Imaging kidney inflammation using an oxidatively activated MRI probe.

Imaging tools for kidney inflammation could improve care for patients suffering inflammatory kidney diseases by lessening reliance on percutaneous biopsy or biochemical tests alone. During kidney inflammation, infiltration of myeloid immune cells generates a kidney microenvironment that is oxidizing relative to normal kidney. Here, we evaluated whether magnetic resonance imaging (MRI) using the redox-active iron (Fe) complex Fe-PyC3A as an oxidatively activated probe could serve as a marker of kidney inflammation using mouse models of unilateral ischemia-reperfusion injury (IRI) and lupus nephritis (MRL-lpr mice). We imaged unilateral IRI in gp91phox knockout mice, which are deficient in the nicotinamide oxidase II (NOX2) enzyme required for myeloid oxidative burst, as loss of function control, and imaged MRL/MpJ mice as non-kidney involved lupus control. Gadoterate meglumine was used as a non-oxidatively activated control MRI probe. Fe-PyC3A safety was preliminarily examined following a single acute dose. FePyC3A generated significantly greater MRI signal enhancement in the IRI kidney compared to the contralateral kidney in wild-type mice, but the effect was not observed in the NOX2-deficient control. Fe-PyC3A also generated significantly greater kidney enhancement in MRL-lpr mice compared to MRL/MpJ control. Gadoterate meglumine did not differentially enhance the IRI kidney over the contralateral kidney and did not differentially enhance the kidneys of MRL-lpr over MRL/MpJ mice. Fe-PyC3A was well tolerated at the highest dose evaluated, which was a 40-fold greater than required for imaging. Thus, our data indicate that MRI using Fe-PyC3A is specific to an oxidizing kidney environment shaped by activity of myeloid immune cells and support further evaluation of Fe-PyC3A for imaging kidney inflammation.

Dual Hydrazine-Equipped Turn-On Manganese-Based Probes for Magnetic Resonance Imaging of Liver Fibrogenesis.

Liver fibrogenesis is accompanied by upregulation of lysyl oxidase enzymes, which catalyze oxidation of lysine ε-amino groups on the extracellular matrix proteins to form the aldehyde containing amino acid allysine (LysAld). Here, we describe the design and synthesis of novel manganese-based MRI probes with high signal amplification for imaging liver fibrogenesis. Rational design of a series of stable hydrazine-equipped manganese MRI probes gives Mn-2CHyd with the highest affinity and turn-on relaxivity (4-fold) upon reaction with LysAld. A dynamic PET-MRI study using [52Mn]Mn-2CHyd showed low liver uptake of the probe in healthy mice. The ability of the probe to detect liver fibrogenesis was then demonstrated in vivo in CCl4-injured mice. This study enables further development and application of manganese-based hydrazine-equipped probes for imaging liver fibrogenesis.

Determination of multipool contributions to endogenous amide proton transfer effects in global ischemia with high spectral resolution in vivo chemical exchange saturation transfer MRI.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI has been used for quantitative assessment of dilute metabolites and/or pH in disorders such as acute stroke and tumor. However, routine asymmetry analysis (MTRasym ) may be confounded by concomitant effects such as semisolid macromolecular magnetization transfer (MT) and nuclear Overhauser enhancement. Resolving multiple contributions is essential for elucidating the origins of in vivo CEST contrast. METHODS: Here we used a newly proposed image downsampling expedited adaptive least-squares fitting on densely sampled Z-spectrum to quantify multipool contribution from water, nuclear Overhauser enhancement, MT, guanidinium, amine, and amide protons in adult male Wistar rats before and after global ischemia. RESULTS: Our results revealed the major contributors to in vivo T1 -normalized MTRasym (3.5 ppm) contrast between white and gray matter (WM/GM) in normal brain (-1.96%/second) are pH-insensitive macromolecular MT (-0.89%/second) and nuclear Overhauser enhancement (-1.04%/second). Additionally, global ischemia resulted in significant changes of MTRasym , being -2.05%/second and -1.56%/second in WM and GM, which are dominated by changes in amide (-1.05%/second, -1.14%/second) and MT (-0.88%/second, -0.62%/second). Notably, the pH-sensitive amine and amide effects account for nearly 60% and 80% of the MTRasym changes seen in WM and GM, respectively, after global ischemia, indicating that MTRasym is predominantly pH-sensitive. CONCLUSION: Combined amide and amine effects dominated the MTRasym changes after global ischemia, indicating that MTRasym is predominantly pH-sensitive and suitable for detecting tissue acidosis following acute stroke.

