Analysis on efficacy of magnetic resonance lymphangiography using INV-001 in healthy beagle dogs.

We aimed to conduct a proof-of-concept study of INV-001 in visualizing lymphatic vessels and nodes without venous contamination and to determine the optimal dose condition of INV-001 for magnetic resonance lymphangiography (MRL) in healthy beagles. MRL was performed using a 3.0-Tesla (T) whole body clinical magnetic resonance imaging (MRI) scanner. A dose-finding study of INV-001 for MRL in beagles (N = 6) was carried out according to an adaptive optimal dose finding design. For the reproducibility study (N = 6), MRL was conducted at selected INV-001 doses (0.056 and 0.112 mg Fe/kg) with a 15 mM concentration. Additionally, an excretion study (N = 3) of INV-001 was conducted by analyzing T1, T2, and T2* maps of the liver and kidney 48 h post-administration. INV-001 administration at doses of 0.056 and 0.112 mg Fe/kg (concentration: 15 mM) consistently demonstrated the visualization of contrast-enhanced lymphatic vessels and nodes without venous contamination in the beagles. The contrast enhancement effect was highest at 30 min after INV-001 administration, then gradually decreasing. No toxicity-related issues were identified during the study. After 48 h, the T1, T2, and T2* values in the liver and both kidneys were found to be comparable to the pre-administration values, indicating thorough INV-001 excretion. The optimal dosing conditions of INV-001 for MRL for contrast-enhanced visualization of lymphatic vessels and nodes exclusively with no venous contamination in beagles was determined to be 0.056 mg Fe/kg with a 15 mM concentration.

Comparison of the Pharmacokinetics of Gadolinium-Based and Iron Oxide-Based Contrast Agents inside the Lymphatic Structure using Magnetic Resonance Lymphangiography.

PURPOSE: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. PROCEDURES: All animals utilized in this study were male Sprague-Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. RESULTS: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 µmol (15 mM, 30 µL) and 0.75 µmol (15 mM, 50 µL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. CONCLUSION: In MRL, INV-001, a novel T1 contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination.

Mapping Changes in Glutamate with Glutamate-Weighted MRI in Forced Swim Test Model of Depression in Rats.

Chemical exchange saturation transfer with glutamate (GluCEST) imaging is a novel technique for the non-invasive detection and quantification of cerebral Glu levels in neuromolecular processes. Here we used GluCEST imaging and 1H magnetic resonance spectroscopy (1H MRS) to assess in vivo changes in Glu signals within the hippocampus in a rat model of depression induced by a forced swim test. The forced swimming test (FST) group exhibited markedly reduced GluCEST-weighted levels and Glu concentrations when examined using 1H MRS in the hippocampal region compared to the control group (GluCEST-weighted levels: 3.67 ± 0.81% vs. 5.02 ± 0.44%, p < 0.001; and Glu concentrations: 6.560 ± 0.292 µmol/g vs. 7.133 ± 0.397 µmol/g, p = 0.001). Our results indicate that GluCEST imaging is a distinctive approach to detecting and monitoring Glu levels in a rat model of depression. Furthermore, the application of GluCEST imaging may provide a deeper insight into the neurochemical involvement of glutamate in various psychiatric disorders.

CCR8 as a Therapeutic Novel Target: Omics-Integrated Comprehensive Analysis for Systematically Prioritizing Indications.

Target identification is a crucial process in drug development, aiming to identify key proteins, genes, and signal pathways involved in disease progression and their relevance in potential therapeutic interventions. While C-C chemokine receptor 8 (CCR8) has been investigated as a candidate anti-cancer target, comprehensive multi-omics analyzes across various indications are limited. In this study, we conducted an extensive bioinformatics analysis integrating genomics, proteomics, and transcriptomics data to establish CCR8 as a promising anti-cancer drug target. Our approach encompassed data collection from diverse knowledge resources, gene function analysis, differential gene expression profiling, immune cell infiltration assessment, and strategic prioritization of target indications. Our findings revealed strong correlations between CCR8 and specific cancers, notably Breast Invasive Carcinoma (BRCA), Colon Adenocarcinoma (COAD), Head and Neck Squamous Cell Carcinoma (HNSC), Rectum adenocarcinoma (READ), Stomach adenocarcinoma (STAD), and Thyroid carcinoma (THCA). This research advances our understanding of CCR8 as a potential target for anti-cancer drug development, bridging the gap between molecular insights and creating opportunities for personalized treatment of solid tumors.

