Quasi-steady-state (QUASS) reconstruction enhances T1 normalization in apparent exchange-dependent relaxation (AREX) analysis: A reevaluation of T1 correction in quantitative CEST MRI of rodent brain tumor models.

PURPOSE: The apparent exchange-dependent relaxation (AREX) analysis has been proposed as an effective means to correct T1 contribution in CEST quantification. However, it has been recognized that AREX T1 correction is not straightforward if CEST scans are not performed under the equilibrium condition. Our study aimed to test if quasi-steady-state (QUASS) reconstruction could boost the accuracy of the AREX metric under common non-equilibrium scan conditions. THEORY AND METHODS: Numerical simulation and in vivo scans were performed to assess the AREX metric accuracy. The CEST signal was simulated under different relaxation delays, RF saturation amplitudes, and durations. The AREX was evaluated as a function of the bulk water T1 and labile proton concentration using the multiple linear regression model. AREX MRI was also assessed in brain tumor rodent models, with both apparent CEST scans and QUASS reconstruction. RESULTS: Simulation showed that the AREX calculation from apparent CEST scans, under non-equilibrium conditions, had significant dependence on labile proton fraction ratio, RF saturation time, and T1 . In comparison, QUASS-boosted AREX depended on the labile proton fraction ratio without significant dependence on T1 and RF saturation time. Whereas the apparent (2.7 ± 0.8%) and QUASS MTR asymmetry (2.8 ± 0.8%) contrast between normal and tumor regions of interest (ROIs) were significant, the difference was small. In comparison, AREX contrast between normal and tumor ROIs calculated from the apparent CEST scan and QUASS reconstruction was 3.8 ± 1.1%/s and 4.4 ± 1.2%/s, respectively, statistically different from each other. CONCLUSIONS: AREX analysis benefits from the QUASS-reconstructed equilibrium CEST effect for improved T1 correction and quantitative CEST analysis.

Specific and rapid guanidinium CEST imaging using double saturation power and QUASS analysis in a rodent model of global ischemia.

PURPOSE: Guanidinium CEST is sensitive to metabolic changes and pH variation in ischemia, and it can offer advantages over conventional pH-sensitive amide proton transfer (APT) imaging by providing hyperintense contrast in stroke lesions. However, quantifying guanidinium CEST is challenging due to multiple overlapping components and a close frequency offset from water. This study aims to evaluate the applicability of a new rapid and model-free CEST quantification method using double saturation power, termed DSP-CEST, for isolating the guanidinium CEST effect from confounding factors in ischemia. To further reduce acquisition time, the DSP-CEST was combined with a quasi-steady state (QUASS) CEST technique to process non-steady-state CEST signals. METHODS: The specificity and accuracy of the DSP-CEST method in quantifying the guanidinium CEST effect were assessed by comparing simulated CEST signals with/without the contribution from confounding factors. The feasibility of this method for quantifying guanidinium CEST was evaluated in a rat model of global ischemia induced by cardiac arrest and compared to a conventional multiple-pool Lorentzian fit method. RESULTS: The DSP-CEST method was successful in removing all confounding components and quantifying the guanidinium CEST signal increase in ischemia. This suggests that the DSP-CEST has the potential to provide hyperintense contrast in stroke lesions. Additionally, the DSP-CEST was shown to be a rapid method that does not require the acquisition of the entire or a portion of the CEST Z-spectrum that is required in conventional model-based fitting approaches. CONCLUSION: This study highlights the potential of DSP-CEST as a valuable tool for rapid and specific detection of viable tissues.

Fast and robust pulsed chemical exchange saturation transfer (CEST) MRI using a quasi-steady-state (QUASS) algorithm at 3 T.