In vivo microscopic diffusional kurtosis imaging with symmetrized double diffusion encoding EPI.

PURPOSE: Diffusional kurtosis imaging (DKI) measures the deviation of the displacement probability from a normal distribution, complementing the data commonly acquired by diffusion MRI. It is important to elucidate the sources of kurtosis contrast, particularly in biological tissues where microscopic kurtosis (intrinsic kurtosis) and diffusional heterogeneity may co-exist. METHODS: We have developed a technique for microscopic kurtosis MRI, dubbed microscopic diffusional kurtosis imaging (µDKI), using a symmetrized double diffusion encoding (s-DDE) EPI sequence. We compared this newly developed µDKI to conventional DKI methods in both a triple compartment phantom and in vivo. RESULTS: Our results showed that whereas conventional DKI and µDKI provided similar measurements in a compartment of monosphere beads, kurtosis measured by µDKI was significantly less than that measured by conventional DKI in a compartment of mixed Gaussian pools. For in vivo brain imaging, µDKI showed small yet significantly lower kurtosis measurement in regions of the cortex, CSF, and internal capsule compared to the conventional DKI approach. CONCLUSIONS: Our study showed that µDKI is less susceptible than conventional DKI to sub-voxel diffusional heterogeneity. Our study also provided important preliminary demonstration of our technique in vivo, warranting future studies to investigate its diagnostic use in examining neurological disorders.

pH-sensitive amide proton transfer effect dominates the magnetization transfer asymmetry contrast during acute ischemia-quantification of multipool contribution to in vivo CEST MRI.

PURPOSE: To determine the origins of in vivo magnetization transfer asymmetry contrast during acute ischemic stroke, particularly in the diffusion lesion, perfusion lesion, and their mismatch using a middle cerebral artery occlusion rat model of acute stroke. METHODS: Adult male Wistar rats underwent multiparametric MRI of diffusion, perfusion, T1 , and amide proton transfer (APT) imaging at 4.7 T following a middle cerebral artery occlusion procedure. A multipool Lorentzian model, including the nuclear Overhauser effect, magnetization transfer, direct water saturation, amine and amide chemical exchange saturation transfer effects, was applied for Z-spectrum fitting to determine the sources of in vivo magnetization transfer asymmetry following acute stroke. RESULTS: We showed that changes in amine chemical exchange saturation transfer (2 ppm) and APT (3.5 ppm) effects, particularly the APT MRI effect, dominate the commonly used magnetization transfer asymmetry analysis and hence confer pH sensitivity to APT imaging of acute stroke. Also, the nuclear Overhauser effect and magnetization transfer show small changes that counteracted each other, contributing less than 0.3% to magnetization transfer asymmetry at 3.5 ppm. Moreover, we showed that diffusion lesion had worsened acidosis from perfusion/diffusion lesion mismatch (P < 0.05). CONCLUSIONS: The study complements recent in vivo quantitative chemical exchange saturation transfer work to shed light on the sensitivity and specificity of endogenous APT MRI to tissue acidosis. Magn Reson Med 79:1602-1608, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

JOURNAL CLUB: Evaluation of Diffusion Kurtosis Imaging of Stroke Lesion With Hemodynamic and Metabolic MRI in a Rodent Model of Acute Stroke.

