIFU. Changes in composition of these clusters were considered to be HIFU induced. Qualitative H&E histology showed that HIFU‐induced alterations in these clusters may be associated with hemorrhage and structural tissue disruption. Combined microvasculature and hypoxia staining suggested that these tissue changes may affect blood vessel functionality and thereby tumor oxygenation. In conclusion, it was demonstrated that, in addition to assessment of the non‐perfused tumor volume, the presented methodology gives further insight into HIFU‐induced effects on tumor vascular status. This method may aid in assessment of the consequences of vascular alterations for the fate of the tissue. Copyright © 2015 John Wiley & Sons, Ltd.     

An adaptive model for rapid and direct estimation of extravascular extracellular space in dynamic contrast enhanced MRI studies

Extravascular extracellular space (v_e) is a key parameter to characterize the tissue of cerebral tumors. This study introduces an artificial neural network (ANN) as a fast, direct, and accurate estimator of v_e from a time trace of the longitudinal relaxation rate, ΔR₁ (R₁ = 1/T₁), in DCE‐MRI studies. Using the extended Tofts equation, a set of ΔR₁ profiles was simulated in the presence of eight different signal to noise ratios. A set of gain‐ and noise‐insensitive features was generated from the simulated ΔR₁ profiles and used as the ANN training set. A K‐fold cross‐validation method was employed for training, testing, and optimization of the ANN. The performance of the optimal ANN (12:6:1, 12 features as input vector, six neurons in hidden layer, and one output) in estimating v_e at a resolution of 10% (error of ±5%) was 82%. The ANN was applied on DCE‐MRI data of 26 glioblastoma patients to estimate v_e in tumor regions. Its results were compared with the maximum likelihood estimation (MLE) of v_e. The two techniques showed a strong agreement (r = 0.82, p < 0.0001). Results implied that the perfected ANN was less sensitive to noise and outperformed the MLE method in estimation of v_e.     

Blood oxygenation level-dependent (BOLD) total and extravascular signal changes and ΔR2* in human visual cortex at 1.5, 3.0 and 7.0 T

The characterisation of the extravascular (EV) contribution to the blood oxygenation level‐dependent (BOLD) effect is important for understanding the spatial specificity of BOLD contrast and for modelling approaches that aim to extract quantitative metabolic parameters from the BOLD signal. Using bipolar crusher gradients, total (b = 0 s/mm²) and predominantly EV (b = 100 s/mm²) gradient echo BOLD ΔR₂* and signal changes (ΔS/S) in response to visual stimulation (flashing checkerboard; f = 8 Hz) were investigated sequentially (within < 3 h) at 1.5, 3.0 and 7.0 T in the same subgroup of healthy volunteers (n = 7) and at identical spatial resolutions (3.5 × 3.5 × 3.5 mm³). Total ΔR₂* (z‐score analysis) values were ?0.61 ± 0.10 s^?1 (1.5 T), ?0.74 ± 0.05 s^?1 (3.0 T) and ?1.37 ± 0.12 s^?1 (7.0 T), whereas EV ΔR₂* values were ?0.28 ± 0.07 s^?1 (1.5 T), ?0.52 ± 0.07 s^?1 (3.0 T) and ?1.25 ± 0.11 s^?1 (7.0 T). Although EV ΔR₂* increased linearly with field, as expected, it was found that EV ΔS/S increased less than linearly with field in a manner that varied with TE choice. Furthermore, unlike ΔR₂*, total and EV ΔS/S did not converge at 7.0 T. These trends were similar whether a z‐score analysis or occipital lobe‐based region‐of‐interest approach was used for voxel selection. These findings suggest that calibrated BOLD approaches may benefit from an EV ΔR₂* measurement as opposed to a ΔS/S measurement at a single TE. Copyright © 2010 John Wiley & Sons, Ltd.     

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.     

Quantification of regional myocardial mean intracellular water lifetime: A nonhuman primate study in myocardial stress

Heart failure with preserved ejection fraction (HFpEF) is typically associated with early metabolic remodeling. Noninvasive imaging biomarkers that reflect these changes will be crucial in determining responses to early drug interventions in these patients. Mean intracellular water lifetime (τ_i) has been shown to be partially inversely related to Na, K‐ATPase transporter activity and may thus provide insight into the metabolic status in HFpEF patients. Here, we aim to perform regional quantification of τ_i using dynamic contrast‐enhanced (DCE) magnetic resonance imaging (MRI) in the nonhuman primate (NHP) heart and evaluate its region‐specific variations under conditions of myocardial stress in the context of perturbed myocardial function. Cardiac stress was induced in seven naïve cynomolgus macaques using a dobutamine stepwise infusion protocol. All animals underwent 3 T cardiac dual‐bolus DCE and tagging MRI experiments. The shutter‐speed model was employed to quantify regional τ_i from the DCE‐MR images. Additionally, τ_i values were correlated with myocardial strains. During cardiac stress, there was a significant decrease in global τ_i (192.9 ± 76.3 ms vs 321.6 ± 70 ms at rest, P < 0.05) in the left ventricle, together with an increase in global peak circumferential strain (?15.4% ± 2.7% vs ?10.1% ± 2.9% at rest, P < 0.05). Specifically, slice‐level analysis further revealed that a greater significant decrease in mean τ_i was observed in the apical region (Δτ_I = 182.4 ms) compared with the basal (Δτ_i = 113.2 ms) and midventricular regions (Δτ_i = 108.4 ms). Regional analysis revealed that there was a greater significant decrease in mean τ_i in the anterior (Δτ_i = 243.9 ms) and antero‐lateral (Δτ_i = 177.2 ms) regions. In the inferior and infero‐septal regions, although a decrease in τ_i was observed, it was not significant. Whole heart regional quantification of τ_i is feasible using DCE‐MRI. τ_i is sensitive to regional changes in metabolic state during cardiac stress, and its value correlates with strain.