Chemical exchange saturation transfer (CEST) has emerged as a powerful technique to image dilute labile protons. However, its measurement depends on the RF saturation duration (Tsat) and relaxation delay (Trec). Although the recently developed quasi-steady-state (QUASS) solution can reconstruct equilibrium CEST effects under continuous-wave RF saturation, it does not apply to pulsed-CEST MRI on clinical scanners with restricted hardware or specific absorption rate limits. This study proposed a QUASS algorithm for pulsed-CEST MRI and evaluated its performance in muscle CEST measurement. An approximated expression of a steady-state pulsed-CEST signal was incorporated in the off-resonance spin-lock model, from which the QUASS pulsed-CEST effect was derived. Numerical simulation, creatine phantom, and healthy volunteer scans were conducted at 3 T. The CEST effect was quantified with asymmetry analysis in the simulation and phantom experiments. CEST effects of creatine, amide proton transfer, phosphocreatine, and combined magnetization transfer and nuclear Overhauser effects were isolated from a multi-pool Lorentzian model in muscles. Apparent and QUASS CEST measurements were compared under different Tsat/Trec and duty cycles. Paired Student's t-test was employed with P < 0.05 as statistically significant. The simulation, phantom, and human studies showed the strong impact of Tsat/Trec on apparent CEST measurements, which were significantly smaller than the corresponding QUASS CEST measures, especially under short Tsat/Trec times. In comparison, the QUASS algorithm mitigates such impact and enables accurate CEST measurements under short Tsat/Trec times. In conclusion, the QUASS algorithm can accelerate robust pulsed-CEST MRI, promising the efficient detection and evaluation of muscle diseases in clinical settings.

A Pilot Study of Ratiometric Creatine CEST MRI Assessment of Rabbit Skeletal Muscle Energy Metabolism at 3 T.

BACKGROUND: pH MRI may provide useful information to evaluate metabolic disruption following ischemia. Radiofrequency amplitude-based creatine chemical exchange saturation transfer (CrCEST) ratiometric MRI is pH-sensitive, which could but has not been explored to examine muscle ischemia. PURPOSE: To investigate skeletal muscle energy metabolism alterations with CrCEST ratiometric MRI. STUDY TYPE: Prospective. ANIMAL MODEL: Seven adult New Zealand rabbits with ipsilateral hindlimb muscle ischemia. FIELD STRENGTH/SEQUENCE: 3 T/two MRI scans, including MRA and CEST imaging, were performed under two B1 amplitudes of 0.5 and 1.25 µT after 2 hours of hindlimb muscle ischemia and 1 hour of reperfusion recovery, respectively. ASSESSMENT: CEST effects of two energy metabolites of creatine and phosphocreatine (PCrCEST) were resolved with the multipool Lorentzian fitting approach. The pixel-wise CrCEST ratio was quantified by calculating the ratio of the resolved CrCEST peaks under a B1 amplitude of 1.25 µT to those under 0.5 µT in the entire muscle. STATISTICAL TESTS: One-way ANOVA and Pearson's correlation. P < 0.05 was considered statistically significant. RESULTS: MRA images confirmed the blood flow loss and restoration in the ischemic hindlimb at the ischemia and recovery phases, respectively. Ischemic muscles exhibited a significant decrease of PCr at the ischemia (under both B1 amplitudes) and recovery phases (under B1 amplitude of 0.5 µT) and significantly increased CrCEST from normal tissues at both phases (under both B1 levels). Specifically, CrCEST decreased, and PCrCEST increased with the CrCEST ratio. Significantly strong correlations were observed among the CrCEST ratio, and CrCEST and PCrCEST under both B1 levels (r > 0.80). DATA CONCLUSION: The CrCEST ratio altered substantially with muscle pathological states and was closely related to CEST effects of energy metabolites of Cr and PCr, suggesting that the pH-sensitive CrCEST ratiometric MRI is feasible to evaluate muscle injuries at the metabolic level. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1.

3D CEST MRI with an unevenly segmented RF irradiation scheme: A feasibility study in brain tumor imaging.

