Digital reference object toolkit of breast DCE MRI for quantitative evaluation of image reconstruction and analysis methods.

PURPOSE: To develop a digital reference object (DRO) toolkit to generate realistic breast DCE-MRI data for quantitative assessment of image reconstruction and data analysis methods. METHODS: A simulation framework in a form of DRO toolkit has been developed using the ultrafast and conventional breast DCE-MRI data of 53 women with malignant (n = 25) or benign (n = 28) lesions. We segmented five anatomical regions and performed pharmacokinetic analysis to determine the ranges of pharmacokinetic parameters for each segmented region. A database of the segmentations and their pharmacokinetic parameters is included in the DRO toolkit that can generate a large number of realistic breast DCE-MRI data. We provide two potential examples for our DRO toolkit: assessing the accuracy of an image reconstruction method using undersampled simulated radial k-space data and assessing the impact of the B 1 + $$ {\mathrm{B}}_1^{+} $$ field inhomogeneity on estimated parameters. RESULTS: The estimated pharmacokinetic parameters for each region showed agreement with previously reported values. For the assessment of the reconstruction method, it was found that the temporal regularization resulted in significant underestimation of estimated parameters by up to 57% and 10% with the weighting factor λ = 0.1 and 0.01, respectively. We also demonstrated that spatial discrepancy of v p $$ {v}_p $$ and PS $$ \mathrm{PS} $$ increase to about 33% and 51% without correction for B 1 + $$ {\mathrm{B}}_1^{+} $$ field. CONCLUSION: We have developed a DRO toolkit that includes realistic morphology of tumor lesions along with the expected pharmacokinetic parameter ranges. This simulation framework can generate many images for quantitative assessment of DCE-MRI reconstruction and analysis methods.

Improving measurement of blood-brain barrier permeability with reduced scan time using deep-learning-derived capillary input function.

PURPOSE: In Dynamic contrast-enhanced MRI (DCE-MRI), Arterial Input Function (AIF) has been shown to be a significant contributor to uncertainty in the estimation of kinetic parameters. This study is to assess the feasibility of using a deep learning network to estimate local Capillary Input Function (CIF) to estimate blood-brain barrier (BBB) permeability, while reducing the required scan time. MATERIALS AND METHOD: A total of 13 healthy subjects (younger (<40 y/o): 8, older (> 67 y/o): 5) were recruited and underwent 25-min DCE-MRI scans. The 25 min data were retrospectively truncated to 10 min to simulate a reduced scan time of 10 min. A deep learning network was trained to predict the CIF using simulated tissue contrast dynamics with two vascular transport models. The BBB permeability (PS) was measured using 3 methods: (i) Ca-25min, using DCE-MRI data of 25 min with individually sampled AIF (Ca); (ii) Ca-10min, using truncated 10min data with AIF (Ca); and (iii) Cp-10min, using truncated 10 min data with CIF (Cp). The PS estimates from the Ca-25min method were used as reference standard values to assess the accuracy of the Ca-10min and Cp-10min methods in estimating the PS values. RESULTS: When compared to the reference method(Ca-25min), the Ca-10min and Cp-10min methods resulted in an overestimation of PS by 217 ± 241 % and 48.0 ± 30.2 %, respectively. The Bland Altman analysis showed that the mean difference from the reference was 8.85 ± 1.78 (x10-4 min-1) with the Ca-10min, while it was reduced to 1.63 ± 2.25 (x10-4 min-1) with the Cp-10min, resulting in an average reduction of 81%. The limits of agreement also reduced by up to 39.2% with the Cp-10min. We found a 75% increase of BBB permeability in the gray matter and a 35% increase in the white matter, when comparing the older group to the younger group. CONCLUSIONS: We demonstrated the feasibility of estimating the capillary-level input functions using a deep learning network. We also showed that this method can be used to estimate subtle age-related changes in BBB permeability with reduced scan time, without compromising accuracy. Moreover, the trained deep learning network can automatically select CIF, reducing the potential uncertainty resulting from manual user-intervention.

Time-dependent diffusivity and kurtosis in phantoms and patients with head and neck cancer.