OBJECTIVE: Diffusion kurtosis imaging (DKI) has emerged as a new acute stroke imaging approach, augmenting routine DWI. Although it has been shown that a diffusion lesion without kurtosis abnormality is more likely to recover after reperfusion, whereas a kurtosis lesion shows poor response, little is known about the underlying pathophysiologic profile of the kurtosis lesion versus the kurtosis lesion-diffusion lesion mismatch. MATERIALS AND METHODS: We performed multiparametric MRI, including arterial spin labeling, pH-sensitive amide proton transfer, and DKI, in a rodent model of acute stroke caused by embolic middle cerebral artery occlusion. Diffusion and kurtosis lesions were semiautomatically segmented, and multiparametric MRI indexes were compared among the kurtosis lesion, diffusion lesion, kurtosis lesion-diffusion lesion mismatch, and the contralateral normal tissue area. RESULTS: We confirmed a significant difference between diffusion lesion and kurtosis lesion volumes (mean [± SD] volume, 151 ± 65 vs 125 ± 47 mm3; p < 0.05). Although ischemic lesions have significantly reduced cerebral blood flow compared with contralateral normal tissue, we did not find a significant difference in cerebral blood flow between the kurtosis lesion and the kurtosis lesion-diffusion lesion mismatch (mean cerebral blood flow, 0.53 ± 0.10 vs 0.47 ± 0.14 mL/g of tissue per minute; p > 0.05). Of importance, the pH of the kurtosis lesion was significantly lower than that of the lesion mismatch (mean pH, 6.81 ± 0.08 vs 6.89 ± 0.09; p < 0.01). CONCLUSION: The present study confirms that DKI provides an expedient approach for refining the heterogeneous DWI lesion that is associated with graded metabolic derangement, which is promising for improving the infarction core definition and ultimately helping to guide stroke treatment.

pH-sensitive MRI demarcates graded tissue acidification during acute stroke - pH specificity enhancement with magnetization transfer and relaxation-normalized amide proton transfer (APT) MRI.

pH-sensitive amide proton transfer (APT) MRI provides a surrogate metabolic biomarker that complements the widely-used perfusion and diffusion imaging. However, the endogenous APT MRI is often calculated using the asymmetry analysis (MTRasym), which is susceptible to an inhomogeneous shift due to concomitant semisolid magnetization transfer (MT) and nuclear overhauser (NOE) effects. Although the intact brain tissue has little pH variation, white and gray matter appears distinct in the MTRasym image. Herein we showed that the heterogeneous MTRasym shift not related to pH highly correlates with MT ratio (MTR) and longitudinal relaxation rate (R1w), which can be reasonably corrected using the multiple regression analysis. Because there are relatively small MT and R1w changes during acute stroke, we postulate that magnetization transfer and relaxation-normalized APT (MRAPT) analysis increases MRI specificity to acidosis over the routine MTRasym image, hence facilitates ischemic lesion segmentation. We found significant differences in perfusion, pH and diffusion lesion volumes (P<0.001, ANOVA). Furthermore, MRAPT MRI depicted graded ischemic acidosis, with the most severe acidosis in the diffusion lesion (-1.05±0.29%/s), moderate acidification within the pH/diffusion mismatch (i.e., metabolic penumbra, -0.67±0.27%/s) and little pH change in the perfusion/pH mismatch (i.e., benign oligemia, -0.04±0.14%/s), providing refined stratification of ischemic tissue injury.

Tissue Characterization with Quantitative High-Resolution Magic Angle Spinning Chemical Exchange Saturation Transfer Z-Spectroscopy.

Chemical exchange saturation transfer (CEST) provides sensitive magnetic resonance (MR) contrast for probing dilute compounds via exchangeable protons, serving as an emerging molecular imaging methodology. CEST Z-spectrum is often acquired by sweeping radiofrequency saturation around bulk water resonance, offset by offset, to detect CEST effects at characteristic chemical shift offsets, which requires prolonged acquisition time. Herein, combining high-resolution magic angle spinning (HRMAS) with concurrent application of gradient and rf saturation to achieve fast Z-spectral acquisition, we demonstrated the feasibility of fast quantitative HRMAS CEST Z-spectroscopy. The concept was validated with phantoms, which showed excellent agreement with results obtained from conventional HRMAS MR spectroscopy (MRS). We further utilized the HRMAS Z-spectroscopy for fast ex vivo quantification of ischemic injury with rodent brain tissues after ischemic stroke. This method allows rapid and quantitative CEST characterization of biological tissues and shows potential for a host of biomedical applications.

Comparison of image sensitivity between conventional tensor-based and fast diffusion kurtosis imaging protocols in a rodent model of acute ischemic stroke.

