Comparison of dosimetric impact of intra-fractional setup discrepancy between multiple- and single-isocenter approaches in linac-based stereotactic radiotherapy of multiple brain metastases.

INTRODUCTION: Treatment of multiple brain metastases by linac-based stereotactic radiotherapy (SRT) can employ either a multiple-isocenter (MI) or single-isocenter (SI) approach. The purposes of this study were to evaluate the dosimetric results of MI and SI approaches and compare the impacts of intra-fractional setup discrepancies on the robustness of respective approaches using isocenter shifts, whether the same magnitude of translational and rotational effects could lead to a significant difference between the two approaches. METHODS: Twenty-two patients with multiple brain metastases treated by linac-based SRT were recruited. Treatment plans were computed with both the MI and SI approaches. For the MI approach, the isocenter was located at the geometric center of each planning target volumes (PTVs), whereas the isocenter of the SI approach was located midway between the PTV centroids. To simulate the intra-fractional errors, isocenter displacements including translational and rotational shifts were hypothetically applied. Apart from the dosimetric outcomes of the two approaches, the impact of the isocenter shifts on PTVs and organs at risk (OARs) were recorded in terms of the differences (δ) in dose parameters relative to the reference plan and was then compared between the MI and SI approaches. RESULTS: Both MI and SI plans met the plan acceptance criteria. The mean Paddick conformity index (Paddick CI) and Dmax of most OARs between MI and SI plans did not show a significant difference, except that higher doses to the left optic nerve and optic chiasm were found in SI plans (p = 0.03). After the application of the isocenter shifts, δCI increased with an increase in the magnitude of the isocenter shift. When comparing between MI and SI plans, the δCIs were similar (p > 0.05) for all extents of translational shifts, but δCIs were significantly higher in SI plans after application of all rotations particularly ±1.5° and ±2.0° shifts. Despite the result that the majority of δDMax of OARs were higher in the SI plans, only the differences in the left optic nerve and chiasm showed generally consistent significance after both translational ≥±1 mm and rotational shifts of ≥±1 ∘ $^\circ $ . CONCLUSION: Both MI and SI approaches could produce clinically acceptable plans. However, isocenter shifts brought dosimetric impacts to both MI and SI approaches and the effects increased with the increase of the shift magnitude. Although similar impacts were shown in plans of both approaches after translational isocenter shift, SI plans were relatively more vulnerable than MI plans to rotational shifts.

Mapping tissue pH in an experimental model of acute stroke - Determination of graded regional tissue pH changes with non-invasive quantitative amide proton transfer MRI.

pH-weighted amide proton transfer (APT) MRI is sensitive to tissue pH change during acute ischemia, complementing conventional perfusion and diffusion stroke imaging. However, the currently used pH-weighted magnetization transfer (MT) ratio asymmetry (MTRasym) analysis is of limited pH specificity. To overcome this, MT and relaxation normalized APT (MRAPT) analysis has been developed that to homogenize the background signal, thus providing highly pH conspicuous measurement. Our study aimed to calibrate MRAPT MRI toward absolute tissue pH mapping and determine regional pH changes during acute stroke. Using middle cerebral artery occlusion (MCAO) rats, we performed lactate MR spectroscopy and multi-parametric MRI. MRAPT MRI was calibrated against a region of interest (ROI)-based pH spectroscopy measurement (R2 = 0.70, P < 0.001), showing noticeably higher correlation coefficient than the simplistic MTRasym index. Capitalizing on this, we mapped brain tissue pH and semi-automatically segmented pH lesion, in addition to routine perfusion and diffusion lesions. Tissue pH from regions of the contralateral normal, perfusion/diffusion lesion mismatch and diffusion lesion was found to be 7.03 ±â€¯0.04, 6.84 ±â€¯0.10, 6.52 ±â€¯0.19, respectively. Most importantly, we delineated the heterogeneous perfusion/diffusion lesion mismatch into perfusion/pH and pH/diffusion lesion mismatches, with their pH being 7.01 ±â€¯0.04 and 6.71 ±â€¯0.12, respectively (P < 0.05). To summarize, our study calibrated pH-sensitive MRAPT MRI toward absolute tissue pH mapping, semi-automatically segmented and determined graded tissue pH changes in ischemic tissue and demonstrated its feasibility for refined demarcation of heterogeneous metabolic disruption following acute stroke.