PURPOSE: To assess the reliability of measuring diffusivity, diffusional kurtosis, and cellular-interstitial water exchange time with long diffusion times (100-800 ms) using stimulated-echo DWI. METHODS: Time-dependent diffusion MRI was tested on two well-established diffusion phantoms and in 5 patients with head and neck cancer. Measurements were conducted using an in-house diffusion-weighted STEAM-EPI pulse sequence with multiple diffusion times at a fixed TE on three scanners. We used the weighted linear least-squares fit method to estimate time-dependent diffusivity, D ( t ) $$ D(t) $$ , and diffusional kurtosis, K ( t ) $$ K(t) $$ . Additionally, the Kärger model was used to estimate cellular-interstitial water exchange time ( τ ex $$ {\tau}_{ex} $$ ) from K ( t ) $$ K(t) $$ . RESULTS: Diffusivity measured by time-dependent STEAM-EPI measurements and commercial SE-EPI showed comparable results with R2 above 0.98 and overall 5.4 ± 3.0% deviation across diffusion times. Diffusional kurtosis phantom data showed expected patterns: constant D $$ D $$ and K $$ K $$  = 0 for negative controls and slow varying D $$ D $$ and K $$ K $$ for samples made of nanoscopic vesicles. Time-dependent diffusion MRI in patients with head and neck cancer found that the Kärger model could be considered valid in 72% ± 23% of the voxels in the metastatic lymph nodes. The median cellular-interstitial water exchange time estimated for lesions was between 58.5 ms and 70.6 ms. CONCLUSIONS: Based on two well-established diffusion phantoms, we found that time-dependent diffusion MRI measurements can provide stable diffusion and kurtosis values over a wide range of diffusion times and across multiple MRI systems. Moreover, estimation of cellular-interstitial water exchange time can be achieved using the Kärger model for the metastatic lymph nodes in patients with head and neck cancer.

Simultaneous estimation of the cellular water exchange rate, intracellular volume fraction, and longitudinal relaxation rate in cancer cells.

The purpose of the current study was to investigate the feasibility of simultaneously estimating the cellular water efflux rate ( k ie ), intracellular longitudinal relaxation rate ( R 10 i ), and intracellular volume fraction ( v i ) of a cell suspension using multiple samples with different gadolinium concentrations. Numerical simulation studies were conducted to assess the uncertainty in the estimation of k ie , R 10 i , and v i from saturation recovery data using single (SC) or multiple concentrations (MC) of gadolinium-based contrast agent (GBCA). In vitro experiments with 4 T1 murine breast cancer and SCCVII squamous cell cancer models were conducted at 11 T to compare parameter estimation using the SC protocol with that using the MC protocol. The cell lines were challenged with a Na+ /K+ -ATPase inhibitor, digoxin, to assess the treatment response in terms of k ie , R 10 i , and v i . Data analysis was conducted using the two-compartment exchange model for parameter estimation. The simulation study data demonstrate that the MC method, compared with the SC method, reduces the uncertainty of the estimated k ie by decreasing the interquartile ranges from 27.3% ± 3.7% to 18.8% ± 5.1% and the median differences from ground truth from 15.0% ± 6.3% to 7.2% ± 4.2%, while estimating R 10 i and v i simultaneously. In the cell studies, the MC method demonstrated reduced uncertainty in overall parameter estimation compared with the SC approach. MC method-measured parameter changes in cells treated with digoxin increased R 10 i by 11.7% (p = 0.218) and k ie by 5.9% (p = 0.234) for 4 T1 cells, respectively, and decreased R 10 i by 28.8% (p = 0.226) and k ie by 1.6% (p = 0.751) for SCCVII cells, respectively. v i did not change noticeably by the treatment. The results of this study substantiate the feasibility of using saturation recovery data of multiple samples with different GBCA concentrations for simultaneous measurement of the cellular water efflux rate, intracellular volume fraction, and intracellular longitudinal relaxation rate in cancer cells.

Estimation of the capillary level input function for dynamic contrast-enhanced MRI of the breast using a deep learning approach.

