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Simple Summary: Although primary central nervous system lymphoma (PCNSL) is sometimes indistinguishable from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype, the role of operation on them is very different; therefore, accurate preoperative diagnosis is crucial. In this study, we evaluated whether amide proton transfer-weighted (APTw) imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. The mean APTw signal value did not significantly differ between them; however, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1–100 APTw signals between the two diseases were significantly different. The area under the curve, sensitivity, and specificity were 0.796, 64.3%, and 88.9%, respectively, using the width1–100 APTw signal values. APTw imaging was useful to differentiate between PCNSL and glioblastoma, IDH-wildtype. Performing APTw imaging is recommended in cases in which PCNSL is one of the differential diagnoses. Distinguishing primary central nervous system lymphoma (PCNSL) from glioblastoma, isocitrate dehydrogenase (IDH)-wildtype is sometimes hard. Because the role of operation on them varies, accurate preoperative diagnosis is crucial. In this study, we evaluated whether a specific kind of chemical exchange saturation transfer imaging, i.e., amide proton transfer-weighted (APTw) imaging, was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. A total of 14 PCNSL and 27 glioblastoma, IDH-wildtype cases were evaluated. There was no significant difference in the mean APTw signal values between the two groups. However, the percentile values from the 1st percentile to the 20th percentile APTw signals and the width1–100 APTw signals significantly differed. The highest area under the curve was 0.796, which was obtained from the width1–100 APTw signal values. The sensitivity and specificity values were 64.3% and 88.9%, respectively. APTw imaging was useful to distinguish PCNSL from glioblastoma, IDH-wildtype. To avoid unnecessary aggressive surgical resection, APTw imaging is recommended for cases in which PCNSL is one of the differential diagnoses. [ABSTRACT FROM AUTHOR]

Purpose: Standardized blood tests often lack adequate sensitivity and specificity to capture the gradual progression of renal injuries. We suggest a multiparametric molecular MRI approach as a noninvasive tool for monitoring renal function loss and distinguishing different types of renal injuries. Methods: CEST and quantitative magnetization transfer (qMT) imaging were performed on cisplatin (n = 16) and aristolochic acid (AA)‐induced nephropathy (n = 22) mouse models at 7T with an infusion of either saline or urea. Seven‐pool Lorentzian fitting was applied for the analysis of CEST Z‐spectra, and the T1‐corrected CEST contrast apparent exchange‐dependent relaxation (AREX) from urea (+1 ppm) and two nuclear Overhauser enhancement (NOE) pools (−1.6 and −3.5 ppm) were measured. Similarly, qMT spectra were fitted into two‐pool Ramani equation and the relative semi‐solid macromolecular pool‐size ratio was measured. Histology of mouse kidneys was performed to validate the MR findings. Results: AA model showed disrupted spatial gradients of urea in the kidney and significantly decreased NOE CEST and qMT contrast. The cisplatin model showed slightly decreased qMT contrast only. The orrelation of MR parameters to histological features showed that NOE CEST and qMT imaging are sensitive to both acute and chronic injuries, whereas urea CEST shows a significant correlation only to acute injuries. Conclusion: These results indicate that our multiparametric approach allows comprehensive and totally noninvasive monitoring of renal function and histological changes for distinguishing different nephropathies. [ABSTRACT FROM AUTHOR]

Purpose: Design an efficient CEST scheme for exchange‐dependent images with high contrast‐to‐noise ratio. Theory: Reassembled saturation transfer (REST) signals were defined as Δ$$ \Delta $$r.Z = r.Zref ‐ r.ZCEST and the reassembled exchange‐dependen magnetization transfer ratio r.MTRRex = r.1/Zref ‐ r.1/ZCEST, utilizing the averages over loosely sampled reference frequency offsets as Zref and over densely sampled target offsets as ZCEST. Using r.MTRRex measured under 2 B1,sat values, exchange rate could be estimated. Methods: The REST approach was optimized and assessed quantitatively by simulations for various exchange rates, pool concentration, and water T1. In vivo evaluation was performed on ischemic rat brains at 7 Tesla and human brains at 3 Tesla, in comparison with conventional asymmetrical analysis, Lorentzian difference (LD), an MTRRex_LD. Results: For a broad choice of Δωref$$ \Delta {\omega}_{ref} $$ ranges and numbers, Δr.Z and r.MTRRex exhibited comparable quantification features with conventional LD and MTRRex_LD, respectively, when B1,sat ≤ 1 μT. The subtraction of 2 REST values under distinct B1,sat values showed linear relationships with exchange rate and obtained immunity to field inhomogeneity and variation in MT and water T1. For both rat and human studies, REST images exhibited similar contrast distribution to MTRRex_LD, with superiority in contrast‐to‐noise ratio and acquisition efficiency. Compared with MTRRex_LD, 2‐B1,sat subtraction REST images displayed better resistance to B1 inhomogeneity, with more specific enhanced regions. They also showed higher signals for amide than for nuclear Overhauser enhancement effect in human brain, presumably reflecting the higher increment from faster‐exchanging species as B1,sat increased. Conclusion: Featuring high contrast‐to‐noise ratio efficiency, REST could be a practical exchange‐dependent approach readily applicable to either retrospective Z‐spectra analysis or perspective 6‐offset acquisition. [ABSTRACT FROM AUTHOR]

Purpose: The average saturation efficiency filter (ASEF) is a novel method of improving the specificity of CEST; however, there is a mismatch between the magnetization transfer (MT) effect under high‐duty cycle and low‐duty cycle pulse trains. We explore measures of mitigation and the sensitivity and potential of ASEF imaging in phantoms and stroke rats. Methods: Simulation and nicotinamide phantoms in denatured protein were used to investigate the effect of different average saturation powers and MT pool parameters on matching coefficients used for correction as well as the ASEF ratio signal and baseline. Then, in vivo studies were performed in stroke rodents to further investigate the sensitivity and fidelity of ASEF ratio spectra. Results: Simulation and studies of nicotinamide phantoms show that the matching coefficient needed to correct the baseline MT mismatch is strongly dependent on the average saturation power. In vivo studies in stroke rodents show that the matching coefficient required to correct the baseline MT mismatch is different for normal versus ischemic tissue. Thus, a baseline correction was performed to further suppress the residue MT mismatch. After correction of the mismatch, ASEF ratio achieved comparable contrast at 3.6 ppm between normal and ischemic tissue when compared to the apparent amide proton transfer (APT*) approach. Moreover, contrasts for 2.0 and 2.6 ppm were also ascertainable from the same spectra. Conclusion: ASEF can improve the CEST signal specificity of slow exchange labile protons such as amide and guanidyl, with small loss to sensitivity. It has strong potential in the CEST imaging of various diseases. [ABSTRACT FROM AUTHOR]

Purpose: Chemical exchange saturation transfer (CEST) MRI is promising for detecting dilute metabolites and microenvironment properties, which has been increasingly adopted in imaging disorders such as acute stroke and cancer. However, in vivo CEST MRI quantification remains challenging because routine asymmetry analysis (MTRasym) or Lorentzian decoupling measures a combined effect of the labile proton concentration and its exchange rate. Therefore, our study aimed to quantify amide proton concentration and exchange rate independently in a cardiac arrest‐induced global ischemia rat model. Methods: The amide proton CEST (APT) effect was decoupled from tissue water, macromolecular magnetization transfer, nuclear Overhauser enhancement, guanidinium, and amine protons using the image downsampling expedited adaptive least‐squares (IDEAL) fitting algorithm on Z‐spectra obtained under multiple RF saturation power levels, before and after global ischemia. Omega plot analysis was applied to determine amide proton concentration and exchange rate simultaneously. Results: Global ischemia induces a significant APT signal drop from intact tissue. Using the modified omega plot analysis, we found that the amide proton exchange rate decreased from 29.6 ± 5.6 to 12.1 ± 1.3 s−1 (P < 0.001), whereas the amide proton concentration showed little change (0.241 ± 0.035% vs. 0.202 ± 0.034%, P = 0.074) following global ischemia. Conclusion: Our study determined the labile proton concentration and exchange rate underlying the in vivo APT MRI. The significant change in the exchange rate, but not the concentration of amide proton demonstrated that the pH effect dominates the APT contrast during tissue ischemia. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the benefits and challenges of dynamic parallel transmit (pTx) pulses for fat saturation (FS) and water‐excitation (WE), in the context of CEST MRI. Methods: "Universal" kT‐points (for FS) and spiral non‐selective (for WE) trajectories were optimized offline for flip angle (FA) homogeneity. Routines to optimize the pulse shape online, based on the subject's fields maps, were implemented (target FA of 110°/0° for FS, 0°/5° for WE at fat/water frequencies). The pulses were inserted in a CEST sequence with a pTx readout. The different fat suppression schemes and their effects on CEST contrasts were compared in 12 volunteers at 7T. Results: With a 25%‐shorter pulse duration, pTx FS largely improved the FA homogeneity (root‐mean‐square‐error (RMSE) = 12.3° vs. 53.4° with circularly‐polarized mode, at the fat frequency). However, the spectral selectivity was degraded mainly in the cerebellum and close to the sinuses (RMSE = 5.8° vs. 0.2° at the water frequency). Similarly, pTx WE showed a trade‐off between FA homogeneity and spectral selectivity compared to pTx non‐selective pulses (RMSE = 0.9° and 1.1° at the fat and water frequencies, vs. 4.6° and 0.5°). In the brain, CEST metrics were reduced by up to 31.9% at −3.3 ppm with pTx FS, suggesting a mitigated lipid‐induced bias. Conclusion: This clinically compatible implementation of dynamic pTx pulses improved the fat suppression homogeneity at 7T taking into account the subject‐specific B0 heterogeneities online. This study highlights the lipid‐induced biases on the CEST z‐spectrum. The results are promising for body applications where B0 heterogeneities and fat are more substantial. [ABSTRACT FROM AUTHOR]