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.

Direct saturation-corrected chemical exchange saturation transfer MRI of glioma: Simplified decoupling of amide proton transfer and nuclear overhauser effect contrasts.

PURPOSE: Chemical exchange saturation transfer (CEST) MRI has shown promise in tissue characterization in diseases like stroke and tumor. However, in vivo CEST imaging such as amide proton transfer (APT) MRI is challenging because of concomitant factors such as direct water saturation, macromolecular magnetization transfer, and nuclear overhauser effect (NOE), which lead to a complex contrast in the commonly used asymmetry analysis (MTRasym). Here, we propose a direct saturation-corrected CEST (DISC-CEST) analysis for simplified decoupling and quantification of in vivo CEST effects. METHODS: CEST MRI and relaxation measurements were carried out on a classical 2-pool creatine-gel CEST phantom and normal rat brains (N = 6) and a rat model of glioma (N = 8) at 4.7T. The proposed DISC-CEST quantification was carried out and compared with conventional MTRasym and the original three-offset method. RESULTS: We demonstrated that the DISC-CEST contrast in the phantom had much stronger correlation with MTRasym than the three-offset method, which showed substantial underestimation. In normal rat brains, the DISC-CEST approach revealed significantly stronger APT effect in gray matter and higher NOE effect in white matter. Furthermore, the APT and NOE maps derived from DISC-CEST showed significantly higher APT effect in the tumors than contralateral normal tissue but no apparent difference in NOE. CONCLUSION: The proposed DISC-CEST method, by correction of nonlinear direct water saturation effect, serves as a promising alternative to both the commonly used MTRasym and the simplistic three-offset analyses. It provides simple yet reliable in vivo CEST quantification such as APT and NOE mapping in brain tumor, which is promising for clinical translation. Magn Reson Med 78:2307-2314, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Stratification of heterogeneous diffusion MRI ischemic lesion with kurtosis imaging: evaluation of mean diffusion and kurtosis MRI mismatch in an animal model of transient focal ischemia.

BACKGROUND AND PURPOSE: Ischemic tissue damage is heterogeneous, resulting in complex patterns in the widely used diffusion-weighted MRI. Our study examined the spatiotemporal characteristics of diffusion kurtosis imaging in an animal model of transient middle cerebral artery occlusion. METHODS: Adult male Wistar rats (N=18) were subjected to 90 minutes middle cerebral artery occlusion. Multiparametric MR images were obtained during middle cerebral artery occlusion and 20 minutes after reperfusion with diffusion-weighted MRI obtained using 8 b-values from 250 to 3000 s/mm(2) in 6 diffusion gradient directions. Diffusion and kurtosis lesions were outlined in shuffled images by 2 investigators independently. T(2) MRI was obtained 24 hours after middle cerebral artery occlusion to evaluate stroke outcome. RESULTS: Mean diffusion lesion (23.5%±8.1%, percentage of the brain slice) was significantly larger than mean kurtosis lesion (13.2%±2.0%) during middle cerebral artery occlusion. Mean diffusion lesion decreased significantly after reperfusion (13.8%±4.3%), whereas mean kurtosis lesion showed little change (13.0%±2.5%) with their lesion size difference being insignificant. CONCLUSIONS: We demonstrated that mean diffusion/mean kurtosis mismatch recovered reasonably well on reperfusion, whereas regions with concurrent mean diffusion and mean kurtosis deficits showed poor recovery. Diffusion kurtosis imaging may help stratify heterogeneous diffusion-weighted MRI lesions for enhanced characterization of ischemic tissue injury.

Imaging acute ischemic tissue acidosis with pH-sensitive endogenous amide proton transfer (APT) MRI--correction of tissue relaxation and concomitant RF irradiation effects toward mapping quantitative cerebral tissue pH.