PURPOSE: To develop a deep learning approach to estimate the local capillary-level input function (CIF) for pharmacokinetic model analysis of DCE-MRI. METHODS: A deep convolutional network was trained with numerically simulated data to estimate the CIF. The trained network was tested using simulated lesion data and used to estimate voxel-wise CIF for pharmacokinetic model analysis of breast DCE-MRI data using an abbreviated protocol from women with malignant (n = 25) and benign (n = 28) lesions. The estimated parameters were used to build a logistic regression model to detect the malignancy. RESULT: The pharmacokinetic parameters estimated using the network-predicted CIF from our breast DCE data showed significant differences between the malignant and benign groups for all parameters. Testing the diagnostic performance with the estimated parameters, the conventional approach with arterial input function (AIF) showed an area under the curve (AUC) between 0.76 and 0.87, and the proposed approach with CIF demonstrated similar performance with an AUC between 0.79 and 0.81. CONCLUSION: This study shows the feasibility of estimating voxel-wise CIF using a deep neural network. The proposed approach could eliminate the need to measure AIF manually without compromising the diagnostic performance to detect the malignancy in the clinical setting.

Bilateral gradient-echo spectroscopic imaging with correction of frequency variations for measurement of fatty acid composition in mammary adipose tissue.

PURPOSE: To develop a simultaneous dual-slab three-dimensional gradient-echo spectroscopic imaging (GSI) technique with frequency drift compensation for rapid (<6 min) bilateral measurement of fatty acid composition (FAC) in mammary adipose tissue. METHODS: A bilateral GSI sequence was developed using a simultaneous dual-slab excitation followed by 128 monopolar echoes. A short train of navigator echoes without phase or partition encoding was included at the beginning of each pulse repetition time period to correct for frequency variation caused by respiration and heating of the cryostat. Voxel-wise spectral fitting was applied to measure the areas of the lipid spectral peaks to estimate the number of double-bond (ndb), number of methylene-interrupted double-bond (nmidb), and chain length (cl). The proposed method was tested in an oil phantom and 10 postmenopausal women to assess the influence of the frequency variation on FAC estimation. RESULTS: The frequency drift observed over 5:27 min during the phantom scan was about 10 Hz. Phase correction based on the navigator reduced the median error of ndb, nmidb, and cl from 9.7%, 17.6%, and 3.2% to 2.1%, 9.5%, and 2.8%, respectively. The in vivo data showed a mean ± standard deviation frequency drift of 17.4 ± 2.5 Hz, with ripples at 0.3 ± 0.1 Hz. Our reconstruction algorithm successfully separated signals from the left and right breasts with negligible residual aliasing. Phase correction reduced the interquartile range within each subject's adipose tissue of ndb, nmidb, and cl by 18.4 ± 10.6%, 18.5 ± 13.9%, and 18.4 ± 10.6%, respectively. CONCLUSION: This study shows the feasibility of obtaining bilateral spectroscopic imaging data in the breast and that incorporation of a frequency navigator improves the estimation of FAC.

Measurement of cellular-interstitial water exchange time in tumors based on diffusion-time-dependent diffusional kurtosis imaging.

PURPOSE: To assess the feasibility of using diffusion-time-dependent diffusional kurtosis imaging (tDKI) to measure cellular-interstitial water exchange time (τex ) in tumors, both in animals and in humans. METHODS: Preclinical tDKI studies at 7 T were performed with the GL261 glioma model and the 4T1 mammary tumor model injected into the mouse brain. Clinical studies were performed at 3 T with women who had biopsy-proven invasive ductal carcinoma. tDKI measurement was conducted using a diffusion-weighted STEAM pulse sequence with multiple diffusion times (20-800 ms) at a fixed echo time, while keeping the b-values the same (0-3000 s/mm2 ) by adjusting the diffusion gradient strength. The tDKI data at each diffusion time t were used for a weighted linear least-squares fit method to estimate the diffusion-time-dependent diffusivity, D(t), and diffusional kurtosis, K(t). RESULTS: Both preclinical and clinical studies showed that, when diffusion time t ≥ 200 ms, D(t) did not have a noticeable change while K(t) decreased monotonically with increasing diffusion time in tumors and t ≥ 100 ms for the cortical ribbon of the mouse brain. The estimated τex averaged median and interquartile range (IQR) of GL261 and 4T1 tumors were 93 (IQR = 89) ms and 68 (78) ms, respectively. For the cortical ribbon, the estimated τex averaged median and IQR were 41 (34) ms for C57BL/6 and 30 (17) ms for BALB/c. For invasive ductal carcinoma, the estimated τex median and IQR of the two breast cancers were 70 (94) and 106 (92) ms. CONCLUSION: The results of this proof-of-concept study substantiate the feasibility of using tDKI to measure cellular-interstitial water exchange time without using an exogenous contrast agent.