Background: Amide proton transfer (APT) imaging is a chemical exchange saturation transfer (CEST) technique offering potential clinical applications such as diagnosis, characterization, and treatment planning and monitoring in glioma patients. While APT‐CEST has demonstrated high potential, reproducibility remains underexplored. Purpose: To investigate whether cerebral APT‐CEST with clinically feasible scan time is reproducible in healthy tissue and glioma for clinical use at 3 T. Study Type: Prospective, longitudinal. Subjects: Twenty‐one healthy volunteers (11 females; mean age ± SD: 39 ± 11 years) and 6 glioma patients (3 females; 50 ± 17 years: 4 glioblastomas, 1 oligodendroglioma, 1 radiologically suspected low‐grade glioma). Field Strength/Sequence: 3 T, Turbo Spin Echo ‐ ampling perfection with application optimized contrasts using different flip angle evolution ‐ chemical exchange saturation transfer (TSE SPACE‐CEST). Assessment: APT‐CEST measurement reproducibility was assessed within‐session (glioma patients, scan session 1; healthy volunteers scan sessions 1, 2, and 3), between‐sessions (healthy volunteers scan sessions 1 and 2), and between‐days (healthy volunteers, scan sessions 1 and 3). The mean APTCEST values and standard deviation of the within‐subject difference (SDdiff) were calculated in whole tumor enclosed by regions of interest (ROIs) in patients, and eight ROIs in healthy volunteers—whole‐brain, cortical gray matter, putamen, thalami, orbitofrontal gyri, occipital lobes, central brain—and compared. Statistical Tests: Brown‐Forsythe tests and variance component analysis (VCA) were used to assess the reproducibility of ROIs for the three time intervals. Significance was set at P < 0.003 after Bonferroni correction. Results: Intratumoral mean APTCEST was significantly higher than APTCEST in healthy‐appearing tissue in patients (0.5 ± 0.46%). The average within‐session, between‐sessions, and between‐days SDdiff of healthy control brains was 0.2% and did not differ significantly with each other (0.76 > P > 0.22). The within‐session SDdiff of whole‐brain was 0.2% in both healthy volunteers and patients, and 0.21% in the segmented tumor. VCA showed that within‐session factors were the most important (60%) for scanning variance. Data Conclusion: Cerebral APT‐CEST imaging may show good scan–rescan reproducibility in healthy tissue and tumors with clinically feasible scan times at 3 T. Short‐term measurement effects may be the dominant components for reproducibility. Level of Evidence: 2 Technical Efficacy: Stage 2 [ABSTRACT FROM AUTHOR]

Purpose: Ultra‐high field MR imaging lacks B1+ inhomogeneity due to shorter RF wavelengths used at higher field strengths compared to human anatomy. CEST techniques tend to be highly susceptible to B1+ inhomogeneities due to a high and uniform B1+ field being necessary to create the endogenous contrast. High‐permittivity dielectric pads have seen increasing usage in MR imaging due to their ability to tailor the spatial distribution of the B1+ field produced. The purpose of this work is to demonstrate that dielectric materials can be used to improve glutamate weighted CEST (gluCEST) at 7T. Theory and Methods: GluCEST images were acquired on a 7T system on six healthy volunteers. Aqueous calcium titanate pads, with a permittivity of approximately 110, were placed on either side in the subject′s head near the temporal lobes. A post‐processing correction algorithm was implemented in combination with dielectric padding to compare contrast improvement. Tissue segmentation was performed to assess the effect of dielectric pads on gray and white matter separately. Results: GluCEST images demonstrated contrast enhancement in the lateral temporal lobe regions with dielectric pad placement. Tissue segmentation analysis showed an increase in correction effectiveness within the gray matter tissue compared to white matter tissue. Statistical testing suggested a significant difference in gluCEST contrast when pads were used and showed a difference in the gray matter tissue segment. Conclusion: The use of dielectric pads improved the B1+ field homogeneity and enhanced gluCEST contrast for all subjects when compared to data that did not incorporate padding. [ABSTRACT FROM AUTHOR]

Purpose: Chemical exchange saturation transfer (CEST) imaging measurement depends not only on the labile proton concentration and pH‐dependent exchange rate but also on experimental conditions, including the relaxation delay and radiofrequency (RF) saturation time. Our study aimed to extend a quasi–steady‐state (QUASS) solution to a modified multi‐slice CEST MRI sequence and test if it provides enhanced pH imaging after acute stroke. Methods: Our study derived the QUASS solution for a modified multislice CEST MRI sequence with an unevenly segmented RF saturation between image readout and signal averaging. Numerical simulation was performed to test if the generalized QUASS solution corrects the impact of insufficiently long relaxation delay, primary and secondary saturation times, and multi‐slice readout. In addition, multiparametric MRI scans were obtained after middle cerebral artery occlusion, including relaxation and CEST Z‐spectrum, to evaluate the performance of QUASS CEST MRI in a rodent acute stroke model. We also performed Lorentzian fitting to isolate multi‐pool CEST contributions. Results: The QUASS analysis enhanced pH‐weighted magnetization transfer asymmetry contrast over the routine apparent CEST measurements in both contralateral normal (−3.46% ± 0.62% (apparent) vs. −3.67% ± 0.66% (QUASS), P < 0.05) and ischemic tissue (−5.53% ± 0.68% (apparent) vs. −5.94% ± 0.73% (QUASS), P < 0.05). Lorentzian fitting also showed significant differences between routine and QUASS analysis of ischemia‐induced changes in magnetization transfer, amide, amine, guanidyl CEST, and nuclear Overhauser enhancement (−1.6 parts per million) effects. Conclusion: Our study demonstrated that generalized QUASS analysis enhanced pH MRI contrast and improved quantification of the underlying CEST contrast mechanism, promising for further in vivo applications. [ABSTRACT FROM AUTHOR]

Based on in silico, in vitro, in situ, and in vivo evaluations, this study aims to establish and optimize the chemical exchange saturation transfer (CEST) imaging of lactate (Lactate-CEST—LATEST). To this end, we optimized LATEST sequences using Bloch–McConnell simulations for optimal detection of lactate with a clinical 3 T MRI scanner. The optimized sequences were used to image variable lactate concentrations in vitro (using phantom measurements), in situ (using nine human cadaveric lower leg specimens), and in vivo (using four healthy volunteers after exertional exercise) that were then statistically analyzed using the non-parametric Friedman test and Kendall Tau-b rank correlation. Within the simulated Bloch–McConnell equations framework, the magnetization transfer ratio asymmetry (MTRasym) value was quantified as 0.4% in the lactate-specific range of 0.5–1 ppm, both in vitro and in situ, and served as the imaging surrogate of the lactate level. In situ, significant differences (p < 0.001) and strong correlations (τ = 0.67) were observed between the MTRasym values and standardized intra-muscular lactate concentrations. In vivo, a temporary increase in the MTRasym values was detected after exertional exercise. In this bench-to-bedside comprehensive feasibility study, different lactate concentrations were detected using an optimized LATEST imaging protocol in vitro, in situ, and in vivo at 3 T, which prospectively paves the way towards non-invasive quantification and monitoring of lactate levels across a broad spectrum of diseases.

Chemical Exchange Saturation Transfer (CEST) magnetic resonance imaging (MRI) provides a novel method for analyzing biomolecule concentrations in tissues without exogenous contrast agents. Despite its potential, achieving a high signal-to-noise ratio (SNR) is imperative for detecting small CEST effects. Traditional metrics such as Magnetization Transfer Ratio Asymmetry (MTRasym) and Lorentzian analyses are vulnerable to image noise, hampering their precision in quantitative concentration estimations. Recent noise-reduction algorithms like principal component analysis (PCA), nonlocal mean filtering (NLM), and block matching combined with 3D filtering (BM3D) have shown promise, as there is a burgeoning interest in the utilization of neural networks (NNs), particularly autoencoders, for imaging denoising. This study uses the Bloch–McConnell equations, which allow for the synthetic generation of CEST images and explores NNs efficacy in denoising these images. Using synthetically generated phantoms, autoencoders were created, and their performance was compared with traditional denoising methods using various datasets. The results underscored the superior performance of NNs, notably the ResUNet architectures, in noise identification and abatement compared to analytical approaches across a wide noise gamut. This superiority was particularly pronounced at elevated noise intensities in the in vitro data. Notably, the neural architectures significantly improved the PSNR values, achieving up to 35.0, while some traditional methods struggled, especially in low-noise reduction scenarios. However, the application to the in vivo data presented challenges due to varying noise profiles. This study accentuates the potential of NNs as robust denoising tools, but their translation to clinical settings warrants further investigation.