PURPOSE: To integrate 3D CEST EPI with an unevenly segmented RF irradiation module and preliminarily demonstrate it in the clinical setting. METHODS: A CEST MRI with unevenly segmented RF saturation was implemented, including a long primary RF saturation to induce the steady-state CEST effect, maintained with repetitive short secondary RF irradiation between readouts. This configuration reduces relaxation-induced blur artifacts during acquisition, allowing fast 3D spatial coverage. Numerical simulations were performed to select parameters such as flip angle (FA), short RF saturation duration (Ts2), and the number of readout segments. The sequence was validated experimentally with data from a phantom, healthy volunteers, and a brain tumor patient. RESULTS: Based on the numerical simulation and l-carnosine gel phantom experiment, FA, Ts2, and the number of segments were set to 20°, 0.3 s, and the range from 4 to 8, respectively. The proposed method minimized signal modulation in the human brain images in the kz direction during the acquisition and provided the blur artifacts-free CEST contrast over the whole volume. Additionally, the CEST contrast in the tumor tissue region is higher than in the contralateral normal tissue region. CONCLUSIONS: It is feasible to implement a highly accelerated 3D EPI CEST imaging with unevenly segmented RF irradiation.

Numerical simulation-based assessment of pH-sensitive chemical exchange saturation transfer MRI quantification accuracy across field strengths.

Chemical exchange saturation transfer (CEST) MRI detects dilute labile protons via their exchange with bulk water, conferring pH sensitivity. Based on published exchange and relaxation properties, a 19-pool simulation was used to model the brain pH-dependent CEST effect and assess the accuracy of quantitative CEST (qCEST) analysis across magnetic field strengths under typical scan conditions. First, the optimal B1 amplitude was determined by maximizing pH-sensitive amide proton transfer (APT) contrast under the equilibrium condition. Apparent and quasi-steady-state (QUASS) CEST effects were then derived under the optimal B1 amplitude as functions of pH, RF saturation duration, relaxation delay, Ernst flip angle, and field strength. Finally, CEST effects, particularly the APT signal, were isolated with spinlock model-based Z-spectral fitting to evaluate the accuracy and consistency of CEST quantification. Our data showed that QUASS reconstruction significantly improved the consistency between simulated and equilibrium Z-spectra. The residual difference between QUASS and equilibrium CEST Z-spectra was, on average, 30 times less than that of the apparent CEST Z-spectra across field strengths, saturation, and repetition times. Also, the spinlock fitting of the QUASS CEST effect significantly reduced the residual errors 9-fold. Furthermore, the isolated APT amplitude from QUASS reconstruction was consistent and higher than the apparent CEST analysis under nonequilibrium conditions. To summarize, this study confirmed that QUASS reconstruction facilitates accurate determination of the CEST system under different scan protocols across field strengths, with the potential to help standardize CEST quantification.

CEST2022 - mapping multi-pool CEST signal changes in an animal model of brain tumor with quasi-steady-state reconstruction-empowered CEST quantification.

Chemical exchange saturated transfer (CEST) MRI has biomarker potential to assess tissue microenvironment in brain tumors. Multi-pool Lorentzian or spinlock models provides useful insights into the CEST contrast mechanism. However, T1 contribution to the complex overlapping effects of brain tumors is difficult under the non-equilibrium state. Therefore, this study evaluated T1 contributions on multi-pool parameters with quasi-steady-state (QUASS) algorithm reconstructed equilibrium data. MRI scans were performed in rat brain tumor models, including relaxation, diffusion, and CEST imaging. A pixel-wise seven-pool spinlock-model was employed to fit QUASS reconstructed CEST Z-spectra and evaluated the magnetization transfer (MT), amide, amine, guanidyl, and nuclear-overhauled effect (NOE) signals in tumor and normal tissues. In addition, T1 was estimated from the spinlock-model fitting and compared with measured T1. We observed tumor had a statistically significant increase in the amide signal (p < 0.001) and decreases in the MT and NOE signals (p < 0.001). On the other hand, the differences in amine and guanidyl between the tumor and contralateral normal regions were not statistically significant. The differences between measured and estimated T1 values were 8% in the normal tissue and 4% in the tumor. Furthermore, the isolated MT signal strongly correlated with R1 (r = 0.96, P < 0.001). In summary, we successfully unraveled multi-factorial effects in the CEST signal using spinlock-model fitting and QUASS method and demonstrated the effect of T1 relaxation on MT and NOE.

