Development, validation, qualification, and dissemination of quantitative MR methods: Overview and recommendations by the ISMRM quantitative MR study group.

On behalf of the International Society for Magnetic Resonance in Medicine (ISMRM) Quantitative MR Study Group, this article provides an overview of considerations for the development, validation, qualification, and dissemination of quantitative MR (qMR) methods. This process is framed in terms of two central technical performance properties, i.e., bias and precision. Although qMR is confounded by undesired effects, methods with low bias and high precision can be iteratively developed and validated. For illustration, two distinct qMR methods are discussed throughout the manuscript: quantification of liver proton-density fat fraction, and cardiac T1 . These examples demonstrate the expansion of qMR methods from research centers toward widespread clinical dissemination. The overall goal of this article is to provide trainees, researchers, and clinicians with essential guidelines for the development and validation of qMR methods, as well as an understanding of necessary steps and potential pitfalls for the dissemination of quantitative MR in research and in the clinic.

Water Exchange Rate Constant as a Biomarker of Treatment Efficacy in Patients With Brain Metastases Undergoing Stereotactic Radiosurgery.

PURPOSE: This study was designed to evaluate whether changes in metastatic brain tumors after stereotactic radiosurgery (SRS) can be seen with quantitative MRI early after treatment. METHODS AND MATERIALS: Using contrast-enhanced MRI, a 3-water-compartment tissue model consisting of intracellular (I), extracellular-extravascular (E), and vascular (V) compartments was used to assess the intra-extracellular water exchange rate constant (kIE), efflux rate constant (kep), and water compartment volume fractions (M0,I, M0,E, M0,V). In this prospective study, 19 patients were MRI-scanned before treatment and 1 week and 1 month after SRS. The change in model parameters between the pretreatment and 1-week posttreatment scans was correlated to the change in tumor volume between pretreatment and 1-month posttreatment scans. RESULTS: At 1 week kIE differentiated (P<.001) tumors that had partial response from tumors with stable and progressive disease, and a high correlation (R=-0.76, P<.001) was observed between early changes in the kIE and tumor volume change 1 month after treatment. Other model parameters had lower correlation (M0,E) or no correlation (kep, M0,V). CONCLUSIONS: This is the first study that measured kIE early after SRS, and it found that early changes in kIE (1 week after treatment) highly correlated with long-term tumor response and could predict the extent of tumor shrinkage at 1 month after SRS.

Differentiation between Radiation Necrosis and Tumor Progression Using Chemical Exchange Saturation Transfer.

Purpose: Stereotactic radiosurgery (SRS) is a common treatment used in patients with brain metastases and is associated with high rates of local control, however, at the risk of radiation necrosis. It is difficult to differentiate radiation necrosis from tumor progression using conventional MRI, making it a major diagnostic dilemma for practitioners. This prospective study investigated whether chemical exchange saturation transfer (CEST) was able to differentiate these two conditions.Experimental Design: Sixteen patients with brain metastases who had been previously treated with SRS were included. Average time between SRS and evaluation was 12.6 months. Lesion type was determined by pathology in 9 patients and the other 7 were clinically followed. CEST imaging was performed on a 3T Philips scanner and the following CEST metrics were measured: amide proton transfer (APT), magnetization transfer (MT), magnetization transfer ratio (MTR), and area under the curve for CEST peaks corresponding to amide and nuclear Overhauser effect (NOE).Results: Five lesions were classified as progressing tumor and 11 were classified as radiation necrosis (using histopathologic confirmation and radiographic follow-up). The best separation was obtained by NOEMTR (NOEMTR,necrosis = 8.9 ± 0.9%, NOEMTR,progression = 12.6 ± 1.6%, P < 0.0001) and AmideMTR (AmideMTR,necrosis = 8.2 ± 1.0%, AmideMTR,progression = 12.0 ± 1.9%, P < 0.0001). MT (MTnecrosis = 4.7 ± 1.0%, MTprogression = 6.7 ± 1.7%, P = 0.009) and NOEAUC (NOEAUC,necrosis = 4.3 ± 2.0% Hz, NOEAUC,progression = 7.2 ± 1.9% Hz, P = 0.019) provided statistically significant separation but with higher P values.Conclusions: CEST was capable of differentiating radiation necrosis from tumor progression in brain metastases. Both NOEMTR and AmideMTR provided statistically significant separation of the two cohorts. However, APT was unable to differentiate the two groups. Clin Cancer Res; 23(14); 3667-75. ©2017 AACR.