The molecular imaging of biomarkers plays an increasing role in medical diagnostics. In particular, the imaging of enzyme activity is a promising approach, as it enables the use of its inherent catalytic activity for the amplification of an imaging signal. The increased activity of a sulfatase enzyme has been observed in several types of cancers. We describe the development and in vitro evaluation of molecular imaging agents that allow for the detection of sulfatase activity using the whole-body, non-invasive MRI and CEST imaging methods. This approach relies on a responsive ligand that features a sulfate ester moiety, which upon sulfatase-catalyzed hydrolysis undergoes an elimination process that changes the functional group, coordinating with the metal ion. When Gd3+ is used as the metal, the complex can be used for MRI, showing a 25% decrease at 0.23T and a 42% decrease at 4.7T in magnetic relaxivity after enzymatic conversion, thus providing a “switch-off” contrast agent. Conversely, the use of Yb3+ as the metal leads to a “switch-on” effect in the CEST imaging of sulfatase activity. Altogether, the results presented here provide a molecular basis and a proof-of-principle for the magnetic imaging of the activity of a key cancer biomarker.

PurposeTo introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI).MethodspH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTRasym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas.ResultsSimulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2  = 6.2 mM-1 ·sec-1 and R2* = 6.9 mM-1 ·sec-1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom-Gill estimates of R2 (R2  = 0.9943) and multi-echo gradient-echo estimates of R2* (R2  = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , indicating high hypoxia and acidity.ConclusionThe CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole-brain acquisition, in-line B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T.

PurposeThere is an increased interest to determine the exchange rate using CEST to provide pH information. However, current CEST quantification methods require lengthy scan times and do not address magnetization transfer effects. The purpose of this work was to apply the magnetic resonance fingerprinting (MRF) concept to CEST to achieve more efficient and accurate exchange rate quantification.MethodsThe proposed CEST fingerprinting method used varying saturation powers and saturation times to create unique signal evolutions for different exchange rates. The acquired signal was matched to a predefined dictionary to determine the exchange rate. The magnetization transfer effects were also addressed in the framework of CEST fingerprinting: The simulated dictionary could predict the signal curves without magnetization transfer effects, and comparing the dictionary to the acquired signals allowed the correction of the magnetization transfer effects. The CEST fingerprinting method was compared with the conventional pulsed quantitative CEST method using omega plots in the creatine phantom study.ResultsThe CEST fingerprinting method has a significantly reduced scan time (10 minutes versus 50 minutes) while providing more accurate exchange rate quantification using literature values as the reference.ConclusionIn this study, we demonstrate that CEST fingerprinting is more efficient (5 times faster) compared with pulsed quantitative CEST. It is also shown that the results of the proposed CEST fingerprinting technique are much closer to the literature values than pulsed quantitative CEST at 3 T.

For precise delineation of glioma extent, amino acid PET is superior to conventional MR imaging. Since metabolic MR sequences such as chemical exchange saturation transfer (CEST) imaging and MR spectroscopy (MRS) were developed, we aimed to evaluate the diagnostic accuracy of combined CEST and MRS to predict glioma infiltration. Eighteen glioma patients of different tumor grades were enrolled in this study; 18F-fluoroethyltyrosine (FET)-PET, amide proton transfer CEST at 7 Tesla(T), MRS and conventional MR at 3T were conducted preoperatively. Multi modalities and their association were evaluated using Pearson correlation analysis patient-wise and voxel-wise. Both CEST (R = 0.736, p < 0.001) and MRS (R = 0.495, p = 0.037) correlated with FET-PET, while the correlation between CEST and MRS was weaker. In subgroup analysis, APT values were significantly higher in high grade glioma (3.923 ± 1.239) and IDH wildtype group (3.932 ± 1.264) than low grade glioma (3.317 ± 0.868, p < 0.001) or IDH mutant group (3.358 ± 0.847, p < 0.001). Using high FET uptake as the standard, the CEST/MRS combination (AUC, 95% CI: 0.910, 0.907–0.913) predicted tumor infiltration better than CEST (0.812, 0.808–0.815) or MRS (0.888, 0.885–0.891) alone, consistent with contrast-enhancing and T2-hyperintense areas. Probability maps of tumor presence constructed from the CEST/MRS combination were preliminarily verified by multi-region biopsies. The combination of 7T CEST/MRS might serve as a promising non-radioactive alternative to delineate glioma infiltration, thus reshaping the guidance for tumor resection and irradiation. [ABSTRACT FROM AUTHOR]

In fibroglandular breast tissue, conventional dynamic contrast-enhanced MR-mammography is known to be affected by water content changes during the menstrual cycle. Likewise, amide proton transfer (APT) chemical exchange saturation transfer (CEST)-MRI might be inherently prone to the menstrual cycle, as CEST signals are indirectly detected via the water signal. The purpose of this study was to investigate the influence of the menstrual cycle on APT CEST-MRI in fibroglandular breast tissue. Ten healthy premenopausal women (19–34 years) were included in this IRB approved prospective study and examined twice during their menstrual cycle. Examination one and two were performed during the first half (day 2–8) and the second half (day 15–21) of the menstrual cycle, respectively. As a reference for the APT signal in malignant breast tumor tissue, previously reported data of nine breast cancer patients were included in this study. CEST-MRI (B 1 = 0.7μT) was performed on a 7 T whole-body scanner followed by a multi-Lorentzian fit analysis. The APT signal was corrected for B 0 /B 1 -field inhomogeneities, fat signal contribution, and relaxation effects of the water signal and evaluated in the fibroglandular breast tissue. Intra-individual APT signal differences between examination one and two were compared using the Wilcoxon signed-rank test. The level of significance was set at p < 0.05. The APT signal showed no significant difference in the fibroglandular breast tissue of healthy premenopausal volunteers throughout the menstrual cycle (p = 1.00) (examination 1 vs. examination 2: mean and standard deviation = 3.24 ± 0.68%Hz vs. 3.30 ± 0.73%Hz, median and IQR = 3.36%Hz and 0.87%Hz vs. 3.38%Hz and 0.71%Hz). The present study provides an important basis for the clinical application of APT CEST-MRI as an additional contrast mechanism in MR-mammography, as menstrual cycle-related APT signal fluctuations seem to be negligible compared to the APT signal increase in breast cancer tissue. • Investigation of the influence of the menstrual cycle on APT CEST-MRI. • Comparison of menstrual cycle-related and breast cancer-related APT signal changes. • APT MR-mammography is not significantly affected by the menstrual cycle. • This study paves the way for reliable clinical application of APT MRI in breast diagnostic. [ABSTRACT FROM AUTHOR]

Purpose: To develop a CEST quantification model to map glutamate concentration in the mouse brain at 11.7 T, overcoming the limitations of conventional glutamate-weighted CEST (gluCEST) contrast (magnetization transfer ratio with asymmetric analysis)., Methods: 1 H-MRS was used as a gold standard for glutamate quantification to calibrate a CEST-based quantitative pipeline. Joint localized measurements of Z-spectra at B 1  = 5 μT and quantitative 1 H-MRS were carried out in two voxels of interest in the mouse brain. A six-pool Bloch-McConnell model was found appropriate to fit experimental data. Glutamate exchange rate was estimated in both regions with this dedicated multi-pool fitting model and using glutamate concentration determined by 1 H-MRS., Results: Glutamate exchange rate was estimated to be ˜1300 Hz in the mouse brain. Using this calibrated value, maps of glutamate concentration in the mouse brain were obtained by pixel-by-pixel fitting of Z-spectra at B 1  = 5 μT. A complementary study of simulations, however, showed that the quantitative model has high sensitivity to noise, and therefore, requires high-SNR acquisitions. Interestingly, fitted [Glu] seemed to be overestimated compared to 1 H-MRS measurements, although it was estimated with simulations that the model has no intrinsic fitting bias with our experimental level of noise. The hypothesis of an unknown proton-exchanging pool contributing to gluCEST signal is discussed., Conclusion: High-resolution mapping of glutamate in the brain was made possible using the proposed calibrated quantification model of gluCEST data. Further studying of the in vivo molecular contributions to gluCEST signal could improve modeling., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Purpose: Dynamic glucose enhanced (DGE) MRI studies employ chemical exchange saturation transfer (CEST) or spin lock (CESL) to study glucose uptake. Currently, these methods are hampered by low effect size and sensitivity to motion. To overcome this, we propose to utilize exchange-based linewidth (LW) broadening of the direct water saturation (DS) curve of the water saturation spectrum (Z-spectrum) during and after glucose infusion (DS-DGE MRI)., Methods: To estimate the glucose-infusion-induced LW changes ( ΔLW ), Bloch-McConnell simulations were performed for normoglycemia and hyperglycemia in blood, gray matter (GM), white matter (WM), CSF, and malignant tumor tissue. Whole-brain DS-DGE imaging was implemented at 3 tesla using dynamic Z-spectral acquisitions (1.2 s per offset frequency, 38 s per spectrum) and assessed on four brain tumor patients using infusion of 35 g of D-glucose. To assess ΔLW , a deep learning-based Lorentzian fitting approach was employed on voxel-based DS spectra acquired before, during, and post-infusion. Area-under-the-curve (AUC) images, obtained from the dynamic ΔLW time curves, were compared qualitatively to perfusion-weighted imaging (PWI)., Results: In simulations, ΔLW was 1.3%, 0.30%, 0.29/0.34%, 7.5%, and 13% in arterial blood, venous blood, GM/WM, malignant tumor tissue, and CSF, respectively. In vivo , ΔLW was approximately 1% in GM/WM, 5-20% for different tumor types, and 40% in CSF. The resulting DS-DGE AUC maps clearly outlined lesion areas., Conclusions: DS-DGE MRI is highly promising for assessing D-glucose uptake. Initial results in brain tumor patients show high-quality AUC maps of glucose-induced line broadening and DGE-based lesion enhancement similar and/or complementary to PWI.