Comparison of model-free Lorentzian and spinlock model-based fittings in quantitative CEST imaging of acute stroke.

PURPOSE: CEST MRI detects complex tissue changes following acute stroke. Our study aimed to test if spinlock model-based fitting of the quasi-steady-state (QUASS)-reconstructed equilibrium CEST MRI improves the determination of multi-pool signal changes over the commonly-used model-free Lorentzian fitting in acute stroke. THEORY AND METHODS: Multiple three-pool CEST Z-spectra were simulated using Bloch-McConnell equations for a range of T1 , relaxation delay, and saturation times. The multi-pool CEST signals were solved from the simulated Z-spectra to test the accuracy of routine Lorentzian (model-free) and spinlock (model-based) fittings without and with QUASS reconstruction. In addition, multiparametric MRI scans were obtained in rat models of acute stroke, including relaxation, diffusion, and CEST Z-spectrum. Finally, we compared model-free and model-based per-pixel CEST quantification in vivo. RESULTS: The spinlock model-based fitting of QUASS CEST MRI provided a nearly T1 -independent determination of multi-pool CEST signals, advantageous over the fittings of apparent CEST MRI (model-free and model-based). In vivo data also demonstrated that the spinlock model-based QUASS fitting captured significantly different changes in semisolid magnetization transfer (-0.9 ± 0.8 vs. 0.3 ± 0.8%), amide (-1.1 ± 0.4 vs. -0.5 ± 0.2%), and guanidyl (1.0 ± 0.4 vs. 0.7 ± 0.3%) signals over the model-free Lorentzian analysis. CONCLUSION: Our study demonstrated that spinlock model-based fitting of QUASS CEST MRI improved the determination of the underlying tissue changes following acute stroke, promising further clinical translation of quantitative CEST imaging.

CEST 2022 - A special issue on CEST MRI from the 9th international chemical exchange saturation transfer workshop.

The CEST2022 workshop was held at the Emory Conference Center Hotel from August 7th to 10th, 2022, and attracted over a hundred international participants from North America, Europe, and Asia. The workshop consisted of four plenary talks, 10 scientific sessions, nine invited talks, and 40 talks selected from abstracts. Four discussion sessions were also conducted to build consensus on CEST imaging standardization and quantification. We thank Professors Peter van Zijl, Ravinder Reddy, and Dean Sherry for their Sunday afternoon education session and Professors Linda Knutsson, John Gore, Mortiz Zaiss, and Fahmeed Hyder for their plenary lectures. Abstracts selected for oral presentations were invited to submit to Magnetic Resonance Imaging for peer review and are included in this special issue. Here, we present a summary of the articles featured in this issue.

Discrimination between progressive penumbra and benign oligemia of the diffusion-perfusion mismatch region by amide proton transfer-weighted imaging.