Diffusion kurtosis imaging (DKI) can offer a useful complementary tool to routine diffusion MRI for improved stratification of heterogeneous tissue damage in acute ischemic stroke. However, its relatively long imaging time has hampered its clinical application in the emergency setting. A recently proposed fast DKI approach substantially shortens the imaging time, which may help to overcome the scan time limitation. However, to date, the sensitivity of the fast DKI protocol for the imaging of acute stroke has not been fully described. In this study, we performed routine and fast DKI scans in a rodent model of acute stroke, and compared the sensitivity of diffusivity and kurtosis indices (i.e. axial, radial and mean) in depicting acute ischemic lesions. In addition, we analyzed the contrast-to-noise ratio (CNR) between the ipsilateral ischemic and contralateral normal regions using both conventional and fast DKI methods. We found that the mean kurtosis shows a relative change of 47.1 ± 7.3% between the ischemic and contralateral normal regions, being the most sensitive parameter in revealing acute ischemic injury. The two DKI methods yielded highly correlated diffusivity and kurtosis measures and lesion volumes (R(2) ⩾ 0.90, p < 0.01). Importantly, the fast DKI method exhibited significantly higher CNR of mean kurtosis (1.6 ± 0.2) compared with the routine tensor protocol (1.3 ± 0.2, p < 0.05), with its CNR per unit time (CNR efficiency) approximately doubled when the scan time was taken into account. In conclusion, the fast DKI method provides excellent sensitivity and efficiency to image acute ischemic tissue damage, which is essential for image-guided and individualized stroke treatment.

Fast diffusion kurtosis imaging (DKI) with Inherent COrrelation-based Normalization (ICON) enhances automatic segmentation of heterogeneous diffusion MRI lesion in acute stroke.

Diffusion kurtosis imaging (DKI) has been shown to augment diffusion-weighted imaging (DWI) for the definition of irreversible ischemic injury. However, the complexity of cerebral structure/composition makes the kurtosis map heterogeneous, limiting the specificity of kurtosis hyperintensity to acute ischemia. We propose an Inherent COrrelation-based Normalization (ICON) analysis to suppress the intrinsic kurtosis heterogeneity for improved characterization of heterogeneous ischemic tissue injury. Fast DKI and relaxation measurements were performed on normal (n = 10) and stroke rats following middle cerebral artery occlusion (MCAO) (n = 20). We evaluated the correlations between mean kurtosis (MK), mean diffusivity (MD) and fractional anisotropy (FA) derived from the fast DKI sequence and relaxation rates R1 and R2 , and found a highly significant correlation between MK and R1 (p < 0.001). We showed that ICON analysis suppressed the intrinsic kurtosis heterogeneity in normal cerebral tissue, enabling automated tissue segmentation in an animal stroke model. We found significantly different kurtosis and diffusivity lesion volumes: 147 ± 59 and 180 ± 66 mm3 , respectively (p = 0.003, paired t-test). The ratio of kurtosis to diffusivity lesion volume was 84% ± 19% (p < 0.001, one-sample t-test). We found that relaxation-normalized MK (RNMK), but not MD, values were significantly different between kurtosis and diffusivity lesions (p < 0.001, analysis of variance). Our study showed that fast DKI with ICON analysis provides a promising means of demarcation of heterogeneous DWI stroke lesions.

Quantitative chemical exchange saturation transfer (qCEST) MRI - omega plot analysis of RF-spillover-corrected inverse CEST ratio asymmetry for simultaneous determination of labile proton ratio and exchange rate.

Chemical exchange saturation transfer (CEST) MRI is sensitive to labile proton concentration and exchange rate, thus allowing measurement of dilute CEST agent and microenvironmental properties. However, CEST measurement depends not only on the CEST agent properties but also on the experimental conditions. Quantitative CEST (qCEST) analysis has been proposed to address the limitation of the commonly used simplistic CEST-weighted calculation. Recent research has shown that the concomitant direct RF saturation (spillover) effect can be corrected using an inverse CEST ratio calculation. We postulated that a simplified qCEST analysis is feasible with omega plot analysis of the inverse CEST asymmetry calculation. Specifically, simulations showed that the numerically derived labile proton ratio and exchange rate were in good agreement with input values. In addition, the qCEST analysis was confirmed experimentally in a phantom with concurrent variation in CEST agent concentration and pH. Also, we demonstrated that the derived labile proton ratio increased linearly with creatine concentration (P < 0.01) while the pH-dependent exchange rate followed a dominantly base-catalyzed exchange relationship (P < 0.01). In summary, our study verified that a simplified qCEST analysis can simultaneously determine labile proton ratio and exchange rate in a relatively complex in vitro CEST system.