Amide proton transfer (APT) MRI is sensitive to ischemic tissue acidosis and has been increasingly used as a research tool to investigate disrupted tissue metabolism during acute stroke. However, magnetization transfer asymmetry (MTR(asym)) analysis is often used for calculating APT contrast, which only provides pH-weighted images. In addition to pH-dependent APT contrast, in vivo MTR(asym) is subject to a baseline shift (ΔMTR'(asym)) attributable to the slightly asymmetric magnetization transfer (MT) effect. Additionally, APT contrast approximately scales with T(1) relaxation time. Tissue relaxation time may also affect the experimentally obtainable APT contrast via saturation efficiency and RF spillover effects. In this study, we acquired perfusion, diffusion, relaxation and pH-weighted APT MRI data, and spectroscopy (MRS) in an animal model of acute ischemic stroke. We modeled in vivo MTR(asym) as a superposition of pH-dependent APT contrast and a baseline shift ΔMTR'(asym) (i.e., MTR(asym)=APTR(pH)+ΔMTR'(asym)), and quantified tissue pH. We found pH of the contralateral normal tissue to be 7.03±0.05 and the ipsilateral ischemic tissue pH was 6.44±0.24, which correlated with tissue perfusion and diffusion rates. In summary, our study established an endogenous and quantitative pH imaging technique for improved characterization of ischemic tissue acidification and metabolism disruption.

Fast radio-frequency enforced steady state (FRESS) spin echo MRI for quantitative T2 mapping: minimizing the apparent repetition time (TR) dependence for fast T2 measurement.

Transverse relaxation time (T(2)) is a basic but very informative MRI parameter, widely used in imaging to examine a host of diseases, including multiple sclerosis, stroke, and tumor. However, short repetition time (TR) is often used to minimize scan time, which may introduce non-negligible errors in T(2) measurement. Specifically, due to the use of refocusing pulse, the steady state magnetization depends not only on TR but also on the TE. Hence, if the TE dependence is not properly accounted for, it may be mistaken as T(2)-induced signal attenuation, leading to non-negligible T(2) underestimation. Our study proposed a fast radio-frequency enforced steady state (FRESS) spin echo (SE) MRI sequence, which saturates the magnetization after the echo and ensures a TE-independent steady state. The proposed FRESS-SE MRI was evaluated with numerical simulation, implemented with echo planar imaging readout, and validated by both phantom and in vivo experiments. In summary, FRESS-SE T(2) MRI technique was developed for fast and accurate T(2) imaging, suitable for in vivo applications.

Simulation and optimization of pulsed radio frequency irradiation scheme for chemical exchange saturation transfer (CEST) MRI-demonstration of pH-weighted pulsed-amide proton CEST MRI in an animal model of acute cerebral ischemia.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is capable of measuring dilute labile protons and microenvironmental properties. However, the CEST contrast is dependent upon experimental conditions-particularly, the radiofrequency (RF) irradiation scheme. Although continuous-wave RF irradiation has been used conventionally, the limited RF pulse duration or duty cycle of most clinical systems requires the use of pulsed RF irradiation. Here, the conventional numerical simulation is extended to describe pulsed-CEST MRI contrast as a function of RF pulse parameters (i.e., RF pulse duration and flip angle) and labile proton properties (i.e., exchange rate and chemical shift). For diamagnetic CEST agents undergoing slow or intermediate chemical exchange, simulation shows a linear regression relationship between the optimal mean RF power of pulsed-CEST MRI and continuous-wave-CEST MRI. The optimized pulsed-CEST contrast is approximately equal to that of continuous-wave-CEST MRI for exchange rates less than 50 s(-1), as confirmed experimentally using a multicompartment pH phantom. In the acute stroke animals, we showed that pulsed- and continuous-wave-amide proton CEST MRI demonstrated similar contrast. In summary, our study elucidated the RF irradiation dependence of pulsed-CEST MRI contrast, providing useful insights to guide its experimental optimization and quantification.

Fast multislice pH-weighted chemical exchange saturation transfer (CEST) MRI with Unevenly segmented RF irradiation.