Cerebral Glutamate Alterations Using Chemical Exchange Saturation Transfer Imaging in a Rat Model of Lipopolysaccharide-Induced Sepsis.

Glutamate-weighted chemical exchange saturation transfer (GluCEST) is a useful imaging tool to detect glutamate signal alterations caused by neuroinflammation. This study aimed to visualize and quantitatively evaluate hippocampal glutamate alterations in a rat model of sepsis-induced brain injury using GluCEST and proton magnetic resonance spectroscopy (1H-MRS). Twenty-one Sprague Dawley rats were divided into three groups (sepsis-induced groups (SEP05, n = 7 and SEP10, n = 7) and controls (n = 7)). Sepsis was induced through a single intraperitoneal injection of lipopolysaccharide (LPS) at a dose of 5 mg/kg (SEP05) or 10 mg/kg (SEP10). GluCEST values and 1H-MRS concentrations in the hippocampal region were quantified using conventional magnetization transfer ratio asymmetry and a water scaling method, respectively. In addition, we examined immunohistochemical and immunofluorescence staining to observe the immune response and activity in the hippocampal region after LPS exposure. The GluCEST and 1H-MRS results showed that GluCEST values and glutamate concentrations were significantly higher in sepsis-induced rats than those in controls as the LPS dose increased. GluCEST imaging may be a helpful technique for defining biomarkers to estimate glutamate-related metabolism in sepsis-associated diseases.

Is aryl hydrocarbon receptor antagonism after ischemia effective in alleviating acute hepatic ischemia-reperfusion injury in rats?

Aryl hydrocarbon receptors (AhRs) have been reported to be important mediators of ischemic injury in the brain. Furthermore, the pharmacological inhibition of AhR activation after ischemia has been shown to attenuate cerebral ischemia-reperfusion (IR) injury. Here, we investigated whether AhR antagonist administration after ischemia was also effective in ameliorating hepatic IR injury. A 70% partial hepatic IR (45-min ischemia and 24-h reperfusion) injury was induced in rats. We administered 6,2',4'-trimethoxyflavone (TMF, 5 mg/kg) intraperitoneally 10 min after ischemia. Hepatic IR injury was observed using serum, magnetic resonance imaging-based liver function indices, and liver samples. TMF-treated rats showed significantly lower relative enhancement (RE) values and serum alanine aminotransferase (ALT) and aspartate aminotransferase levels than did untreated rats at 3 h after reperfusion. After 24 h of reperfusion, TMF-treated rats had significantly lower RE values, ΔT1 values, serum ALT levels, and necrotic area percentage than did untreated rats. The expression of the apoptosis-related proteins, Bax and cleaved caspase-3, was significantly lower in TMF-treated rats than in untreated rats. This study demonstrated that inhibition of AhR activation after ischemia was effective in ameliorating IR-induced liver injury in rats.

Amide Proton Transfer-weighted 7-T MRI Contrast of Myelination after Cuprizone Administration.