Purpose: The objective of this study was to develop a new MRI technique for non-invasive, free-breathing imaging of glycogen in the human liver using the nuclear Overhauser effect (NOE)., Methods: The proposed method, called GraspNOE-Dixon, uses a novel MRI sequence that combines steady-state saturation-transfer preparation with multi-echo golden-angle radial stack-of-stars sampling. Multi-echo acquisition enables fat/water-separated imaging for quantification of water-specific NOE. Image reconstruction is performed using the improved golden-angle radial sparse parallel imaging (GRASP-Pro) technique to exploit spatiotemporal correlations in dynamic images. To evaluate the proposed technique, imaging experiments were first performed on glycogen phantoms, followed by in vivo studies involving healthy volunteers and patients with fatty liver disease. In addition, a comparative assessment of signal changes before and after a 12-h fasting period was performed., Results: Evaluation experiments on glycogen phantoms showed a robust linear correlation between the NOE signal and glycogen concentration. In vivo experiments demonstrated motion-robust NOE-weighted images, with potential for further acceleration. In subjects with varying liver fat content, the fat/water separation approach resulted in distortion-free Z-spectra, enabling the quantification of glycogen NOE. An approximately one-third reduction in the NOE signal was observed following a 12-h fasting period, consistent with a decrease in glycogen level., Conclusion: This study introduces a clinically feasible imaging technique, GraspNOE-Dixon, for free-breathing volumetric multi-echo imaging of hepatic glycogen at 3 T. The motion robust imaging technique developed here may also have applications in other body areas beyond liver imaging., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Quantitative in-situ pH mapping of gliomas is important for therapeutic interventions, given its significant association with tumor progression, invasion, and metastasis. Although chemical exchange saturation transfer (CEST) offers a noninvasive way for pH imaging based on the pH-dependent exchange rate (k sw ), the reliable quantification of k sw in glioma remains constrained due to technical challenges., Purpose: To quantify the pH of gliomas by measuring the proton exchange rate through optimized omega plot analysis., Study Type: Prospective., Phantoms/animal Model/subjects: Creatine and murine brain lysates phantoms, six rats with glioma xenograft model, and three patients with World Health Organization grade 2-4 gliomas., Field Strength/sequence: 11.7 T, 7.0 T, CEST imaging, T 2 -weighted (T 2 W) imaging, and T 1 -mapping., Assessment: Omega plot analysis, quasi-steady-state (QUASS) analysis, multi-pool Lorentzian fitting, amine and amide concentration-independent detection, pH enhanced method with the combination of amide and guanidyl (pH enh ), and magnetization transfer ratio (MTR) were utilized for pH metric quantification. The clinical outcomes were determined through radiologic follow-up and histopathological analysis., Statistical Tests: Mann-Whitney U test was performed to compare glioma with normal tissue, and Pearson's correlation analysis was used to assess the relationship between k sw and other parameters., Results: In vitro experiments reveal that the determined k sw at 2 ppm increases exponentially with pH (creatine phantoms: k sw  = 106 + 0.147 × 10 (pH-4.198) ; lysates: k sw  = 185.1 + 0.101 × 10 (pH-3.914) ). Omega plot analysis exhibits a linear correlation between 1/MTR Rex and 1/ω 1 2 in the glioma xenografts (R 2  > 0.98) and glioma patients (R 2  > 0.99). The exchange rate in the rat glioma decreases compared to the contralateral normal tissue (349.46 ± 30.40 s -1 vs. 403.54 ± 51.01 s -1 , P = 0.025), while keeping independence from changes in concentration (r = 0.5037, P = 0.095). Similar pattern was observed in human data., Data Conclusion: Utilizing QUASS-based, spillover-, and MT-corrected omega plot analysis for the measurement of exchange rates, offers a feasible method for quantifying pH within glioma., Level of Evidence: NA TECHNICAL EFFICACY: Stage 1., (© 2024 International Society for Magnetic Resonance in Medicine.)

Water plays an important role in many essential biological processes of membrane proteins in hydrated lipid environments. In general, the 1H polarization transfers between water molecules and site-specific protons in proteins can be classified as coherent (via dipolar spin diffusion) and incoherent (via chemical exchange and nuclear Overhauser effect) transfers. Solid-state NMR is the technique of choice for studying such water-protein interactions in membrane-bound proteins/peptides through the detection of 1H polarization transfers from water to the proteins. These polarization transfer mechanisms often exist simultaneously and are difficult to quantify individually. Here, we review water-protein polarization transfer techniques in solid-state NMR, with a focus on the recent progress for the direct detection of site-specific kinetic water-protein chemical exchange processes on the sub-millisecond time scale in membrane-bound proteins. The measurements of the pure chemical exchange kinetics provide a unique opportunity to understand the role that water plays in the structure-function relationships of membrane-bound species at the water-bilayer interface. In addition, the perspective of chemical exchange saturation transfer (CEST) experiments in membrane-bound proteins/peptides is further discussed.

Purpose: In many pulse sequences of chemical exchange-sensitive MRI including multi-slice chemical exchange saturation transfer (CEST) or chemical exchange sensitive spin-lock (CESL), there is a finite time delay between the irradiation preparation and the imaging acquisition, during which the T1-relaxation reduces the chemical exchange contrast and affects the accuracy for volumetric imaging. We propose a simple post-acquisition method to correct this contamination.Methods: A simple formula was derived to evaluate the cross-slice T1-relaxation contamination in multi-slice echo-planar imaging (EPI) after the irradiation preparation. CEST and CESL experiments were performed on phantoms to examine the accuracy of this approach.Results: Theoretical derivation showed that the cross-slice T1-relaxation contamination in multi-slice EPI imaging can be corrected by the signals of each slice at a parameter that suppresses the signal, e.g., at the water frequency for CEST, or with very long spin-lock pulse for CESL. This formula was confirmed by the results of phantom experiments, for both long and short irradiation durations with and without a steady-state, respectively. To minimize the effect of B0 inhomogeneity in the CEST experiment, a more accurate measurement of the signal at water frequency can be achieved with a higher pulse power and shorter duration.Conclusion: We proposed and validated a simple approach to correct the cross-slice T1-relaxation effect, which can be applied to volumetric CEST and CESL studies acquired by multi-slice EPI, or other imaging modalities with similar T1-relaxation contamination.

Based on in silico, in situ, and in vivo studies, this study aims to develop a new method for the quantitative chemical exchange saturation transfer (qCEST) technique considering multi-pool systems. To this end, we extended the state-of-the-art apparent exchange-dependent relaxation (AREX) method with a Lorentzian correction (LAREX). We then validated this new method with in situ and in vivo experiments on human intervertebral discs (IVDs) using the Kendall-Tau correlation coefficient. In the in silico experiments, we observed significant deviations of the AREX method as a function of the underlying exchange rate (kba) and fractional concentration (fb) compared to the ground truth due to the influence of other exchange pools. In comparison to AREX, the LAREX-based Ω-plot approach yielded a substantial improvement. In the subsequent in situ and in vivo experiments on human IVDs, no correlation to the histological reference standard or Pfirrmann classification could be found for the fb (in situ: τ = −0.17 p = 0.51; in vivo: τ = 0.13 p = 0.30) and kba (in situ: τ = 0.042 p = 0.87; in vivo: τ = −0.26 p = 0.04) of Glycosaminoglycan (GAG) with AREX. In contrast, the influence of interfering pools could be corrected by LAREX, and a moderate to strong correlation was observed for the fractional concentration of GAG for both in situ (τ = −0.71 p = 0.005) and in vivo (τ = −0.49 p < 0.001) experiments. The study presented here is the first to introduce a new qCEST method that enables qCEST imaging in systems with multiple proton pools. [ABSTRACT FROM AUTHOR]

To assess the performance of two point (2-pt) Dixon-based chemical exchange saturation transfer (CEST) imaging for fat suppression in renal transplant patients. The 2-pt Dixon-based CEST MRI was validated in an egg-phantom and in fourteen renal transplant recipients (5 females and 9 males; age range: 23–78 years; mean age: 51 ± 16.8). All CEST experiments were performed on a 3 T clinical MRI scanner using a dual-echo CEST sequence. The 2-pt Dixon technique was applied to generate water-only CEST images at different frequency offsets, which were further used to calculate the z-spectra. The magnetization transfer ratio asymmetry (MTR asym) values in the frequency ranges of hydroxyl, amine and amide protons were estimated in the renal cortex and medulla. Results of the in vitro experiments suggest that the 2-pt Dixon technique enables effective fat peak removal and does not introduce additional asymmetries to the z-spectrum. Accordingly, our results in vivo show that the fat-corrected amide proton transfer (APT) effect in the kidney is significantly higher compared to that obtained from the CEST data acquired close to the in-phase condition both in the renal cortex (−0.1 [0.7] vs. −0.7 [1.2], P = 0.029) and medulla (0.3 [0.8] vs. 0.01 [1.3], P = 0.049), indicating that the 2-pt Dixon-based CEST method increases the specificity of the APT contrast by correcting the fat-induced artifacts. Combination of the dual-echo CEST acquisition with Dixon post-processing provides effective water-fat separation, allowing more accurate quantification of the APT CEST effect in the transplanted kidney. • Amide Proton Transfer (APT) imaging of the kidney is affected by fat-induced artifacts. • Two point Dixon-based MRI increases the specificity of APT contrast in the human kidney. • Highest CEST effect in the renal tissue is observed at a frequency offset of about 1 ppm. [ABSTRACT FROM AUTHOR]