PURPOSE: Amide proton transfer-weighted (APTw) imaging was an effective tool to reveal the tissue acidosis of acute ischemic stroke. This study aimed to evaluate the ability of APTw MRI to distinguish progressive penumbra and benign oligemia in the diffusion-perfusion mismatch region. MATERIALS AND METHODS: 38 acute cerebral infarction patients who underwent a comprehensive MRI examination, including diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), APT imaging, and a follow-up scan in one week were recruited. There were 12 DWI/PWI match cases. The DWI/PWI mismatch patients were divided into 10 progressive cases and 16 stable cases according to the lesion size on the follow-up DWI image compared to the admission scan. Three ROIs: infarction lesion, peripheral, and contralateral normal regions were measured on each subject's MTRasym map. The Friedman test was used to compare the changes of MTRasym among three different regions within each group. The Kruskal-Wallis ANOVA test was used to compare them among the same region of different groups. The correlation between the MTRasym of the peripheral region and the lesion enlargement was analyzed by the Spearman test. RESULTS: The MTRasym at the infarction lesion of all three groups showed significant decrease to the contralateral normal tissue. In the progressive mismatch group, the MTRasym at the peripheral region within the DWI/PWI mismatch showed a significant difference with the contralateral normal region and no difference with the infarct core. Whereas both the MTRasym at the peripheral region of the stable mismatch and match groups had no significant difference with the contralateral side, but the differences were significant from those of the central core. When comparing the peripheral region of three groups, the MTRasym of the progressive mismatch group showed a significant decrease to that of the stable mismatch and match groups. The MTRasym of the peripheral region showed a negative correlation with lesion enlargement. CONCLUSION: APTw imaging is promising to stratify the heterogeneous PWI/DWI mismatch region and benefit the clinical treatment.

Demonstration of accurate multi-pool chemical exchange saturation transfer MRI quantification - Quasi-steady-state reconstruction empowered quantitative CEST analysis.

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironment properties, yet CEST quantification has been challenging. This difficulty is because the CEST measurement depends not only on the underlying CEST system but also on the scan protocols, including RF saturation amplitude, duration, and repetition time. In addition, T1 normalization is not straightforward under non-equilibrium conditions. Recently, a quasi-steady-state (QUASS) algorithm was established to reconstruct the desired equilibrium state from experimental measurements. Our study aimed to determine the accuracy of spinlock-model-based multi-pool CEST quantification using numerical simulations and phantom experiments. In short, CEST Z-spectra were simulated for a representative 3-pool model, and CEST amplitudes were solved with spinlock model-based multi-pool fitting and assessed as a function of RF saturation time (Ts), repetition time (TR), and T1. Although the apparent CEST signals showed significant T1 dependence, such relationships were not observed following QUASS reconstruction. To test the accuracy of T1 correction, a multi-vial phantom of nicotinamide and creatine was doped with manganese chloride, resulting in T1 ranging from 1 s to beyond 2 s. The multi-labile signals determined from the routine measurements showed significant dependence on Ts, TR, and T1. In contrast, CEST signals from the QUASS reconstruction showed consistent quantification independent of such variables. To summarize, our study demonstrated that accurate CEST quantification is feasible in multi-pool CEST systems with the spinlock-model-based fitting of QUASS CEST MRI.

In vivo pH mapping with omega plot-based quantitative chemical exchange saturation transfer MRI.

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.

Detection of tissue pH with quantitative chemical exchange saturation transfer magnetic resonance imaging.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has emerged as a novel means for sensitive detection of dilute labile protons and chemical exchange rates. By sensitizing to pH-dependent chemical exchange, CEST MRI has shown promising results in monitoring tissue statuses such as pH changes in disorders like acute stroke, tumor, and acute kidney injury. This article briefly reviews the basic principles for CEST imaging and quantitative measures, from the simplistic asymmetry analysis to multipool Lorentzian decoupling and quasi-steady-state reconstruction. In particular, the advantages and limitations of commonly used quantitative approaches for CEST applications are discussed.

Tissue perfusion of the kurtosis/diffusion mismatch differs from the central core and peripheral regions in acute cerebral infarction patients.