Background Investigations of amide proton signal changes in the white matter of demyelinating diseases may provide important biophysical information for diagnostic and prognostic assessments. Purpose To evaluate amide proton signals in cuprizone-induced rats using amide proton transfer-weighted (APTw) MRI, which provides in vivo image contrast by changing amide proton concentrations during demyelination (DEM) and subsequent remyelination (REM). Materials and Methods In this animal study, APTw 7-T MRI was performed in 21 male Wistar rats divided into cuprizone-induced (n = 14) and control (n = 7) groups from February to August 2020. The cuprizone-induced group was further subdivided into DEM (n = 7) and REM (n = 7) groups. Seven weeks after cuprizone feeding, rats in the DEM group were killed prior to transmission electron microscopy and myelin staining, while rats in the REM group were changed to a normal chow diet and fed for 5 weeks. In each group, the APTw signals were calculated using a conventional magnetization transfer ratio at 3.5 ppm based on regions of interest in the corpus callosum. Statistical differences in APTw signals among the groups were analyzed with one-way analysis of variance followed by Tukey post hoc tests. Results The mean APTw signals in the control and DEM groups were -4.42% ± 0.60 (standard deviation) (95% CI: -4.98, -3.86) and -2.57% ± 0.48 (95% CI: -3.01, -2.12), respectively, indicating higher in vivo APTw signals in the DEM lesion (P < .001). After REM, mean APTw signal in the REM group was -3.83% ± 0.67 (95% CI: -4.45, -3.22), similar to that in the control group (P = .18) and lower than that in the DEM group (P < .001). Conclusion Significant amide proton transfer-weighted (APTw) metric changes coupled with the histologic characteristics of the demyelination and remyelination processes indicate the potential usefulness of APTw 7-T MRI to monitor earlier myelination processes. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by van Zijl in this issue.

Temporal Changes in In Vivo Glutamate Signal during Demyelination and Remyelination in the Corpus Callosum: A Glutamate-Weighted Chemical Exchange Saturation Transfer Imaging Study.

BACKGROUND: Glutamate-weighted chemical exchange saturation transfer (GluCEST) is a useful imaging tool that can be used to detect changes in glutamate levels in vivo and could also be helpful in the diagnosis of brain myelin changes. We investigated glutamate level changes in the cerebral white matter of a rat model of cuprizone-administered demyelination and remyelination using GluCEST. METHOD: We used a 7 T pre-clinical magnetic resonance imaging (MRI) system. The rats were divided into the normal control (CTRL), cuprizone-administered demyelination (CPZDM), and remyelination (CPZRM) groups. GluCEST data were analyzed using the conventional magnetization transfer ratio asymmetry in the corpus callosum. Immunohistochemistry and transmission electron microscopy analyses were also performed to investigate the myelinated axon changes in each group. RESULTS: The quantified GluCEST signals differed significantly between the CPZDM and CTRL groups (-7.25 ± 1.42% vs. -2.84 ± 1.30%; p = 0.001). The increased GluCEST signals in the CPZDM group decreased after remyelination (-6.52 ± 1.95% in CPZRM) to levels that did not differ significantly from those in the CTRL group (p = 0.734). CONCLUSION: The apparent temporal signal changes in GluCEST imaging during demyelination and remyelination demonstrated the potential usefulness of GluCEST imaging as a tool to monitor the myelination process.

Aryl hydrocarbon receptor antagonism before reperfusion attenuates cerebral ischaemia/reperfusion injury in rats.

Aryl hydrocarbon receptor (AhR) antagonism can mitigate cellular damage associated with cerebral ischaemia and reperfusion (I/R) injury. This study investigated the neuroprotective effects of AhR antagonist administration before reperfusion in a rat stroke model and influence of the timing of AhR antagonist administration on its neuroprotective effects. Magnetic resonance imaging (MRI) was performed at baseline, immediately after, and 3, 8, and 24 h after ischaemia in the sham, control (I/R injury), TMF10 (trimethoxyflavone [TMF] administered 10 min post-ischaemia), and TMF50 (TMF administered 50 min post-ischaemia) groups. The TMF treatment groups had significantly fewer infarcts than the control group. At 24 h, the relative apparent diffusion coefficient values of the ischaemic core and peri-infarct region were significantly higher and relative T2 values were significantly lower in the TMF10 groups than in the control group. The TMF treatment groups showed significantly fewer terminal deoxynucleotidyl transferase dUTP nick-end labelling positive (+) cells (%) in the peri-infarct region than the control group. This study demonstrated that TMF treatment 10 or 50 min after ischaemia alleviated brain damage. Furthermore, the timing of AhR antagonist administration affected the inhibition of cellular or vasogenic oedema formation caused by a transient ischaemic stroke.