Purpose: Endogenous CEST signal usually has low specificity due to contamination from the magnetization transfer effect and from fast exchanging labile protons with close Larmor frequencies. We propose to improve CEST signal specificity with an average saturation efficiency filter (ASEF). Methods: ASEF measures the difference between CEST signals acquired with similar average irradiation power but largely different duty cycles (DC), for example, a continuous wave or a high DC pulse train versus a low DC one. Simulation and Cr phantom studies were performed to evaluate the characteristics of ASEF for CEST. Results: Theoretical and simulation studies show that ASEF can suppress fast exchanging processes, with only a small loss of chemical exchange contrast for slow‐to‐intermediate exchange rates if the difference in DC is large. In the RF offset range of 2 to 5 ppm with an averaged saturation power of 0.8 and 1.6 microteslas, there is a mismatch of ∼0.1% to 2% in the magnetization transfer signal between saturation by continuous wave and a pulse train with DC = 15% and pulse duration of 24 ms, respectively. This mismatch can be minimized by careful selection of saturation power, pulse duration, and DC differences or by applying a small fudge factor between the 2 irradiation powers. Phantom studies of Cr confirmed that ASEF can minimize the magnetization transfer effect and reduce sensitivity to fast exchange processes. Conclusion: ASEF can improve the specificity of slow‐to‐intermediate exchanging CEST signal with a relatively small loss of sensitivity. [ABSTRACT FROM AUTHOR]

Based on in silico, in vitro, in situ, and in vivo evaluations, this study aims to establish and optimize the chemical exchange saturation transfer (CEST) imaging of lactate (Lactate-CEST—LATEST). To this end, we optimized LATEST sequences using Bloch–McConnell simulations for optimal detection of lactate with a clinical 3 T MRI scanner. The optimized sequences were used to image variable lactate concentrations in vitro (using phantom measurements), in situ (using nine human cadaveric lower leg specimens), and in vivo (using four healthy volunteers after exertional exercise) that were then statistically analyzed using the non-parametric Friedman test and Kendall Tau-b rank correlation. Within the simulated Bloch–McConnell equations framework, the magnetization transfer ratio asymmetry (MTRasym) value was quantified as 0.4% in the lactate-specific range of 0.5–1 ppm, both in vitro and in situ, and served as the imaging surrogate of the lactate level. In situ, significant differences (p < 0.001) and strong correlations (τ = 0.67) were observed between the MTRasym values and standardized intra-muscular lactate concentrations. In vivo, a temporary increase in the MTRasym values was detected after exertional exercise. In this bench-to-bedside comprehensive feasibility study, different lactate concentrations were detected using an optimized LATEST imaging protocol in vitro, in situ, and in vivo at 3 T, which prospectively paves the way towards non-invasive quantification and monitoring of lactate levels across a broad spectrum of diseases. [ABSTRACT FROM AUTHOR]

Macromolecules often exchange between functional states on timescales that can be accessed with NMR spectroscopy and many NMR tools have been developed to characterise the kinetics and thermodynamics of the exchange processes, as well as the structure of the conformers that are involved. However, analysis of the NMR data that report on exchanging macromolecules often hinges on complex least-squares fitting procedures as well as human experience and intuition, which, in some cases, limits the widespread use of the methods. The applications of deep neural networks (DNNs) and artificial intelligence have increased significantly in the sciences, and recently, specifically, within the field of biomolecular NMR, where DNNs are now available for tasks such as the reconstruction of sparsely sampled spectra, peak picking, and virtual decoupling. Here we present a DNN for the analysis of chemical exchange saturation transfer (CEST) data reporting on two- or three-site chemical exchange involving sparse state lifetimes of between approximately 3–60 ms, the range most frequently observed via experiment. The work presented here focuses on the 1H CEST class of methods that are further complicated, in relation to applications to other nuclei, by anti-phase features. The developed DNNs accurately predict the chemical shifts of nuclei in the exchanging species directly from anti-phase 1HN CEST profiles, along with an uncertainty associated with the predictions. The performance of the DNN was quantitatively assessed using both synthetic and experimental anti-phase CEST profiles. The assessments show that the DNN accurately determines chemical shifts and their associated uncertainties. The DNNs developed here do not contain any parameters for the end-user to adjust and the method therefore allows for autonomous analysis of complex NMR data that report on conformational exchange. [ABSTRACT FROM AUTHOR]

PurposePrevious studies have associated low pH in intervertebral discs (IVDs) with discogenic back pain. The purpose of this study was to determine whether quantitative CEST (qCEST) MRI can be used to detect pH changes in IVDs in vivo.MethodsThe exchange rate ksw between glycosaminoglycan (GAG) protons and water protons was determined from qCEST analysis. Its dependence on pH value was investigated in GAG phantoms with varying pH and concentrations. The relationship between ksw and pH was studied further in vivo in a porcine model on a 3T MR scanner and validated using a pH meter. Sodium lactate was injected into the IVDs to induce various pH values within the discs ranging from 5 to 7.ResultsPhantom and animal results revealed that ksw measured using qCEST MRI is highly correlated with pH level. In the animal studies, the relationship can be described as ksw  =9.2 × 106 × 10-pH + 196.9, R2  = 0.7883.ConclusionThe exchange rate between GAG and water protons determined from qCEST MRI is closely correlated with pH value. This technique has the potential to noninvasively measure pH in the IVDs of patients with discogenic pain. Magn Reson Med 76:1677-1683, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

ABSTRACT The cell envelope of Gram-negative bacteria is a complex structure, essential for bacterial survival and for resistance to many antibiotics. Channels that cross the bacterial envelope and the host cell membrane form secretion systems that are activated upon attachment to host, enabling bacteria to inject effector molecules into the host cell, required for bacterium-host interaction. The type III secretion system (T3SS) is critical for the virulence of several pathogenic bacteria, including enteropathogenic Escherichia coli (EPEC). EPEC T3SS activation is associated with repression of carbon storage regulator (CsrA), resulting in gene expression remodeling, which is known to affect EPEC central carbon metabolism and contributes to the adaptation to a cell-adherent lifestyle in a poorly understood manner. We reasoned that the changes in the bacterial envelope upon attachment to the host and the activation of a secretion system may involve a modification of the lipid composition of bacterial envelope. Accordingly, we performed a lipidomics analysis on mutant strains that simulate T3SS activation. We saw a shift in glycerophospholipid metabolism toward the formation of lysophospholipids, attributed to corresponding upregulation of the phospholipase gene pldA and the acyltransferase gene ygiH upon T3SS activation in EPEC. We also detected a shift from menaquinones and ubiquinones to undecaprenyl lipids, concomitant with abnormal synthesis of O antigen. The remodeling of lipid metabolism is mediated by CsrA and associated with increased bacterial cell size and zeta potential and a corresponding alteration in EPEC permeability to vancomycin, increasing the sensitivity of T3SS-activated strains and of adherent wild-type EPEC to the antibiotic. IMPORTANCE The characterization of EPEC membrane lipid metabolism upon attachment to the host is an important step toward a better understanding the shift of EPEC, a notable human pathogen, from a planktonic to adherent lifestyle. It may also apply to other pathogenic bacteria that use this secretion system. We predict that upon attachment to host cells, the lipid remodeling upon T3SS activation contributes to bacterial fitness and promotes host colonization, and we show that it is associated with increased cell permeability and higher sensitivity to vancomycin. To the best of our knowledge, this is the first demonstration of a bacterial lipid remodeling due to activation of a secretion system.

Upper urinary tract obstructions (UTOs) are blockages that inhibit the flow of urine through its normal course, leading to impaired kidney function. Imaging plays a significant role in the initial diagnosis of UTO, with anatomic imaging (primarily ultrasound (US) and non-contrast computed tomography (CT)) serving as screening tools for the detection of the dilation of the urinary collecting systems (i.e., hydronephrosis). Whether hydronephrosis represents UTO or a non-obstructive process is determined by functional imaging (typically nuclear medicine renal scintigraphy). If these exams reveal evidence of UTO but no discernable source, multiphase contrast enhanced CT urography and/or dynamic contrast enhanced MR urography (DCE-MRU) may be performed to delineate a cause. These are often performed in conjunction with direct ureteroscopic evaluation. While contrast-enhanced CT currently predominates, it can induce renal injury due to contrast induced nephropathy (CIN), subject patients to ionizing radiation and is limited in quantifying renal function (traditionally assessed by renal scintigraphy) and establishing the extent to which hydronephrosis is due to functional obstruction. Traditional MRI is similarly limited in its ability to quantify function. DCE-MRU presents concerns regarding nephrogenic systemic fibrosis (NSF), although decreased with newer gadolinium-based contrast agents, and regarding cumulative gadolinium deposition in the basal ganglia. DCE-MR CEST urography is a promising alternative, employing new MRI contrast agents and imaging schemes and allowing for concurrent assessment of renal anatomy and functional parameters. In this review we highlight clinical challenges in the diagnosis and management of UTO, identify key advances in imaging agents and techniques for DCE-MR CEST urography and provide perspective on how this technique may evolve in clinical importance.