Optimization of an Allysine-Targeted PET Probe for Quantifying Fibrogenesis in a Mouse Model of Pulmonary Fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a destructive lung disease with a poor prognosis, an unpredictable clinical course, and inadequate therapies. There are currently no measures of disease activity to guide clinicians making treatment decisions. The aim of this study was to develop a PET probe to identify lung fibrogenesis using a pre-clinical model of pulmonary fibrosis, with potential for translation into clinical use to predict disease progression and inform treatment decisions. METHODS: Eight novel allysine-targeting chelators, PIF-1, PIF-2, …, PIF-8, with different aldehyde-reactive moieties were designed, synthesized, and radiolabeled with gallium-68 or copper-64. PET probe performance was assessed in C57BL/6J male mice 2 weeks after intratracheal bleomycin challenge and in naïve mice by dynamic PET/MR imaging and with biodistribution at 90 min post injection. Lung hydroxyproline and allysine were quantified ex vivo and histological staining for fibrosis and aldehyde was performed. RESULTS: In vivo screening of probes identified 68GaPIF-3 and 68GaPIF-7 as probes with high uptake in injured lung, high uptake in injured lung versus normal lung, and high uptake in injured lung versus adjacent liver and heart tissue. A crossover, intra-animal PET/MR imaging study of 68GaPIF-3 and 68GaPIF-7 confirmed 68GaPIF-7 as the superior probe. Specificity for fibrogenesis was confirmed in a crossover, intra-animal PET/MR imaging study with 68GaPIF-7 and a non-binding control compound, 68GaPIF-Ctrl. Substituting copper-64 for gallium-68 did not affect lung uptake or specificity indicating that either isotope could be used. CONCLUSION: A series of allysine-reactive PET probes with variations in the aldehyde-reactive moiety were evaluated in a pre-clinical model of lung fibrosis. The hydrazine-bearing probe, 68GaPIF-7, exhibited the highest uptake in fibrogenic lung, low uptake in surrounding liver or heart tissue, and low lung uptake in healthy mice and should be considered for further clinical translation.

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.

Positron Emission Tomography-Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A.