Chemical exchange saturation transfer (CEST) MRI is a versatile imaging technique for measuring microenvironment properties via dilute CEST labile groups. Conventionally, CEST MRI is implemented with a long radiofrequency irradiation module, followed by fast image acquisition to obtain the steady state CEST contrast. Nevertheless, the sensitivity, scan time, and spatial coverage of the conventional CEST MRI method may not be optimal. Our study proposed a segmented radiofrequency labeling scheme that includes a long primary radiofrequency irradiation module to generate the steady state CEST contrast and repetitive short secondary radiofrequency irradiation module immediately after the image acquisition so as to maintain the steady state CEST contrast for multislice acquisition and signal averaging. The proposed CEST MRI method was validated experimentally with a tissue-like pH phantom and optimized for the maximal contrast-to-noise ratio. In addition, the proposed sequence was evaluated for imaging ischemic acidosis via pH-weighted endogenous amide proton transfer MRI, which showed similar contrast as conventional amide proton transfer MRI. In sum, a fast multislice relaxation self-compensated CEST MRI sequence was developed, with significantly improved sensitivity and suitable for in vivo applications.

Rapid monitoring of iron-chelating therapy in thalassemia major by a new cardiovascular MR measure: the reduced transverse relaxation rate.

In iron overload, almost all the excess iron is stored intracellularly as rapidly mobilizable ferritin iron and slowly exchangeable hemosiderin iron. Increases in cytosolic iron may produce oxidative damage that ultimately results in cardiomyocyte dysfunction. Because intracellular ferritin iron is evidently in equilibrium with the low-molecular-weight cytosolic iron pool, measurements of ferritin iron potentially provide a clinically useful indicator of changes in cytosolic iron. The cardiovascular magnetic resonance (CMR) index of cardiac iron used clinically, the effective transverse relaxation rate (R(2)*), is principally influenced by hemosiderin iron and changes only slowly over several months, even with intensive iron-chelating therapy. Another conventional CMR index of cardiac iron, the transverse relaxation rate (R(2)), is sensitive to both hemosiderin iron and ferritin iron. We have developed a new MRI measure, the 'reduced transverse relaxation rate' (RR(2)), and have proposed in previous studies that this measure is primarily sensitive to ferritin iron and largely independent of hemosiderin iron in phantoms mimicking ferritin iron and human liver explants. We hypothesized that RR(2) could detect changes produced by 1 week of iron-chelating therapy in patients with transfusion-dependent thalassemia. We imaged 10 patients with thalassemia major at 1.5 T in mid-ventricular short-axis planes of the heart, initially after suspending iron-chelating therapy for 1 week and subsequently after resuming oral deferasirox. After resuming iron-chelating therapy, significant decreases were observed in the mean myocardial RR(2) (7.8%, p < 0.01) and R(2) (5.5%, p < 0.05), but not in R(2)* (1.7%, p > 0.90). Although the difference between changes in RR(2) and R(2) was not significant (p > 0.3), RR(2) was consistently more sensitive than R(2) (and R(2)*) to the resumption of iron-chelating therapy, as judged by the effect sizes of relaxation rate differences detected. Although further studies are needed, myocardial RR(2) may be a promising investigational method for the rapid assessment of the effects of iron-chelating therapy in the heart.

Reduced transverse relaxation rate (RR2) for improved sensitivity in monitoring myocardial iron in thalassemia.

PURPOSE: To evaluate the reduced transverse relaxation rate (RR2), a new relaxation index which has been shown recently to be primarily sensitive to intracellular ferritin iron, as a means of detecting short-term changes in myocardial storage iron produced by iron-chelating therapy in transfusion-dependent thalassemia patients. MATERIALS AND METHODS: A single-breathhold multi-echo fast spin-echo sequence was implemented at 3 Tesla (T) to estimate RR2 by acquiring signal decays with interecho times of 5, 9 and 13 ms. Transfusion-dependent thalassemia patients (N = 8) were examined immediately before suspending iron-chelating therapy for 1 week (Day 0), after a 1-week suspension of chelation (Day 7), and after a 1-week resumption of chelation (Day 14). RESULTS: The mean percent changes in RR2, R2, and R2* off chelation (between Day 0 and 7) were 11.9 ± 8.9%, 5.4 ± 7.7% and -4.4 ± 25.0%; and, after resuming chelation (between Day 7 and 14), -10.6 ± 13.9%, -8.9 ± 8.0% and -8.5 ± 24.3%, respectively. Significant differences in R2 and RR2 were observed between Day 0 and 7, and between Day 7 and 14, with the greatest proportional changes in RR2. No significant differences in R2* were found. CONCLUSION: These initial results demonstrate that significant differences in RR2 are detectable after a single week of changes in iron-chelating therapy, likely as a result of superior sensitivity to soluble ferritin iron, which is in close equilibrium with the chelatable cytosolic iron pool. RR2 measurement may provide a new means of monitoring the short-term effectiveness of iron-chelating agents in patients with myocardial iron overload.