Signal alterations of glutamate-weighted chemical exchange saturation transfer MRI in lysophosphatidylcholine-induced demyelination in the rat brain.

PURPOSE: To compare in vivo glutamate-weighted chemical exchange saturation transfer (GluCEST-weighted) signal changes between in a rat model of demyelinated multiple sclerosis and control groups. PROCEDURES: Using a pre-clinical 7 T magnetic resonance imaging (MRI) system, CEST imaging was applied to a toxin (lysophosphatidylcholine; LPC) induced rat (MSLPC) and control (CTRL) groups to compare in vivo glutamate signal changes. The GluCEST-weighted signals were analyzed based on the magnetization transfer ratio asymmetry approach at 3.0 ppm on the region-of-interests (ROIs) in the corpus callosum and hippocampus at each hemispheric region. RESULTS: GluCEST-weighted signals were significantly changed between the CTRL and MSLPC groups, while higher glutamate signals were indicated in the MSLPC than the CTRL group ([MSLPC / CTRL]; hippocampus: [6.159 ± 0.790 / 4.336 ± 0.446] and corpus callosum: [-3.545 ± 0.945 / -6.038 ± 0.620], all p = 0.001). CONCLUSIONS: Our results show increased GluCEST-weighted signals in the LPC-induced demyelination rat brain compared with control. GluCEST-weighted imaging could be a useful tool for defining a biomarker to estimate the glutamate-related metabolism in MS.

Regional Mapping of Brain Glutamate Distributions Using Glutamate-Weighted Chemical Exchange Saturation Transfer Imaging.

PURPOSE: To investigate glutamate signal distributions in multiple brain regions of a healthy rat brain using glutamate-weighted chemical exchange saturation transfer (GluCEST) imaging. METHOD: The GluCEST data were obtained using a 7.0 T magnetic resonance imaging (MRI) scanner, and all data were analyzed using conventional magnetization transfer ratio asymmetry in eight brain regions (cortex, hippocampus, corpus callosum, and rest of midbrain in each hemisphere). GluCEST data acquisition was performed again one month later in five randomly selected rats to evaluate the stability of the GluCEST signal. To evaluate glutamate level changes calculated by GluCEST data, we compared the results with the concentration of glutamate acquired from 1H magnetic resonance spectroscopy (1H MRS) data in the cortex and hippocampus. RESULTS: GluCEST signals showed significant differences (all p ≤ 0.001) between the corpus callosum (-1.71 ± 1.04%; white matter) and other brain regions (3.59 ± 0.41%, cortex; 5.47 ± 0.61%, hippocampus; 4.49 ± 1.11%, rest of midbrain; gray matter). The stability test of GluCEST findings for each brain region was not significantly different (all p ≥ 0.263). In line with the GluCEST results, glutamate concentrations measured by 1H MRS also appeared higher in the hippocampus (7.30 ± 0.16 µmol/g) than the cortex (6.89 ± 0.72 µmol/g). CONCLUSION: Mapping of GluCEST signals in the healthy rat brain clearly visualize glutamate distributions. These findings may yield a valuable database and insights for comparing glutamate signal changes in pre-clinical brain diseases.

In Vivo Measurement of Neurochemical Abnormalities in the Hippocampus in a Rat Model of Cuprizone-Induced Demyelination.