OBJECTIVES: Mn-PyC3A is an experimental manganese (Mn)-based extracellular fluid magnetic resonance imaging (MRI) contrast agent that is being evaluated as a direct replacement for clinical gadolinium (Gd)-based contrast agents. The goals of this study were to use simultaneous positron emission tomography (PET)-MRI to (1) compare the whole-body pharmacokinetics, biodistribution, and elimination of Mn-PyC3A with the liver-specific contrast agent mangafodipir (Mn-DPDP), (2) determine the pharmacokinetics and fractional excretion of Mn-PyC3A in a rat model of renal impairment, and (3) compare whole-body elimination of Mn-PyC3A to gadoterate (Gd-DOTA) in a rat model of renal impairment. METHODS: Mn-PyC3A and Mn-DPDP were radiolabeled with the positron emitting isotope Mn-52 via Mn2+ exchange with 52MnCl2. Dynamic simultaneous PET-MRI was used to measure whole-body pharmacokinetics and biodistribution of Mn-52 immediately and out to 7 days after an intravenous 0.2 mmol/kg dose of [52Mn]Mn-PyC3A to normal or to 5/6 nephrectomy rats or a 0.01 mmol/kg dose of [52Mn]Mn-DPDP to normal rats. The fractional excretion and 1- and 7-day biodistribution in rats after the injection of 2.0 mmol/kg [52Mn]Mn-PyC3A (n = 11 per time point) or 2.0 mmol/kg Gd-DOTA (n = 8 per time point) were quantified by gamma counting or Gd elemental analysis, respectively. Comparisons of Mn-PyC3A pharmacokinetics and in vivo biodistribution in normal and 5/6 nephrectomy rats and comparisons of ex vivo Mn versus Gd biodistribution data in 5/6 nephrectomy were made with an unpaired t test. RESULTS: Dynamic PET-MRI data demonstrate that both [52Mn]Mn-PyC3A and [52Mn]Mn-DPDP were eliminated by mixed renal and hepatobiliary elimination but that a greater fraction of [52Mn]Mn-PyC3A was eliminated by renal filtration. Whole-body PET images show that Mn-52 from [52Mn]Mn-PyC3A was efficiently eliminated from the body, whereas Mn-52 from [52Mn]Mn-DPDP was retained throughout the body. The blood elimination half-life of [52Mn]Mn-PyC3A in normal and 5/6 nephrectomy rats was 13 ± 3.5 minutes and 23 ± 12 minutes, respectively (P = 0.083). Area under the curve between 0 and 60 minutes postinjection (AUC0-60) in the bladder of normal and 5/6 nephrectomy rats was 2600 ± 1700 %ID/cc*min and 750 ± 180 %ID/cc*min, respectively (P = 0.024), whereas AUC0-60 in the liver of normal and 5/6 nephrectomy rats was 33 ± 13 %ID/cc*min and 71 ± 16 %ID/cc*min, respectively (P = 0.011), indicating increased hepatobiliary elimination in 5/6 nephrectomy rats. The %IDs of Mn from [52Mn]Mn-PyC3A and Gd from Gd-DOTA recovered from 5/6 nephrectomy rats 1 day after injection were 2.0 ± 1.1 and 1.3 ± 0.34, respectively (P = 0.10) and 7 days after injection were 0.14 ± 0.11 and 0.41 ± 0.24, respectively (P = 0.0041). CONCLUSIONS: Mn-PyC3A has different pharmacokinetics and is more efficiently eliminated than Mn-DPDP in normal rats. Mn-PyC3A is efficiently eliminated from both normal and 5/6 nephrectomy rats, with increased fractional hepatobiliary excretion from 5/6 nephrectomy rats. Mn-PyC3A is more completely eliminated than Gd-DOTA from 5/6 nephrectomy rats after 7 days.

pH imaging reveals worsened tissue acidification in diffusion kurtosis lesion than the kurtosis/diffusion lesion mismatch in an animal model of acute stroke.

Diffusion weighted imaging (DWI) has been commonly used in acute stroke examination, yet a portion of DWI lesion may be salvageable. Recently, it has been shown that diffusion kurtosis imaging (DKI) defines the most severely damaged DWI lesion that does not renormalize following early reperfusion. We postulated that the diffusion and kurtosis lesion mismatch experience heterogeneous hemodynamic and/or metabolic injury. We investigated tissue perfusion, pH, diffusion, kurtosis and relaxation from regions of the contralateral normal area, diffusion lesion, kurtosis lesion and their mismatch in an animal model of acute stroke. Our study revealed significant kurtosis and diffusion lesion volume mismatch (19.7 ± 10.7%, P < 0.01). Although there was no significant difference in perfusion and diffusion between the kurtosis lesion and kurtosis/diffusion lesion mismatch, we showed lower pH in the kurtosis lesion (pH = 6.64 ± 0.12) from that of the kurtosis/diffusion lesion mismatch (6.84 ± 0.11, P < 0.05). Moreover, pH in the kurtosis lesion and kurtosis/diffusion mismatch agreed well with literature values for regions of ischemic core and penumbra, respectively. Our work documented initial evidence that DKI may reveal the heterogeneous metabolic derangement within the commonly used DWI lesion.

Quantitative chemical exchange saturation transfer (CEST) MRI of glioma using Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting.