Rapid dynamic contrast-enhanced MRI for small animals at 7T using 3D ultra-short echo time and golden-angle radial sparse parallel MRI.

PURPOSE: To develop a rapid dynamic contrast-enhanced MRI method with high spatial and temporal resolution for small-animal imaging at 7 Tesla. METHODS: An ultra-short echo time (UTE) pulse sequence using a 3D golden-angle radial sampling was implemented to achieve isotropic spatial resolution with flexible temporal resolution. Continuously acquired radial spokes were grouped into subsets for image reconstruction using a multicoil compressed sensing approach (Golden-angle RAdial Sparse Parallel; GRASP). The proposed 3D-UTE-GRASP method with high temporal and spatial resolutions was tested using 7 mice with GL261 intracranial glioma models. RESULTS: Iterative reconstruction with different temporal resolutions and regularization factors λ showed that, in all cases, the cost function decreased to less than 2.5% of its starting value within 20 iterations. The difference between the time-intensity curves of 3D-UTE-GRASP and nonuniform fast Fourier transform (NUFFT) images was minimal when λ was 1% of the maximum signal intensity of the initial NUFFT images. The 3D isotropic images were used to generate pharmacokinetic parameter maps to show the detailed images of the tumor characteristics in 3D and also to show longitudinal changes during tumor growth. CONCLUSION: This feasibility study demonstrated that the proposed 3D-UTE-GRASP method can be used for effective measurement of the 3D spatial heterogeneity of tumor pharmacokinetic parameters.

Estimation of cellular-interstitial water exchange in dynamic contrast enhanced MRI using two flip angles.

PURPOSE: To investigate the feasibility of using multiple flip angles in dynamic contrast enhanced (DCE) MRI to reduce the uncertainty in estimation of intracellular water lifetime (τi ). METHODS: Numerical simulation studies were conducted to assess the uncertainty in estimation of τi using dynamic contrast enhanced MRI with one or two flip angles. In vivo experiments with a murine brain tumor model were conducted at 7T using two flip angles. The in vivo data were used to compare τi estimation using the single-flip-angle (SFA) protocol with that using the double-flip-angle (DFA) protocol. Data analysis was conducted using the two-compartment exchange model combined with the three-site-two-exchange model for water exchange. RESULTS: In the numerical simulation studies with a range of contrast kinetic parameters and signal-to-noise ratio = 20, the median bias of τi estimation decreased from 72 ms with SFA to 65 ms with DFA, and the corresponding median inter-quartile range reduced from 523 ms to 156 ms. In the in vivo studies, τi estimation with SFA was not successful in most voxels in the tumors, as the estimated τi values reached the upper limit of the parameter range (2 s). In contrast, the estimated τi values with DFA were mostly between 0.2 and 1.5 s and homogeneously distributed spatially across the tumor. The τi estimation with DFA was less sensitive to arterial input function scaling but more sensitive to pre-contrast T1 than the other contrast kinetic parameters. CONCLUSION: This study results demonstrate the feasibility of using multiple flip angles to encode the post-contrast time-intensity curve with different weighting of water exchange effect to reduce the uncertainty in τi estimation.

Quantifying myofiber integrity using diffusion MRI and random permeable barrier modeling in skeletal muscle growth and Duchenne muscular dystrophy model in mice.