Chemical exchange saturation transfer for predicting response to stereotactic radiosurgery in human brain metastasis.

PURPOSE: The purpose of this work was to determine the predictive value of chemical exchange saturation transfer (CEST) metrics in brain metastases treated with stereotactic radiosurgery (SRS). METHODS: CEST spectra at a radiofrequency power of 0.52 µT were collected on a 3 Tesla (T) magnetic resonance imaging from 25 patients at three time points: pretreatment, 1 week, and 1 month post-treatment. Amide proton transfer-weighted images and maps of the amplitude and width of Lorentzian-shaped CEST peaks and the relaxation-compensated AREX metric were constructed at the offset frequencies of amide, amine, and relayed nuclear Overhauser effect (NOE) from aliphatic groups as well as the broad magnetization transfer effect. Pretreatment CEST metrics, as well as CEST metric changes at 1 week post-treatment, were compared to changes in tumor volume at 1 month. RESULTS: Significant (P < 0.05) 1-week predictive metrics included NOE peak amplitude (R = 0.69) in normal-appearing white matter (NAWM) and width (R = -0.55) in tumor. Baseline NOE in contralateral NAWM was negatively correlated (R = -0.69) with volume changes at 1 month. Metrics-defined outside tumor margins had higher correlation with volume changes than tumor regions of interest. CONCLUSION: CEST metrics, in particular, the NOE peak amplitude, can predict volume changes 1 month post-SRS. Magn Reson Med 78:1110-1120, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

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

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

Mapping of amide, amine, and aliphatic peaks in the CEST spectra of murine xenografts at 7 T.

PURPOSE: To evaluate the performance of endogenous chemical exchange saturation transfer (CEST) spectra and derived maps in a longitudinal study of tumor xenografts to ascertain the role of CEST parameters in describing tumor progression and in distinguishing between tumor, muscle, and necrosis. METHODS: CEST spectra of 24 mice with tumor xenografts (20 LLC and 4 MDA) were acquired at three time-points. We employed a novel method of decomposing the CEST spectrum into a sum of four Lorentzian shapes, each with a corresponding measured amplitude, width and frequency offset. This semi-quantitative method is an improvement over techniques which simply assess the asymmetry in the spectrum for the presence of CEST, due to the fact that it is not confounded by CEST peaks on opposing sides of the direct effect. The CEST images were compared to several other commonly employed contrast mechanisms: T1 relaxation, T2 relaxation, diffusion (ADC), and magnetization transfer (MT). RESULTS: Tumor spectra had distinct CEST peaks corresponding to the presence of hydrogen exchange between free water and amide, amine, and aliphatic groups. All three CEST peaks (amide, amine, and aliphatic) were larger in the tumor tissue as compared with the adjacent healthy muscle. CONCLUSIONS: CEST contrast (particularly the amine peak amplitude) performed especially well in distinguishing areas of apoptosis and/or necrosis from actively progressing tumor, as validated by histology.

Quantitative magnetization transfer studies of apoptotic cell death.

Magnetization transfer measurements were performed on samples of acute myeloid leukemia cells at early (36 h postcisplatin treatment) and late (48 h posttreatment) stages of apoptosis. Magnetization transfer ratio was calculated and a two-pool model was fitted to data at two powers and 16 offset frequencies of saturation pulse. No parameters changed significantly at early stages of apoptosis. At late stages, changes in magnetization transfer ratio were not significant, but quantitative model parameters showed a decrease in macromolecular proton fraction, M(0B), and an increase in the T(2) relaxation time of free water. Analysis also indicated an increase in the ratio R × M(0B)/R(1A), where R is the exchange rate between free water and macromolecular protons and R(1A) is the T(1) relaxation rate of free water. Changes in the magnetization transfer spectrum were largely attributable to differences in the free water pool and did not occur any earlier than changes in the average T(1) relaxation time, T(1obs).