Enhancement of gas-filled microbubble R2* by iron oxide nanoparticles for MRI.

Gas-filled microbubbles have the potential to become a unique intravascular MR contrast agent due to their magnetic susceptibility effect, biocompatibility, and localized manipulation via ultrasound cavitation. However, microbubble susceptibility effect is relatively weak when compared with other intravascular MR susceptibility contrast agents. In this study, enhancement of microbubble susceptibility effect by entrapping monocrystalline iron oxide nanoparticles (MIONs) into polymeric microbubbles was investigated at 7 T in vitro. Apparent T2 enhancement (DeltaR2*) induced by microbubbles was measured to be 79.2+/-17.5 sec(-1) and 301.2+/-16.8 sec(-1) for MION-free and MION-entrapped polymeric microbubbles at 5% volume fraction, respectively. DeltaR2* and apparent transverse relaxivities (r2*) for MION-entrapped polymeric microbubbles and MION-entrapped solid microspheres (without gas core) were also compared, showing the synergistic effect of the gas core with MIONs. This is the first experimental demonstration of microbubble susceptibility enhancement for MRI application. This study indicates that gas-filled polymeric microbubble susceptibility effect can be substantially increased by incorporating iron oxide nanoparticles into microbubble shells. With such an approach, microbubbles can potentially be visualized with higher sensitivity and lower concentrations by MRI.

Diffusion tensor imaging of renal ischemia reperfusion injury in an experimental model.

Renal ischemia reperfusion injury (IRI) is a major cause of acute renal failure. It occurs in various clinical settings such as renal transplantation, shock and vascular surgery. Serum creatinine level has been used as an index for estimating the degree of renal functional loss in renal IRI. However, it only evaluates the global renal function. In this study, diffusion tensor imaging (DTI) was used to characterize renal IRI in an experimental rat model. Spin-echo echo-planar DTI with b-value of 300 s/mm(2) and 6 diffusion gradient directions was performed at 7 T in 8 Sprague-Dawley (SD) with 60-min unilateral renal IRI and 8 normal SD rats. Apparent diffusion coefficient (ADC), directional diffusivities and fractional anisotropy (FA) were measured at the acute stage of IRI. The IR-injured animals were also examined by diffusion-weighted imaging with 7 b-values up to 1000 s/mm(2) to estimate true diffusion coefficient (D(true)) and perfusion fraction (P(fraction)) using a bi-compartmental model. ADC of injured renal cortex (1.69 +/- 0.24 x 10(-3) mm(2)/s) was significantly lower (p < 0.01) than that of contralateral intact cortex (2.03 +/- 0.35 x 10(-3) mm(2)/s). Meanwhile, both ADC and FA of IR-injured medulla (1.37 +/- 0.27 x 10(-3) mm(2)/s and 0.28 +/- 0.04, respectively) were significantly less (p < 0.01) than those of contralateral intact medulla (2.01 +/- 0.38 x 10(-3) mm(2)/s and 0.36 +/- 0.04, respectively). The bi-compartmental model analysis revealed the decrease in D(true) and P(fraction) in the IR-injured kidneys. Kidney histology showed widespread cell swelling and erythrocyte congestion in both cortex and medulla, and cell necrosis/apoptosis and cast formation in medulla. These experimental findings demonstrated that DTI can probe both structural and functional information of kidneys following renal IRI.

Diffusion tensor imaging of liver fibrosis in an experimental model.