PURPOSE: To measure the microstructural changes during skeletal muscle growth and progressive pathologies using the random permeable model with diffusion MRI, and compare findings to conventional imaging modalities such as three-point Dixon and T2 imaging. METHODS: In vivo and ex vivo DTI experiments with multiple diffusion times (20-700 ms) were completed on wild-type (n = 22) and muscle-dystrophic mdx mice (n = 8) at various developmental time points. The DTI data were analyzed with the random permeable model framework that provides estimates of the unrestricted diffusion coefficient (D0 ), membrane surface-to-volume ratio (S/V), and membrane permeability (κ). In addition, the MRI experiments included conventional measures, such as tissue fat fractions and T2 relaxation. RESULTS: During normal muscle growth between week 4 and week 13, the in vivo S/V, fractional anisotropy, and fat fraction correlated positively with age (ρ = 0.638, 0.664, and 0.686, respectively), whereas T2 correlated negatively (ρ = -0.847). In mdx mice, all DTI random permeable model parameters and fat fraction had significant positive correlation with age, whereas fractional anisotropy and T2 did not have significant correlation with age. Histological measurements of the perimeter-to-area ratio served as a proxy for the model-derived S/V in the cylindrical myofiber geometry, and had a significant correlation with the ex vivo S/V (r = 0.71) as well as the in vivo S/V (r = 0.56). CONCLUSION: The present study demonstrates that DTI at multiple diffusion times with the random permeable model analysis allows for noninvasively quantifying muscle fiber microstructural changes during both normal muscle growth and disease progression. Future studies can apply our technique to evaluate current and potential treatments to muscle myopathies.

Measurement of blood-brain barrier permeability using dynamic contrast-enhanced magnetic resonance imaging with reduced scan time.

PURPOSE: To investigate the feasibility of measuring the subtle disruption of blood-brain barrier (BBB) using DCE-MRI with a scan duration shorter than 10 min. METHODS: The extended Patlak-model (EPM) was introduced to include the effect of plasma flow (Fp ) in the estimation of vascular permeability-surface area product (PS). Numerical simulation studies were carried out to investigate how the reduction in scan time affects the accuracy in estimating contrast kinetic parameters. DCE-MRI studies of the rat brain were conducted with Fisher rats to confirm the results from the simulation. Intracranial F98 glioblastoma models were used to assess areas with different levels of permeability. In the normal brain tissues, the Patlak model (PM) and EPM were compared, whereas the 2-compartment-exchange-model (TCM) and EPM were assessed in the peri-tumor and the tumor regions. RESULTS: The simulation study results demonstrated that scan time reduction could lead to larger bias in PS estimated by PM (>2000%) than by EPM (<47%), especially when Fp is low. When Fp was high as in the gray matter, the bias in PM-PS (>900%) were larger than that in EPM-PS (<42%). The animal study also showed similar results, where the PM parameters were more sensitive to the scan duration than the EPM parameters. It was also demonstrated that, in the peri-tumor region, the EPM parameters showed less change by scan duration than the TCM parameters. CONCLUSION: The results of this study suggest that EPM can be used to measure PS with a scan duration of 10 min or less.

Simultaneous measurement of T1 /B1 and pharmacokinetic model parameters using active contrast encoding (ACE)-MRI.

The aim of this study was to assess the feasibility of combining dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) with the measurement of the radiofrequency (RF) transmit field B1 and pre-contrast longitudinal relaxation time T10 . A novel approach has been proposed to simultaneously estimate B1 and T10 from a modified DCE-MRI scan that actively encodes the washout phase of the curve with different amounts of T1 and B1 weighting using multiple flip angles and repetition times, hence referred to as active contrast encoding (ACE)-MRI. ACE-MRI aims to simultaneously measure B1 and T10 , together with contrast kinetic parameters, such as the transfer constant Ktrans , interstitial space volume fraction ve and vascular space volume fraction vp . The proposed method was tested using numerical simulations and in vivo studies with mouse models of breast cancer implanted in the flank and mammary fat pad, and glioma in the brain. In the numerical simulation study with a signal-to-noise ratio of 10, both B1 and T10 were estimated accurately with errors of 5.1 ± 3.5% and 12.3 ± 8.8% and coefficients of variation (CV) of 14.9 ± 8.6% and 15.0 ± 5.0%, respectively. Using the same ACE-MRI data, the kinetic parameters Ktrans , ve and vp were also estimated with errors of 14.2 ± 8.3% (CV = 13.5 ± 4.6%), 14.7 ± 9.9% (CV = 13.3 ± 4.5%) and 14.0 ± 9.3% (CV = 14.0 ± 4.5%), respectively. For the in vivo tumor data from 11 mice, voxel-wise comparisons between ACE-MRI and DCE-MRI methods showed that the mean differences for the five parameters were as follows: ΔKtrans  = 0.006 (/min), Δve  = 0.016, Δvp  = 0.000, ΔB1  = -0.014 and ΔT1  = -0.085 (s), which suggests a good agreement between the two methods. When compared with separately measured B1 and T10 , and DCE-MRI estimated kinetic parameters as a reference, the mean relative errors of ACE-MRI estimation were B1  = -0.3%, T10  = -8.5%, Ktrans  = 11.4%, ve  = 14.5% and vp  = 4.5%. This proof-of-concept study demonstrates that the proposed ACE-MRI method can be used to estimate B1 and T10 , together with contrast kinetic model parameters.