Multimodal imaging has emerged as a powerful tool in biomedical research and clinical diagnostics. Ideally, it combines multiple imaging techniques to provide complementary anatomical and molecular information in living subjects. Particularly desirable are multimodal imaging probes capable of providing differential diagnostic signals upon interaction with specific molecular targets. Hydrogen peroxide (H 2 O 2) is a key target in this regard, since it is typically overexpressed in cancer cells. In this study, we present a small-molecule probe that not only selectively detects endogenous H 2 O 2 through multimodal imaging, with a significant H 2 O 2 -triggered 15-fold fluorescence enhancement but also turns "on" a chemical exchange saturation transfer (CEST) magnetic resonance (MR) response with 60-fold signal enhancement at pH 7.4. Excellent selectivity against various other biologically relevant species is seen. Using this probe, we observed 3.4–4.5-fold and 2.8–5.8-fold higher H 2 O 2 levels in cancerous cell lines and tumor tissues compared to normal cell lines and tissues, respectively. Time-dependent in vivo fluorescence and CEST imaging in a HeLa (Henrietta Lacks) tumor xenograft mouse model revealed probe-dependent tumor detection by fluorescence and CEST MRI contrast in the tumor area. These observations are attributed to the relatively high endogenous H 2 O 2 levels produced during mitosis. This newly developed probe holds promise for advancing our understanding of H 2 O 2 -related biology and for cancer detection both in vitro and in vivo. [Display omitted] • Novel H 2 O 2 -activatable probe: Enables NIR fluorescence & CEST MRI imaging in tumors • Key features: Photo-stability, selective NIR fluorescence, distinct CEST peak shift • Substantial Stokes shift, nontoxic, lower detection limit, highly sensitive • Clinical potential: Selective detection of endogenous H 2 O 2 in cancer cells • Promising for early cancer detection and treatment [ABSTRACT FROM AUTHOR]

[Display omitted] • The transverse relaxation rate of the minor state resonance R 2 , B plays a critical role in determining the B 1 fields that lead to the most informative CEST datasets. • To obtain accurate exchange parameters, K = k ex k ex + R 2 , B 1 2 rather than the exchange rate (k ex) should guide the choice of B 1 (~0.7K & ~1.7K) fields used to record CEST experiments. • When R 2 , B is greater than k ex , CEST datasets recorded with 'large' B 1 fields ≫ k e x / 2 π are required to obtain accurate exchange parameters. Over the last decade chemical exchange saturation transfer (CEST) NMR methods have emerged as powerful tools to characterize biomolecular conformational dynamics occurring between a visible major state and 'invisible' minor states. The ability of the CEST experiment to detect these minor states, and provide precise exchange parameters, hinges on using appropriate B 1 field strengths during the saturation period. Typically, a pair of B 1 fields with ω 1 (= 2 π B 1) values around the exchange rate k ex are chosen. Here we show that the transverse relaxation rate of the minor state resonance (R 2 , B) also plays a crucial role in determining the B 1 fields that lead to the most informative datasets. Using K = k ex k ex + R 2 , B 1 2 ≥ k ex , to guide the choice of B 1 , instead of k ex , leads to data wherefrom substantially more accurate exchange parameters can be derived. The need for higher B 1 fields, guided by K , is demonstrated by studying the conformational exchange in two mutants of the 71 residue FF domain with k e x ∼ 11 s−1 and ∼ 72 s−1, respectively. In both cases analysis of CEST datasets recorded using B 1 field values guided by k e x lead to imprecise exchange parameters, whereas using B 1 values guided by K resulted in precise site-specific exchange parameters. The conclusions presented here will be valuable while using CEST to study slow processes at sites with large intrinsic relaxation rates, including carbonyl sites in small to medium sized proteins, amide 15N sites in large proteins and when the minor state dips are broadened due to exchange among the minor states. [ABSTRACT FROM AUTHOR]

Chemical exchange saturation transfer (CEST) is one of the molecular magnetic resonance imaging (MRI) techniques that indirectly measures low-concentration metabolite or free protein signals that are difficult to detect by conventional MRI techniques. We applied CEST to Alzheimer's disease (AD) and analyzed both region of interest (ROI) and pixel dimensions. Through the analysis of the ROI dimension, we found that the content of glutamate in the brains of AD mice was higher than that of normal mice of the same age. In the pixel-dimensional analysis, we obtained a map of the distribution of glutamate in the mouse brain. According to the experimental data of this study, we designed an algorithm framework based on data migration and used Resnet neural network to classify the glutamate distribution images of AD mice, with an accuracy rate of 75.6%. We evaluate the possibility of glutamate imaging as a biomarker for AD detection for the first time, with important implications for the detection and treatment of AD. [ABSTRACT FROM AUTHOR]

Chemical exchange saturation transfer (CEST) imaging is a non-invasive molecular imaging technique for indirectly measuring low-concentration endogenous metabolites. Conventional CEST has low specificity, owing to the effects of spillover, magnetization transfer (MT), and T1 relaxation, thus necessitating an inverse Z-spectrum analysis. We aimed to investigate the usefulness of inverse Z-spectrum analysis in creatine (Cr)-CEST in mice, by conducting preclinical 7T-magnetic resonance imaging (MRI) and comparing the conventional analysis metric magnetization transfer ratio (MTRconv) with the novel metric apparent exchange-dependent relaxation (AREX). We performed Cr-CEST imaging using 7T-MRI on mouse testes, using C57BL/6 mice as the control and a cisplatin-treated model. We prepared different doses of cisplatin to observe its dose dependence effect on testicular function. CEST imaging was obtained using an MT pulse with varying saturation frequencies, ranging from −4.8 ppm to +4.8 ppm. The application of control mouse testes improved the specificity of the CEST effect and image contrast between the testes and testicular epithelium. The cisplatin-treated model revealed impaired testicular function, and the Cr-CEST imaging displayed decreased Cr levels in the testes. There was a significant difference between the low- and high-dose models. The MTR values of Cr-CEST reflected the cisplatin dose dependence of testicular dysfunction. [ABSTRACT FROM AUTHOR]

Magnetization transfer contrast MR fingerprinting (MTC‐MRF) is a novel quantitative imaging method that simultaneously quantifies free bulk water and semisolid macromolecule parameters using pseudo‐randomized scan parameters. To improve acquisition efficiency and reconstruction accuracy, the optimization of MRF sequence design has been of recent interest in the MRF field, but has been challenging due to the large number of degrees of freedom to be optimized in the sequence. Herein, we propose a framework for learning‐based optimization of the acquisition schedule (LOAS), which optimizes RF saturation‐encoded MRF acquisitions with a minimal number of scan parameters for tissue parameter determination. In a supervised learning framework, scan parameters were subsequently updated to minimize a predefined loss function that can directly represent tissue quantification errors. We evaluated the performance of the proposed approach with a numerical phantom and in in vivo experiments. For validation, MRF images were synthesized using the tissue parameters estimated from a fully connected neural network framework and compared with references. Our results showed that LOAS outperformed existing indirect optimization methods with regard to quantification accuracy and acquisition efficiency. The proposed LOAS method could be a powerful optimization tool in the design of MRF pulse sequences. [ABSTRACT FROM AUTHOR]

A relationship between an acidic pH in the joints, osteoarthritis (OA), and pain has been previously demonstrated. Acidosis Chemical Exchange Saturation Transfer (acidoCEST) indirectly measures the extracellular pH through the assessment of the exchange of protons between amide groups on iodinated contrast agents and bulk water. It is possible to estimate the extracellular pH in the osteoarthritic joint using acidoCEST MRI. However, conventional MR sequences cannot image deep layers of cartilage, meniscus, ligaments, and other musculoskeletal tissues that present with short echo time and fast signal decay. Ultrashort echo time (UTE) MRI, on the other hand, has been used successfully to image those joint tissues. Here, our goal is to compare the pH measured in the knee joints of volunteers without OA and patients with severe OA using acidoCEST-UTE MRI. Patients without knee OA and patients with severe OA were examined using acidoCEST-UTE MRI and the mean pH of cartilage, meniscus, and fluid was calculated. Additionally, the relationship between the pH measurements and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was investigated. AcidoCEST-UTE MRI can detect significant differences in the pH of knee cartilage, meniscus, and fluid between joints without and with OA, with OA showing lower pH values. In addition, symptoms and knee-joint function become worse at lower pH measurements. [ABSTRACT FROM AUTHOR]