BACKGROUND: Despite its wide adoption in stroke imaging, the diffusion-weighted imaging (DWI) lesion is heterogeneous. The emerging diffusion kurtosis imaging (DKI) has been postulated to resolve the graded DWI lesion. PURPOSE: To determine the perfusion characteristics of the central infarction core, kurtosis/diffusion mismatch, and peripheral regions. MATERIAL AND METHODS: Patients with acute ischemic stroke underwent DWI, DKI, and perfusion-weighted imaging (PWI) scans. The patients were divided into mean kurtosis (MK)/mean diffusivity (MD) match and mismatch groups. Perfusion parameters were measured in the MK/MD lesion and peripheral areas in the MK/MD match group. We also analyzed perfusion status in the MK/MD lesion mismatch area for the mismatch group. RESULTS: A total of 40 eligible patients (24 MK/MD match and 16 MK/MD mismatch) were enrolled in the final data analysis. The MTT and TTP progressively decreased, while the cerebral blood flow (CBF) and cerebral blood volume (CBV) increased from the central to peripheral areas. In addition, CBF in the MK/MD mismatch region was significantly higher than that in the central region (P < 0.05), but similar to the peripheral region. Furthermore, CBV in the MK/MD mismatch region did not differ significantly from that of the central region, but both were significantly lower than that of the peripheral area (P < 0.05). CONCLUSION: The MK/MD mismatch region had blood flow similar to the peripheral region but with a reduced blood volume, indicating that it was less ischemic from the infarction core, albeit insufficient collateral circulation.

Demonstration of pH imaging in acute stroke with endogenous ratiometric chemical exchange saturation transfer magnetic resonance imaging at 2 ppm.

pH change is often considered a hallmark of metabolic disruption in diseases such as ischemic stroke and cancer. Chemical exchange saturation transfer (CEST) MRI, particularly amide proton transfer (APT), has emerged as a noninvasive pH imaging approach. However, there are changes in multipool CEST effects besides APT MRI. Our study investigated radiofrequency (RF) amplitude-based ratiometric CEST pH imaging in acute stroke. Briefly, adult male Wistar rats underwent CEST MRI under two RF saturation (B1 ) levels of 0.75 and 1.5 µT following middle cerebral artery occlusion. Magnetization transfer (MT), direct water saturation, CEST at 2 ppm (CEST@2 ppm), amine (2.75 ppm), and APT (3.5 ppm) effects were resolved with the multipool Lorentzian fitting approach. The ratiometric analysis was measured in the ischemic lesion and the contralateral normal area, which was also correlated with pH-specific MT and the relaxation normalized APT (MRAPT) index. MT, amine CEST effect, and their respective ratiometric indices did not show significant changes in ischemic regions (p > 0.05), as expected. Whereas APT decreased in the ischemic lesion for B1 of 1.5 µT (p < 0.01), the correlation between the amide ratio with MRAPT index was moderate (r = 0.52, p = 0.02). By comparison, the ischemic tissue showed a significantly increased CEST@2 ppm for both saturation levels from the contralateral normal area (p ≤ 0.01). Importantly, the CEST@2 ppm ratio decreased in the ischemic lesion (p < 0.01), which highly correlated with the MRAPT index (r = 0.93, p < 0.001). To summarize, our study demonstrated the feasibility of endogenous CEST@2 ppm ratiometric imaging of pH upon acute stroke, promising to detect pH changes in metabolic diseases.

Generalization of quasi-steady-state reconstruction to CEST MRI with two-tiered RF saturation and gradient-echo readout-Synergistic nuclear Overhauser enhancement contribution to brain tumor amide proton transfer-weighted MRI.

PURPOSE: While amide proton transfer-weighted (APTw) MRI has been adopted in tumor imaging, there are concurrent APT, magnetization transfer, and nuclear Overhauser enhancement changes. Also, the APTw image is confounded by relaxation changes, particularly when the relaxation delay and saturation time are not sufficiently long. Our study aimed to extend a quasi-steady-state (QUASS) solution to determine the contribution of the multipool CEST signals to the observed tumor APTw contrast. METHODS: Our study derived the QUASS solution for a multislice CEST-MRI sequence with an interleaved RF saturation and gradient-echo readout between signal averaging. Multiparametric MRI scans were obtained in rat brain tumor models, including T1 , T2 , diffusion, and CEST scans. Finally, we performed spinlock model-based multipool fitting to determine multiple concurrent CEST signal changes in the tumor. RESULTS: The QUASS APTw MRI showed small but significant differences in normal and tumor tissues and their contrast from the acquired asymmetry calculation. The spinlock model-based fitting showed significant differences in semisolid magnetization transfer, amide, and nuclear Overhauser enhancement effects between the apparent and QUASS CEST MRI. In addition, we determined that the tumor APTw contrast is due to synergistic APT increase (+3.5 ppm) and NOE decrease (-3.5 ppm), with their relative contribution being about one third and two thirds under a moderate B1 of 0.75 µT at 4.7 T. CONCLUSION: Our study generalized QUASS analysis to gradient-echo image readout and quantified the underlying tumor CEST signal changes, providing an improved elucidation of the commonly used APTw MRI.