This study quantitatively measured the changes in metabolites in the hippocampal lesions of a rat model of cuprizone-induced demyelination as detected using in vivo 7 T proton magnetic resonance spectroscopy. Nineteen Sprague Dawley rats were randomly divided into two groups and fed a normal chow diet or cuprizone (0.2%, w/w) for 7 weeks. Demyelinated hippocampal lesions were quantitatively measured using a 7 T magnetic resonance imaging scanner. All proton spectra were quantified for metabolite concentrations and relative ratios. Compared to those in the controls, the cuprizone-induced rats had significantly higher concentrations of glutamate (p = 0.001), gamma-aminobutyric acid (p = 0.019), and glutamate + glutamine (p = 0.001); however, creatine + phosphocreatine (p = 0.006) and myo-inositol (p = 0.001) concentrations were lower. In addition, we found that the glutamine and glutamate complex/total creatine (p < 0.001), glutamate/total creatine (p < 0.001), and GABA/total creatine (p = 0.002) ratios were significantly higher in cuprizone-treated rats than in control rats. Our results showed that cuprizone-induced neuronal demyelination may influence the severe abnormal metabolism in hippocampal lesions, and these responses could be caused by microglial activation, mitochondrial dysfunction, and astrocytic necrosis.

Optimization of Keyhole Imaging Parameters for Glutamate Chemical Exchange Saturation Transfer MRI at 7.0 T.

PURPOSE: To evaluate the effects of a reference image and keyhole factor (Kf) selections for high-frequency substitution on keyhole imaging technique for applications in glutamate chemical exchange saturation transfer (GluCEST) imaging. PROCEDURES: The CEST data were obtained using a 7.0 T MRI scanner. We used varied Kf ranges that constituted from 16.67 to 75 % of the full k-space. The reference image was respectively selected for - 3 and + 3 ppm images that associated with the GluCEST calculation and the unsaturated image. The zero-padding algorithm was applied for the missing k-space lines in the low-frequency data collected to compare the results obtained from using the keyhole imaging technique. All the techniques were evaluated using a healthy rat group and extended to the status epilepticus rat group to explore their applicability and usability. RESULTS: The calculated GluCEST signals and visually inspected results from the reconstructed GluCEST maps indicated that the combination of unsaturated image as a reference image, and over 50 % of Kf showed consistent signals and image quality compared with the fully sampled CEST data. CONCLUSIONS: Combining the keyhole imaging technique with GluCEST imaging enables stable image reconstruction and quantitative evaluation, and this approach is potentially applicable in various CEST imaging applications.

Retrospective Brain Motion Correction in Glutamate Chemical Exchange Saturation Transfer (GluCEST) MRI.

PURPOSE: To evaluate the feasibility of motion correction in glutamate chemical exchange saturation transfer (GluCEST) imaging, using a rat model of epileptic seizure. PROCEDURES: Epileptic seizure was induced in six male Wistar rats by intraperitoneal injection of kainic acid (KA). CEST data were obtained using a 7.0 T Bruker MRI scanner before and 3 h after KA injection. Retrospective motion correction was performed in CEST images using a gradient-based motion correction (GradMC) algorithm. GluCEST signals in the hippocampal regions were quantitatively evaluated with and without motion correction. RESULTS: Calculated GluCEST signals differed significantly between the pre-KA injection group, regardless of motion-correction implementation, and the post-KA injection group with motion correction (3.662 ± 1.393 % / 3.726 ± 1.982 % for pre-KA injection group with/without motion correction vs. 6.996 ± 1.684 % for post-KA injection group with motion correction; all P < 0.05). CONCLUSIONS: Our results clearly show that GradMC can be used in CEST imaging for efficient correction of seizure-like motion. The GradMC can be further implemented in various CEST imaging techniques to increase the accuracy of analysis.

Cerebral mapping of glutamate using chemical exchange saturation transfer imaging in a rat model of stress-induced sleep disturbance at 7.0T.