Purpose: To identify a reliable metric for predicting the encoding capability of CEST MR fingerprinting acquisition schedules for pH quantification, which may facilitate CEST MR fingerprinting protocol optimization. Methods: Numerical simulations and Cr phantom MRI experiments were conducted at 3 Tesla under representative CEST MR fingerprinting sampling scenarios, including the pseudorandomization of imaging parameters (e.g., saturation power B1, saturation frequency offset, saturation time, and relaxation time), and variation of the maximum saturation power B1max, B1 number, and sampling pattern. The CEST effect at 2 ppm was measured using asymmetry analysis and matched to a predefined dictionary to determine the pH. The pH quantification error was assessed using RMSE. Three metrics, namely the Cramer‐Rao bound, dot product, and Euclidean distance, were calculated for each sampling scenario, and their relationships with the pH RMSE were investigated to examine their effectiveness for predicting the encoding capability of sampling schedules for pH quantification. Results: Both simulation and phantom studies revealed that the Cramer‐Rao bound metric consistently exhibited superior performance for predicting the pH quantification error. Although dot product exhibited good encoding capability prediction in most sampling scenarios, it failed in the scenario with varied B1 numbers. In contrast, Euclidean distance exhibited the worst performance among the 3 metrics in all scenarios. Conclusion: Superior over dot product and Euclidean distance, the Cramer‐Rao bound metric may reliably predicting the encoding capability of CEST MR fingerprinting sampling strategies and may be useful for guiding CEST MRI protocol optimization. [ABSTRACT FROM AUTHOR]

The nucleocapsid domain (NCd), located at the C-terminus of the HIV-1 Gag protein, is involved in numerous stages of the replication cycle, such as the packaging of the viral genome and reverse transcription. It exists under different forms through the viral life cycle, depending on the processing of Gag by the HIV-1 protease. NCd is constituted of two adjacent zinc knuckles (ZK1 and ZK2), separated by a flexible linker and flanked by disordered regions. Here, conformational equilibria between a major and two minor states were highlighted exclusively in ZK2, by using CPMG and CEST NMR experiments. These minor states appear to be temperature dependent, and their populations are highest at physiological temperature. These minor states are present both in NCp7, the mature form of NCd, and in NCp9 and NCp15, the precursor forms of NCd, with increased populations. The role of these minor states in the targeting of NCd by drugs and its binding properties is discussed. [ABSTRACT FROM AUTHOR]

In recent years, various quantitative and functional magnetic resonance imaging (MRI) sequences have been developed and used in clinical practice for the diagnosis of patients with low back pain (LBP). Until now, T2-weighted imaging (T2WI), a visual qualitative evaluation method, has been used to diagnose intervertebral disc (IVD) degeneration. However, this method has limitations in terms of reproducibility and inter-observer agreement. Moreover, T2WI observations do not directly relate with LBP. Therefore, new sequences such as T2 mapping, T1ρ mapping, and MR spectroscopy have been developed as alternative quantitative evaluation methods. These new quantitative MRIs can evaluate the anatomical and physiological changes of IVD degeneration in more detail than conventional T2WI. However, the values obtained from these quantitative MRIs still do not directly correlate with LBP, and there is a need for more widespread use of techniques that are more specific to clinical symptoms such as pain. In this paper, we review the state-of-the-art methodologies and future challenges of quantitative MRI as an imaging diagnostic tool for IVD degeneration and painful discs. [ABSTRACT FROM AUTHOR]

Natural and synthetic sugars have great potential for developing highly biocompatible and translatable chemical exchange saturation transfer (CEST) MRI contrast agents. In this study, we aimed to develop the smallest clinically available form of dextran, Dex1 (molecular weight, MW ~ 1 kDa), as a new CEST agent. We first characterized the CEST properties of Dex1 in vitro at 11.7 T and showed that the Dex1 had a detectable CEST signal at ~1.2 ppm, attributed to hydroxyl protons. In vivo CEST MRI studies were then carried out on C57BL6 mice bearing orthotopic GL261 brain tumors (n = 5) using a Bruker BioSpec 11.7 T MRI scanner. Both steady‐state full Z‐spectral images and single offset (1.2 ppm) dynamic dextran‐enhanced (DDE) images were acquired before and after the intravenous injection of Dex1 (2 g/kg). The steady‐state Z‐spectral analysis showed a significantly higher CEST contrast enhancement in the tumor than in contralateral brain (∆MTRasym1.2 ppm = 0.010 ± 0.006 versus 0.002 ± 0.008, P = 0.0069) at 20 min after the injection of Dex1. Pharmacokinetic analyses of DDE were performed using the area under the curve (AUC) in the first 10 min after Dex1 injection, revealing a significantly higher uptake of Dex1 in the tumor than in brain tissue for tumor‐bearing mice (AUC[0‐10 min] = 21.9 ± 4.2 versus 5.3 ± 6.4%·min, P = 0.0294). In contrast, no Dex1 uptake was foundling in the brains of non‐tumor‐bearing mice (AUC[0‐10 min] = −1.59 ± 2.43%·min). Importantly, the CEST MRI findings were consistent with the measurements obtained using DCE MRI and fluorescence microscopy, demonstrating the potential of Dex1 as a highly translatable CEST MRI contrast agent for assessing tumor hemodynamics. [ABSTRACT FROM AUTHOR]

Chemical exchange saturation transfer (CEST) is one of the molecular magnetic resonance imaging (MRI) techniques that indirectly measures low-concentration metabolite or free protein signals that are difficult to detect by conventional MRI techniques. We applied CEST to Alzheimer’s disease (AD) and analyzed both region of interest (ROI) and pixel dimensions. Through the analysis of the ROI dimension, we found that the content of glutamate in the brains of AD mice was higher than that of normal mice of the same age. In the pixel-dimensional analysis, we obtained a map of the distribution of glutamate in the mouse brain. According to the experimental data of this study, we designed an algorithm framework based on data migration and used Resnet neural network to classify the glutamate distribution images of AD mice, with an accuracy rate of 75.6%. We evaluate the possibility of glutamate imaging as a biomarker for AD detection for the first time, with important implications for the detection and treatment of AD.

Purpose: To implement rosette readout trajectories with compressed sensing reconstruction for fast and motion-robust CEST and magnetization transfer contrast imaging with inherent correction of B 0 inhomogeneity., Methods: A pulse sequence was developed for fast saturation transfer imaging using a stack of rosette trajectories with a higher sampling density near the k-space center. Each rosette lobe was segmented into two halves to generate dual-echo images. B 0 inhomogeneities were estimated using the phase difference between the images and corrected subsequently. The rosette-based imaging was evaluated in comparison to a fully sampled Cartesian trajectory and demonstrated on CEST phantoms (creatine solutions and egg white) and healthy volunteers at 3 T., Results: Compared with the conventional Cartesian acquisition, compressed sensing reconstructed rosette images provided image quality with overall higher contrast-to-noise ratio and significantly faster readout time. Accurate B 0 map estimation was achieved from the rosette acquisition with a negligible bias of 0.01 Hz between the rosette and dual-echo Cartesian gradient echo B 0 maps, using the latter as ground truth. The water-saturation spectra (Z-spectra) and amide proton transfer weighted signals obtained from the rosette-based sequence were well preserved compared with the fully sampled data, both in the phantom and human studies., Conclusions: Fast, motion-robust, and inherent B 0 -corrected CEST and magnetization transfer contrast imaging using rosette trajectories could improve subject comfort and compliance, contrast-to-noise ratio, and provide inherent B 0 homogeneity information. This work is expected to significantly accelerate the translation of CEST-MRI into a robust, clinically viable approach., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Chemical exchange saturation transfer (CEST) MRI at 3 T suffers from low specificity due to overlapping CEST effects from multiple metabolites, while higher field strengths (B 0 ) allow for better separation of Z-spectral "peaks," aiding signal interpretation and quantification. However, data acquisition at higher B 0 is restricted by equipment access, field inhomogeneity and safety issues. Herein, we aim to synthesize higher-B 0 Z-spectra from readily available data acquired with 3 T clinical scanners using a deep learning framework. Trained with simulation data using models based on Bloch-McConnell equations, this framework comprised two deep neural networks (DNNs) and a singular value decomposition (SVD) module. The first DNN identified B 0 shifts in Z-spectra and aligned them to correct frequencies. After B 0 correction, the lower-B 0 Z-spectra were streamlined to the second DNN, casting into the key feature representations of higher-B 0 Z-spectra, obtained through SVD truncation. Finally, the complete higher-B 0 Z-spectra were recovered from inverse SVD, given the low-rank property of Z-spectra. This study constructed and validated two models, a phosphocreatine (PCr) model and a pseudo-in-vivo one. Each experimental dataset, including PCr phantoms, egg white phantoms, and in vivo rat brains, was sequentially acquired on a 3 T human and a 9.4 T animal scanner. Results demonstrated that the synthetic 9.4 T Z-spectra were almost identical to the experimental ground truth, showing low RMSE (0.11% ± 0.0013% for seven PCr tubes, 1.8% ± 0.2% for three egg white tubes, and 0.79% ± 0.54% for three rat slices) and high R 2 (>0.99). The synthesized amide and NOE contrast maps, calculated using the Lorentzian difference, were also well matched with the experiments. Additionally, the synthesis model exhibited robustness to B 0 inhomogeneities, noise, and other acquisition imperfections. In conclusion, the proposed framework enables synthesis of higher-B 0 Z-spectra from lower-B 0 ones, which may facilitate CEST MRI quantification and applications., (© 2024 John Wiley & Sons Ltd.)