Chemical Exchange Saturation Transfer (CEST) MRI is sensitive to dilute metabolites with exchangeable protons, allowing tissue characterization in diseases such as acute stroke and tumor. CEST quantification using multi-pool Lorentzian fitting is challenging due to its strong dependence on image signal-to-noise ratio (SNR), initial values and boundaries. Herein we proposed an Image Downsampling Expedited Adaptive Least-squares (IDEAL) fitting algorithm that quantifies CEST images based on initial values from multi-pool Lorentzian fitting of iteratively less downsampled images until the original resolution. The IDEAL fitting in phantom data with superimposed noise provided smaller coefficient of variation and higher contrast-to-noise ratio at a faster fitting speed compared to conventional fitting. We further applied the IDEAL fitting to quantify CEST MRI in rat gliomas and confirmed its advantage for in vivo CEST quantification. In addition to significant changes in amide proton transfer and semisolid macromolecular magnetization transfer effects, the IDEAL fitting revealed pronounced negative contrasts of tumors in the fitted CEST maps at 2 ppm and -1.6 ppm, likely arising from changes in creatine level and nuclear overhauser effects, which were not found using conventional method. It is anticipated that the proposed method can be generalized to quantify MRI data where SNR is suboptimal.

A method for accurate pH mapping with chemical exchange saturation transfer (CEST) MRI.

Chemical exchange saturation transfer (CEST) MRI holds enormous promise for imaging pH. Whereas the routine CEST-weighted MRI contrast is complex and susceptible to confounding factors such as labile proton ratio, chemical shift, bulk water relaxation and RF saturation, ratiometric CEST imaging simplifies pH determination. However, the conventional ratiometric CEST (RCEST) MRI approach is limited to CEST agents with multiple exchangeable groups. To address this limitation, RF power-based ratiometric CEST (PRCEST) imaging has been proposed that ratios CEST effects obtained under different RF power levels. Nevertheless, due to concomitant RF saturation (spillover) effect, the recently proposed PRCEST imaging is somewhat dependent on parameters including bulk water relaxation time and chemical shift. Herein we hypothesized that RF power-based ratiometric analysis of RF spillover effect-corrected inverse CEST asymmetry (PRICEST) provides enhanced pH measurement. The postulation was verified numerically, and validated experimentally using an in vitro phantom. Briefly, our study showed that the difference between MRI-determined pH (pHMRI ) and electrode-measured pH being 0.12 ± 0.13 and 0.04 ± 0.03 for PRCEST and PRICEST imaging, respectively, and the newly proposed PRICEST imaging provides significantly more accurate pH determination than PRCEST imaging (P < 0.01, Wilcoxon signed-rank test). Notably, the exchange rate shows dominantly base-catalysed relationship with pH, independent of creatine concentration (P > 0.10, Analysis of Covariance). In addition, the derived labile proton ratio linearly scales with creatine concentration (P < 0.01, Pearson Regression). To summarize, PRICEST MRI provides concentration-independent pH imaging, augmenting prior quantitative CEST methods for accurate pH mapping. Copyright © 2015 John Wiley & Sons, Ltd.

A theoretical analysis of chemical exchange saturation transfer echo planar imaging (CEST-EPI) steady state solution and the CEST sensitivity efficiency-based optimization approach.

Chemical exchange saturation transfer (CEST) MRI is sensitive to dilute labile protons and microenvironmental properties, augmenting routine relaxation-based MRI. Recent developments of quantitative CEST (qCEST) analysis such as omega plots and RF-power based ratiometric calculation have extended our ability to elucidate the underlying CEST system beyond the simplistic apparent CEST measurement. CEST MRI strongly varies with experimental factors, including the RF irradiation level and duration as well as repetition time and flip angle. In addition, the CEST MRI effect is typically small, and experimental optimization strategies have to be carefully evaluated in order to enhance the CEST imaging sensitivity. Although routine CEST MRI has been optimized largely based on maximizing the magnitude of the CEST effect, the CEST signal-to-noise (SNR) efficiency provides a more suitable optimization index, particularly when the scan time is constrained. Herein, we derive an analytical solution of the CEST effect that takes into account key experimental parameters including repetition time, imaging flip angle and RF irradiation level, and solve its SNR efficiency. The solution expedites CEST imaging sensitivity calculation, substantially faster than the Bloch-McConnell equation-based numerical simulation approach. In addition, the analytical solution-based SNR formula enables the exhaustive optimization of CEST MRI, which simultaneously predicts multiple optimal parameters such as repetition time, flip angle and RF saturation level based on the chemical shift and exchange rate. The sensitivity efficiency-based optimization approach could simplify and guide imaging of CEST agents, including glycogen, glucose, creatine, gamma-aminobutyric acid and glutamate. Copyright © 2016 John Wiley & Sons, Ltd.