BACKGROUND: Glutamate chemical exchange saturation transfer (GluCEST) imaging has been widely used in brain psychiatric disorders. Glutamate signal changes may help to evaluate the sleep-related disorders, and could be useful in diagnosis. PURPOSE: To evaluate signal changes in the hippocampus and cortex of a rat model of stress-induced sleep disturbance using GluCEST. STUDY TYPE: Prospective animal study. ANIMAL MODEL: Fourteen male Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: 7.0T small bore MRI / fat-suppressed, turbo-rapid acquisition with relaxation enhancement (RARE) for CEST, and spin-echo, point-resolved proton MR spectroscopy (1 H MRS). ASSESSMENT: Rats were divided into two groups: the stress-induced sleep-disturbance group (SSD, n = 7) and the control group (CTRL, n = 7), to evaluate and compare the cerebral glutamate signal changes. GluCEST data were quantified using a conventional magnetization transfer ratio asymmetry in the left- and right-side hippocampus and cortex. The correlation between GluCEST signal and glutamate concentrations, derived from 1 H MRS, was evaluated. STATISTICAL ANALYSIS: Wilcoxon rank-sum test between CEST signals and multiparametric MR signals, Wilcoxon signed-rank test between CEST signals on the left and right hemispheres, and a correlation test between CEST signals and glutamate concentrations derived from 1 H MRS. RESULTS: Measured GluCEST signals showed significant differences between the two groups (left hippocampus; 4.23 ± 0.27% / 5.27 ± 0.42% [SSD / CTRL, P = 0.002], right hippocampus; 4.50 ± 0.44% / 5.04 ± 0.34% [P = 0.035], left cortex; 2.81 ± 0.38% / 3.56 ± 0.41% [P = 0.004], and right cortex; 2.95 ± 0.47% / 3.82 ± 0.26% [P = 0.003]). GluCEST signals showed positive correlation with glutamate concentrations (R2 = 0.312; P = 0.038). DATA CONCLUSION: GluCEST allowed the visualization of cerebral glutamate changes in rats subjected to sleep disturbance, and may yield valuable insights for interpreting alterations in cerebral biochemical information. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1866-1872.

Changes to gamma-aminobutyric acid levels during short-term epileptiform activity in a kainic acid-induced rat model of status epilepticus: A chemical exchange saturation transfer imaging study.

PURPOSE: To evaluate temporal changes in gamma-aminobutyric acid (GABA) signals in the hippocampus during epileptiform activity induced by kainic acid (KA) in a rat model of status epilepticus using chemical exchange saturation transfer (CEST) imaging technique. METHODS: CEST imaging and 1H magnetic resonance spectroscopy (1H MRS) were applied to a systemic KA-induced rat model to compare GABA signals. All data acquisition and analytical procedures were performed at three different time points (before KA injection, and 1 and 3 h after injection). The CEST signal was analyzed based on regions of interests (ROIs) in the hippocampus, while 1H MRS was analyzed within a 12.0 µL ROI in the left hippocampus. Signal correlations between the two methods were evaluated as a function of time change up to 3 h after KA injection. RESULTS: The measured GABA CEST-weighted signal intensities of the rat epileptic hippocampus before injection showed significant differences from those after (averaged signals from both hippocampi: 4.37% ±â€¯0.87% and 7.305 ±â€¯1.11%; P < 0.05), although the signal had increased slightly at both time points after KA injection, the differences were not significant (P > 0.05). In contrast, the correlation between the CEST imaging values and 1H MRS was significant (r ≥ 0.64; P < 0.05; in all cases). CONCLUSIONS: GABA signal changes during epileptiform activity in the rat hippocampus, as detected using CEST imaging, provided a significant contrast according to changes in metabolic activity. Our technical approach may serve as a potential supplemental option to provide biomarkers for brain disease.

Does the Apparent Diffusion Coefficient Value Predict Permanent Cerebral Ischemia/Reperfusion Injury in Rats?