Separation of benign and malignant breast lesions using dynamic contrast enhanced MRI in a biopsy cohort.

PURPOSE: To assess the diagnostic utility of contrast kinetic analysis for breast lesions and background parenchyma of women undergoing MRI-guided biopsies, for whom standard clinical analysis had failed to separate benign and malignant lesions. MATERIALS AND METHODS: This study included 115 women who had indeterminate lesions based on routine diagnostic breast MRI exams and underwent an MRI (3 Tesla) -guided biopsy of one or more lesions suspicious for breast cancer. Breast dynamic contrast-enhanced (DCE)-MRI was performed using a radial stack-of-stars three-dimensional spoiled gradient echo pulse sequence and modified k-space weighted image contrast image reconstruction. Contrast kinetic model analysis was conducted to characterize the contrast enhancement patterns measured in lesions and background parenchyma (BP). The transfer rate (Ktrans ), interstitial volume fraction (ve ), and vascular volume fraction (vp ) estimated from the lesion and BP were used to separate malignant from benign lesions. RESULTS: The patients with malignant lesions had significantly (P < 0.05) higher median lesion-Ktrans (0.081 min-1 ), higher median BP-Ktrans (0.032 min-1 ), and BP-vp (0.020) than those without malignant lesions (0.056 min-1 , 0.017 min-1 and 0.012, respectively). The area under the receiver operating characteristic curve (AUC) of the BP-Ktrans (0.687) was highest among the single parameters and higher than that of the lesion-Ktrans (0.664). The combined logistic regression model of lesion-Ktrans , lesion-ve , BP-Ktrans , BP-ve , and BP-vp had the highest AUC of 0.730. CONCLUSION: Our results suggest that the contrast kinetic analysis of DCE-MRI data can be used to differentiate the malignant lesions from the benign and high-risk lesions among the indeterminate breast lesions recommended for MRI-guided biopsy exams. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1385-1393.

Surface-to-volume ratio mapping of tumor microstructure using oscillating gradient diffusion weighted imaging.

PURPOSE: To disentangle the free diffusivity (D0 ) and cellular membrane restrictions, by means of their surface-to-volume ratio (S/V), using the frequency-dependence of the diffusion coefficient D(ω), measured in brain tumors in the short diffusion-time regime using oscillating gradients (OGSE). METHODS: In vivo and ex vivo OGSE experiments were performed on mice bearing the GL261 murine glioma model (n = 10) to identify the relevant time/frequency (t/ω) domain where D(ω) linearly decreases with ω(-1/2) . Parametric maps (S/V, D0 ) are compared with conventional DWI metrics. The impact of frequency range and temperature (20°C versus 37°C) on S/V and D0 is investigated ex vivo. RESULTS: The validity of the short diffusion-time regime is demonstrated in vivo and ex vivo. Ex vivo measurements confirm that the purely geometric restrictions embodied in S/V are independent from temperature and frequency range, while the temperature dependence of the free diffusivity D0 is similar to that of pure water. CONCLUSION: Our results suggest that D(ω) in the short diffusion-time regime can be used to uncouple the purely geometric restriction effect, such as S/V, from the intrinsic medium diffusivity properties, and provides a nonempirical and objective way to interpret frequency/time-dependent diffusion changes in tumors in terms of objective biophysical tissue parameters. Magn Reson Med 76:237-247, 2016. © 2015 Wiley Periodicals, Inc.