Background: The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin scale (mRS) scores have important shortcomings. Amide proton transfer-weighted (APTw) imaging might offer more valuable information in ischemic strokes assessment., Purpose: To utilize APTw, apparent diffusion coefficient (ADC), and computed tomography perfusion (CTP) for the assessment of clinical symptom severity and 90-day prognosis in patients diagnosed with ischemic stroke., Study Type: Prospective., Subjects: 61 patients (mean age 63.2 ± 9.7 years; 46 males, 15 females) with ischemic strokes were included in the study., Field Strength/sequence: 3T/turbo spin echo (TSE) T 1 -weighted imaging, T 2 -weighted imaging, T 2 -fluid attenuated inversion recovery (T 2 -FLAIR), diffusion-weighted imaging (DWI), and single-shot TSE APTw imaging., Assessment: APTw, ADC, and CTP were used to compare patient subgroups and construct a prognostic nomogram model., Statistical Tests: Kolmogorov-Smirnov test, t-test, Mann-Whitney U test, chi-square test, Pearson correlation analysis, multivariate logistic regression analysis, decision curve analysis (DCA), receiver operating characteristic curves (ROCs). The significance threshold was set at P < 0.05., Results: Correlation analysis revealed that APTw and NIHSS exhibit the highest correlation (r = -0.634, 95% confidence interval [CI] -0.418 to -0.782), surpassing that of ADC and lesion size. Multivariable analysis revealed APTw (odds ratio [OR] 0.905, 95% CI 0.845-0.970), ADC (OR 0.745, 95% CI 0.609-0.911), and infarct core-cerebral blood volume (IC-CBV) (OR 0.547, 95% CI 0.310-0.964) as potential risk factors associated with a poor prognosis. The nomogram model demonstrated the highest predictive efficacy, with an area under the curve (AUC) of 0.960 (95% CI 0.911-0.988), exceeding that of APTw, ADC, and IC-CBV individually., Data Conclusion: The APTw technique holds potential value in categorizing and managing patients with ischemic stroke, offering guidance for the implementation of clinical treatment strategies., Level of Evidence: 1 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Acidity within the extracellular milieu is a hallmark of cancer. There is a current need for fast, high spatial resolution pH imaging techniques for clinical evaluation of cancers, including gliomas. Chemical exchange saturation transfer (CEST) MRI targeting fast-exchanging amine protons can be used to obtain high-resolution pH-weighted images, but conventional CEST acquisition strategies are slow. There is also a need for more accurate MR simulations to better understand the effects of amine CEST pulse sequence parameters on pH-weighted image contrast. In the current study we present a simulation of amine CEST contrast specific for a newly developed CEST echoplanar imaging (EPI) pulse sequence. The accuracy of the simulations was validated by comparing the exchange rates and Z-spectrum under a variety of conditions using physical phantoms of glutamine with different pH values. The effects of saturation pulse shapes, pulse durations, pulse train lengths, repetition times, and relaxation rates of bulk water and exchangeable amine protons on the CEST signal were explored for normal-appearing white matter (NAWM), glioma, and cerebrospinal fluid. Last, 18 patients with WHO II-IV gliomas were evaluated. Results showed that the Z-spectrum was highly dependent on saturation pulse shape, repetition time, saturation amplitude, magnetic field strength, and T2 within bulk water; however, the Z-spectrum was only minimally influenced by saturation pulse duration and the specific relaxation rates of amine protons. Results suggest that a Gaussian saturation pulse train consisting of 3 × 100 ms pulses using the minimum allowable repetition time is optimal for achieving over 90% available contrast across all tissues. Results also demonstrate that high saturation pulse amplitude and scanner field strength (>3 T) are necessary for adequate endogenous pH-weighted amine CEST contrast. pH-weighted amine CEST contrast increased with increasing tumor grade, with glioblastoma showing significantly higher contrast compared with WHO II or III gliomas.

Objective: To summarize evidence for use of advanced MRI techniques as monitoring biomarkers in the clinic, and to highlight the latest bench-to-bedside developments. Methods: The current evidence regarding the potential for monitoring biomarkers was reviewed and individual modalities of metabolism and/or chemical composition imaging discussed. Perfusion, permeability, and microstructure imaging were similarly analyzed in Part 1 of this two-part review article and are valuable reading as background to this article. We appraise the clinic readiness of all the individual modalities and consider methodologies involving machine learning (radiomics) and the combination of MRI approaches (multiparametric imaging). Results: The biochemical composition of high-grade gliomas is markedly different from healthy brain tissue. Magnetic resonance spectroscopy allows the simultaneous acquisition of an array of metabolic alterations, with choline-based ratios appearing to be consistently discriminatory in treatment response assessment, although challenges remain despite this being a mature technique. Promising directions relate to ultra-high field strengths, 2-hydroxyglutarate analysis, and the use of non-proton nuclei. Labile protons on endogenous proteins can be selectively targeted with chemical exchange saturation transfer to give high resolution images. The body of evidence for clinical application of amide proton transfer imaging has been building for a decade, but more evidence is required to confirm chemical exchange saturation transfer use as a monitoring biomarker. Multiparametric methodologies, including the incorporation of nuclear medicine techniques, combine probes measuring different tumor properties. Although potentially synergistic, the limitations of each individual modality also can be compounded, particularly in the absence of standardization. Machine learning requires large datasets with high-quality annotation; there is currently low-level evidence for monitoring biomarker clinical application. Conclusion: Advanced MRI techniques show huge promise in treatment response assessment. The clinical readiness analysis highlights that most monitoring biomarkers require standardized international consensus guidelines, with more facilitation regarding technique implementation and reporting in the clinic. [ABSTRACT FROM AUTHOR]

Objective: Clinical application of chemical exchange saturation transfer (CEST) can be performed with investigation of amide proton transfer (APT) and nuclear Overhauser enhancement (NOE) effects. Here, we investigated APT- and NOE-weighted imaging based on advanced CEST metrics to map tumor heterogeneity of non-enhancing glioma at 3 T. Materials and methods: APT- and NOE-weighted maps based on Lorentzian difference (LD) and inverse magnetization transfer ratio (MTRREX) were acquired with a 3D snapshot CEST acquisition at 3 T. Saturation power was investigated first by varying B1 (0.5–2 µT) in 5 healthy volunteers then by applying B1 of 0.5 and 1.5 µT in 10 patients with non-enhancing glioma. Tissue contrast (TC) and contrast-to-noise ratios (CNR) were calculated between glioma and normal appearing white matter (NAWM) and grey matter, in APT- and NOE-weighted images. Volume percentages of the tumor showing hypo/hyperintensity (VPhypo/hyper,CEST) in APT/NOE-weighted images were calculated for each patient. Results: LD APT resulting from using a B1 of 1.5 µT was found to provide significant positive TCtumor,NAWM and MTRREX NOE (B1 of 1.5 µT) provided significant negative TCtumor,NAWM in tissue differentiation. MTRREX-based NOE imaging under 1.5 µT provided significantly larger VPhypo,CEST than MTRREX APT under 1.5 µT. Conclusion: This work showed that with a rapid CEST acquisition using a B1 saturation power of 1.5 µT and covering the whole tumor, analysis of both LD APT and MTRREX NOE allows for observing tumor heterogeneity, which will be beneficial in future studies using CEST-MRI to improve imaging diagnostics for non-enhancing glioma. [ABSTRACT FROM AUTHOR]

Cancer is one of the most devastating diseases that the world is currently facing, accounting for 10 million deaths in 2020 (WHO). In the last two decades, advanced medical imaging has played an ever more important role in the early detection of the disease, as it increases the chances of survival and the potential for full recovery. To date, dynamic glucose-enhanced (DGE) MRI using glucose-based chemical exchange saturation transfer (glucoCEST) has demonstrated the sensitivity to detect both d-glucose and glucose analogs, such as 3-oxy-methyl-d-glucose (3OMG) uptake in tumors. As one of the recent international efforts aiming at pushing the boundaries of translation of the DGE MRI technique into clinical practice, a multidisciplinary team of eight partners came together to form the "glucoCEST Imaging of Neoplastic Tumors (GLINT)" consortium, funded by the Horizon 2020 European Commission. This paper summarizes the progress made to date both by these groups and others in increasing our knowledge of the underlying mechanisms related to this technique as well as translating it into clinical practice. [ABSTRACT FROM AUTHOR]

Objective: Clinical relevance of dynamic glucose enhanced (DGE) chemical exchange saturation transfer (CEST) imaging has mostly been demonstrated at ultra-high field (UHF) due to low effect size. Results of a cohort study at clinical field strength are shown herein. Materials and methods: Motion and field inhomogeneity corrected T1ρ‐based DGE (DGE⍴) images were acquired before, during and after a d-glucose injection with 6.3 s temporal resolution to detect accumulation in the brain. Six glioma patients with clear blood–brain barrier (BBB) leakage, two glioma patients with suspected BBB leakage, and three glioma patients without BBB leakage were scanned at 3 T. Results: In high-grade gliomas with BBB leakage, d-glucose uptake could be detected in the gadolinium (Gd) enhancing region as well as in the tumor necrosis with a maximum increase of ∆DGE⍴ around 0.25%, whereas unaffected white matter did not show any significant DGE⍴ increase. Glioma patients without Gd enhancement showed no detectable DGE⍴ effect within the tumor. Conclusion: First application of DGE⍴ in a patient cohort shows an association between BBB leakage and DGE signal irrespective of the tumor grade. This indicates that glucoCEST corresponds more to the disruptions of BBB with Gd uptake than to the molecular tumor profile or tumor grading. [ABSTRACT FROM AUTHOR]