RATIONALE AND OBJECTIVES: Variation in tissue damage after cerebral ischemia/reperfusion (I/R) can cause uncertainty in stroke-related studies, which can be reduced if the damage can be predicted early after ischemia by measuring the apparent diffusion coefficient (ADC). We investigated whether ADC measurement in the acute phase can predict permanent cerebral I/R injury. MATERIALS AND METHODS: The middle cerebral artery occlusion model was established using the intraluminal suture method to induce 60 minutes of ischemia followed by reperfusion in rats. T2-weighted images and diffusion-weighted images were obtained at 30 minutes and 24 hours after ischemia. Neuronal cell survival was assessed by neuronal nuclei (NeuN) immunofluorescence staining. The correlation between relative ADC (rADC) values at 30 minutes and I/R injury at 24 hours after ischemia was analyzed. Magnetic resonance imaging results were confirmed by histologic analysis. RESULTS: The correlation between rADC values at 30 minutes and 24 hours was strong in the ischemic core and peri-infarct region but moderate in the anterior choroidal and hypothalamic region. Histologic analysis revealed that the correlation between rADC values at 30 minutes and the number of NeuN-positive cells at 24 hours was strong in the ischemic core and peri-infarct region but moderate in the anterior choroidal and hypothalamic region. Furthermore, there was a strong positive correlation between the sum of rADC values of three regions at 30 minutes and the infarct volume at 24 hours. CONCLUSION: ADC measurement in the acute phase can predict permanent cerebral I/R injury and provide important information for the evaluation of ischemic stroke.

In Vivo Mapping and Quantification of Creatine Using Chemical Exchange Saturation Transfer Imaging in Rat Models of Epileptic Seizure.

PURPOSE: To evaluate signal changes in the hippocampus of epileptic seizure rat models, based on quantified creatine chemical exchange saturation transfer (CrCEST) signals. PROCEDURES: CEST data and 1H magnetic resonance spectroscopy (1H MRS) data were obtained for the two imaging groups: control (CTRL) and epileptic seizure-induced (ES; via kainic acid [KA] injection) groups. CrCEST signals in the hippocampal regions were quantitatively evaluated; correlations between CrCEST signals and phosphocreatine (PCr) and total creatine (tCr; PCr + Cr) concentrations, derived from the analysis of 1H MRS data, were investigated as a function of time changes (before KA injection, 3 and 5 h after KA injection). RESULTS: Measured CrCEST signals were exhibited significant differences between before and after KA injection in the ES group. At each time point, CrCEST signals showed significant correlations with PCr concentration (all |r| > 0.59; all P < 0.05); no significant correlations were found between CrCEST signals and tCr concentrations (all |r| < 0.22; all P > 0.05). CONCLUSIONS: CrCEST can adequately detect changes in the concentration of Cr as a result of energy metabolism, and may serve as a potentially useful tool for diagnosis and assessment of prognosis in epilepsy.

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters.

Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic-contrast-enhanced MRI (DCE-MRI) using extravascular extracellular agent (Gd-DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region-dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment-induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α-caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

Minimisation of Signal Intensity Differences in Distortion Correction Approaches of Brain Magnetic Resonance Diffusion Tensor Imaging.

OBJECTIVES: To evaluate the effects of signal intensity differences between the b0 image and diffusion tensor imaging (DTI) in the image registration process. METHODS: To correct signal intensity differences between the b0 image and DTI data, a simple image intensity compensation (SIMIC) method, which is a b0 image re-calculation process from DTI data, was applied before the image registration. The re-calculated b0 image (b0ext) from each diffusion direction was registered to the b0 image acquired through the MR scanning (b0nd) with two types of cost functions and their transformation matrices were acquired. These transformation matrices were then used to register the DTI data. For quantifications, the dice similarity coefficient (DSC) values, diffusion scalar matrix, and quantified fibre numbers and lengths were calculated. RESULTS: The combined SIMIC method with two cost functions showed the highest DSC value (0.802 ± 0.007). Regarding diffusion scalar values and numbers and lengths of fibres from the corpus callosum, superior longitudinal fasciculus, and cortico-spinal tract, only using normalised cross correlation (NCC) showed a specific tendency toward lower values in the brain regions. CONCLUSION: Image-based distortion correction with SIMIC for DTI data would help in image analysis by accounting for signal intensity differences as one additional option for DTI analysis. KEY POINTS: • We evaluated the effects of signal intensity differences at DTI registration. • The non-diffusion-weighted image re-calculation process from DTI data was applied. • SIMIC can minimise the signal intensity differences at DTI registration.