Pulsed and oscillating gradient MRI for assessment of cell size and extracellular space (POMACE) in mouse gliomas.

Solid tumor microstructure is related to the aggressiveness of the tumor, interstitial pressure and drug delivery pathways, which are closely associated with treatment response, metastatic spread and prognosis. In this study, we introduce a novel diffusion MRI data analysis framework, pulsed and oscillating gradient MRI for assessment of cell size and extracellular space (POMACE), and demonstrate its feasibility in a mouse tumor model. In vivo and ex vivo POMACE experiments were performed on mice bearing the GL261 murine glioma model (n = 8). Since the complete diffusion time dependence is in general non-analytical, the tumor microstructure was modeled in an appropriate time/frequency regime by impermeable spheres (radius Rcell , intracellular diffusivity Dics ) surrounded by extracellular space (ECS) (approximated by constant apparent diffusivity Decs in volume fraction ECS). POMACE parametric maps (ECS, Rcell , Dics , Decs ) were compared with conventional diffusion-weighted imaging metrics, electron microscopy (EM), alternative ECS determination based on effective medium theory (EMT), and optical microscopy performed on the same samples. It was shown that Decs can be approximated by its long time tortuosity limit in the range [1/(88 Hz)-31 ms]. ECS estimations (44 ± 7% in vivo and 54 ± 11% ex vivo) were in agreement with EMT-based ECS and literature on brain gliomas. Ex vivo, ECS maps correlated well with optical microscopy. Cell sizes (Rcell = 4.8 ± 1.3 in vivo and 4.3 ± 1.4 µm ex vivo) were consistent with EM measurements (4.7 ± 1.8 µm). In conclusion, Rcell and ECS can be quantified and mapped in vivo and ex vivo in brain tumors using the proposed POMACE method. Our experimental results support the view that POMACE provides a way to interpret the frequency or time dependence of the diffusion coefficient in tumors in terms of objective biophysical parameters of neuronal tissue, which can be used for non-invasive monitoring of preclinical cancer studies and treatment efficacy. Copyright © 2016 John Wiley & Sons, Ltd.

Potential Role of PET/MRI for Imaging Metastatic Lymph Nodes in Head and Neck Cancer.

OBJECTIVE: This article explores recent developments in PET and MRI, separately or combined, for assessing metastatic lymph nodes in patients with head and neck cancer. CONCLUSION: The synergistic role of PET and MRI for imaging metastatic lymph nodes has not been fully explored. To facilitate the understanding of the areas that need further investigation, we discuss potential mechanisms and evidence reported so far, as well as future directions and challenges for continued development and clinical research.

Feasibility of measuring blood-brain barrier permeability using ultra-short echo time radial magnetic resonance imaging.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate the feasibility of using 3-dimensional (3D) ultra-short echo time (UTE) radial imaging method for measurement of the permeability of the blood-brain barrier (BBB) to gadolinium-based contrast agent. In this study, we propose to use the golden-angle radial sparse parallel (GRASP) method with 3D center-out trajectories for UTE, hence named as 3D UTE-GRASP. We first examined the feasibility of using 3D UTE-GRASP dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) for differentiating subtle BBB disruptions induced by focused ultrasound (FUS). Then, we examined the BBB permeability changes in Alzheimer's disease (AD) pathology using Alzheimer's disease transgenic mice (5xFAD) at different ages. METHODS: For FUS experiments, we used four Sprague Dawley rats at similar ages where we compared BBB permeability of each rat receiving the FUS sonication with different acoustic power (0.4-1.0 MPa). For AD transgenic mice experiments, we included three 5xFAD mice (6, 12, and 16 months old) and three wild-type mice (4, 8, and 12 months old). RESULTS: The result from FUS experiments showed a progressive increase in BBB permeability with increase of acoustic power (p < .05), demonstrating the sensitivity of DCE-MRI method for detecting subtle changes in BBB disruption. Our AD transgenic mice experiments suggest an early BBB disruption in 5xFAD mice, which is further impaired with aging. CONCLUSION: The results in this study substantiate the feasibility of using the proposed 3D UTE-GRASP method for detecting subtle BBB permeability changes expected in neurodegenerative diseases, such as AD.