Use of multimodality imaging, histology, and treatment feasibility to characterize a transgenic Rag2-null rat model of glioblastoma.

Many drugs that show potential in animal models of glioblastoma (GBM) fail to translate to the clinic, contributing to a paucity of new therapeutic options. In addition, animal model development often includes histologic assessment, but multiparametric/multimodality imaging is rarely included despite increasing utilization in patient cancer management. This study developed an intracranial recurrent, drug-resistant, human-derived glioblastoma tumor in Sprague-Dawley Rag2-Rag2 tm1Hera knockout rat and was characterized both histologically and using multiparametric/multimodality neuroimaging. Hybrid 18F-fluoroethyltyrosine positron emission tomography and magnetic resonance imaging, including chemical exchange saturation transfer (18F-FET PET/CEST MRI), was performed for full tumor viability determination and characterization. Histological analysis demonstrated human-like GBM features of the intracranially implanted tumor, with rapid tumor cell proliferation (Ki67 positivity: 30.5 ± 7.8%) and neovascular heterogeneity (von Willebrand factor VIII:1.8 to 5.0% positivity). Early serial MRI followed by simultaneous 18F-FET PET/CEST MRI demonstrated consistent, predictable tumor growth, with exponential tumor growth most evident between days 35 and 49 post-implantation. In a second, larger cohort of rats, 18F-FET PET/CEST MRI was performed in mature tumors (day 49 post-implantation) for biomarker determination, followed by evaluation of single and combination therapy as part of the model development and validation. The mean percentage of the injected dose per mL of 18F-FET PET correlated with the mean %CEST (r = 0.67, P < 0.05), but there was also a qualitative difference in hot spot location within the tumor, indicating complementary information regarding the tumor cell demand for amino acids and tumor intracellular mobile phase protein levels. Finally, the use of this glioblastoma animal model for therapy assessment was validated by its increased overall survival after treatment with combination therapy (temozolomide and idasanutlin) (P < 0.001). Our findings hold promise for a more accurate tumor viability determination and novel therapy assessment in vivo in a recently developed, reproducible, intracranial, PDX GBM.

Effects of the New Thrombolytic Compound LT3001 on Acute Brain Tissue Damage After Focal Embolic Stroke in Rats.

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10 mg/kg LT3001 or tPA at 1.5, 3, or 4.5 h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5 h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3 h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5 h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke.

Quasi-steady-state amide proton transfer (QUASS APT) MRI enhances pH-weighted imaging of acute stroke.

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.

Review and consensus recommendations on clinical APT-weighted imaging approaches at 3T: Application to brain tumors.

Amide proton transfer-weighted (APTw) MR imaging shows promise as a biomarker of brain tumor status. Currently used APTw MRI pulse sequences and protocols vary substantially among different institutes, and there are no agreed-on standards in the imaging community. Therefore, the results acquired from different research centers are difficult to compare, which hampers uniform clinical application and interpretation. This paper reviews current clinical APTw imaging approaches and provides a rationale for optimized APTw brain tumor imaging at 3 T, including specific recommendations for pulse sequences, acquisition protocols, and data processing methods. We expect that these consensus recommendations will become the first broadly accepted guidelines for APTw imaging of brain tumors on 3 T MRI systems from different vendors. This will allow more medical centers to use the same or comparable APTw MRI techniques for the detection, characterization, and monitoring of brain tumors, enabling multi-center trials in larger patient cohorts and, ultimately, routine clinical use.