Textural Features of Mouse Glioma Models Measured by Dynamic Contrast-Enhanced MR Images with 3D Isotropic Resolution.

This paper investigates the effect of anisotropic resolution on the image textural features of pharmacokinetic (PK) parameters of a murine glioma model using dynamic contrast-enhanced (DCE) MR images acquired with an isotropic resolution at 7T with pre-contrast T1 mapping. The PK parameter maps of whole tumors at isotropic resolution were generated using the two-compartment exchange model combined with the three-site-two-exchange model. The textural features of these isotropic images were compared with those of simulated, thick-slice, anisotropic images to assess the influence of anisotropic voxel resolution on the textural features of tumors. The isotropic images and parameter maps captured distributions of high pixel intensity that were absent in the corresponding anisotropic images with thick slices. A significant difference was observed in 33% of the histogram and textural features extracted from anisotropic images and parameter maps, compared to those extracted from corresponding isotropic images. Anisotropic images in different orthogonal orientations demonstrated 42.1% of the histogram and textural features to be significantly different from those of isotropic images. This study demonstrates that the anisotropy of voxel resolution needs to be carefully considered when comparing the textual features of tumor PK parameters and contrast-enhanced images.

Evaluation of cellular water exchange in a mouse glioma model using dynamic contrast-enhanced MRI with two flip angles.

This manuscript aims to evaluate the robustness and significance of the water efflux rate constant (kio) parameter estimated using the two flip-angle Dynamic Contrast-Enhanced (DCE) MRI approach with a murine glioblastoma model at 7 T. The repeatability of contrast kinetic parameters and kio measurement was assessed by a test-retest experiment (n = 7). The association of kio with cellular metabolism was investigated through DCE-MRI and FDG-PET experiments (n = 7). Tumor response to a combination therapy of bevacizumab and fluorouracil (5FU) monitored by contrast kinetic parameters and kio (n = 10). Test-retest experiments demonstrated compartmental volume fractions (ve and vp) remained consistent between scans while the vascular functional measures (Fp and PS) and kio showed noticeable changes, most likely due to physiological changes of the tumor. The standardized uptake value (SUV) of tumors has a linear correlation with kio (R2 = 0.547), a positive correlation with Fp (R2 = 0.504), and weak correlations with ve (R2 = 0.150), vp (R2 = 0.077), PS (R2 = 0.117), Ktrans (R2 = 0.088) and whole tumor volume (R2 = 0.174). In the treatment study, the kio of the treated group was significantly lower than the control group one day after bevacizumab treatment and decreased significantly after 5FU treatment compared to the baseline. This study results support the feasibility of measuring kio using the two flip-angle DCE-MRI approach in cancer imaging.

Rapid In Vitro Quantification of a Sensitized Gadolinium Chelate via Photoinduced Triplet Harvesting.

Gadolinium (Gd) based contrast agents (GBCAs) are widely used in magnetic resonance imaging (MRI) and are paramount to cancer diagnostics and tumor pharmacokinetic analysis. Accurate quantification of gadolinium concentration is essential to monitoring the biodistribution, clearance, and pharmacodynamics of GBCAs. However, current methods of quantifying gadolinium in blood or plasma (biological media) are both low throughput and clinically unavailable. Here, we have demonstrated the use of a sensitized gadolinium chelate, Gd[DTPA-cs124], as an MRI contrast agent that can be used to measure the concentration of gadolinium via luminescence quantification in biological media following transmetalation with a terbium salt. Gd[DTPA-cs124] was synthesized by conjugating carbostyril-124 (cs124) to diethylenetriaminepentaacetic acid (DTPA) and chelating to gadolinium. We report increases in both stability and relaxivity compared to the clinically approved analog Gd[DTPA] (gadopentetic acid or Magnevist). In vivo MRI experiments were conducted using C57BL6 mice in order to further illustrate the performance of Gd[DTPA-cs124] as an MRI contrast agent in comparison to Magnevist. Our results indicate that similar chemical modification to existing clinically approved GBCA may likewise provide favorable property changes, with the ability to be used in a gadolinium quantification assay. Furthermore, our assay provides a straightforward and high-throughput method of measuring gadolinium in biological media using a standard laboratory plate reader.