PURPOSE: To characterize changes in diffusion properties of liver using diffusion tensor imaging (DTI) in an experimental model of liver fibrosis. MATERIALS AND METHODS: Liver fibrosis was induced in Sprague-Dawley rats (n = 12) by repetitive dosing of carbon tetrachloride (CCl(4)). The animals were examined with a respiratory-gated single-shot spin-echo echo-planar DTI protocol at 7 T before, 2 weeks after, and 4 weeks after CCl(4) insult. Apparent diffusion coefficient (ADC), directional diffusivities (ADC(//) and ADC(⊥)), and fractional anisotropy (FA) were measured. Liver histology was performed with hematoxylin-eosin staining and Masson's trichrome staining. RESULTS: Significant decrease (P < 0.01) in ADC was found at 2 weeks (0.86 ± 0.09 × 10(-3) mm(2)/s) and 4 weeks (0.74 ± 0.09 × 10(-3) mm(2)/s) following CCl(4) insult, as compared with that before insult (0.97 ± 0.08 × 10(-3) mm(2)/s). Meanwhile, FA at 2 weeks (0.18 ± 0.03) after CCl(4) insult was significantly lower (P < 0.01) than that before insult (0.26 ± 0.05), and subsequently normalized at 4 weeks (0.26 ± 0.07) after the insult. Histology showed collagen deposition, presence of intracellular fat vacuoles, and cell necrosis/apoptosis in livers with CCl(4) insult. CONCLUSION: DTI detected the progressive changes in water diffusivities and diffusion anisotropy of liver tissue in this liver fibrosis model. ADC and FA are potentially valuable in detecting liver fibrosis at early stages and monitoring its progression. Future human studies are warranted to further verify the applicability of DTI in characterizing liver fibrosis and to determine its role in clinical settings.

Microbubbles as a novel contrast agent for brain MRI.

Gas-filled microbubbles have the potential to become a unique MR contrast agent due to their magnetic susceptibility effect, biocompatibility and localized manipulation via ultrasound cavitation. In this study, two types of microbubbles, custom-made albumin-coated microbubbles (A-MB) and a commercially available lipid-based clinical ultrasound contrast agent (SonoVue), were investigated with in vivo dynamic brain MRI in Sprague-Dawley rats at 7 T. Microbubble suspensions (A-MB: 0.2 mL of approximately 4% volume fraction; SonoVue: 0.2 mL of approximately 3.5% volume fraction) were injected intravenously. Transverse relaxation rate enhancements (DeltaR(2)(*)) of 2.49+/-1.00 s(-1) for A-MB and 2.41+/-1.18 s(-1) for SonoVue were observed in the brain (N=5). Brain DeltaR(2)(*) maps were computed, yielding results similar to the cerebral blood volume maps obtained with a common MR blood pool contrast agent. Microbubble suspension DeltaR(2)(*) was measured for different volume fractions. These results indicate that gas-filled microbubbles can serve as an intravascular contrast agent for brain MRI at high field. Such capability has the potential to lead to real-time MRI guidance in various microbubble-based drug delivery and therapeutic applications in the central nervous system.

Multifunctional yolk-shell nanoparticles: a potential MRI contrast and anticancer agent.

We report a new type of multifunctional nanomaterials, FePt@Fe2O3 yolk-shell nanoparticles, that exhibit high cytotoxicity originated from the FePt yolks and strong MR contrast enhancement resulting from the Fe2O3 shells. Encouraged by the recently observed high cytotoxicity of FePt@CoS2 yolk-shell nanoparticles, we used Fe2O3 to replace CoS2 as the shells to further explore the applications of the yolk-shell nanostructures. The ultralow IC50 value (238 +/- 9 ng of Pt/mL) of FePt@Fe2O3 yolk-shell nanoparticles likely originates from the fact that the slow oxidation and release of FePt yolks increases the cytotoxicity. Moreover, compared with two commercial magnetic resonance imaging (MRI) contrast agents, MION and Sinerem, the FePt@Fe2O3 yolk-shell nanoparticle showed stronger contrast enhancement according to their apparent transverse relaxivity values (r2* = 3.462 (microg/mL)(-1) s(-1)). The bifunctional FePt@Fe2O3 yolk-shell nanoparticles may serve both as an MRI contrast agent and as a potent anticancer drug. This work indicates that these unique yolk-shell nanoparticles may ultimately lead to new designs of multifunctional nanostructures for nanomedicine.

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.

Molecular MRI of liver fibrosis by a peptide-targeted contrast agent in an experimental mouse model.

OBJECTIVES: Cyclic decapeptide CGLIIQKNEC (CLT1) has been demonstrated to target fibronectin-fibrin complexes in the extracellular matrix of different tumors and tissue lesions. Although liver fibrosis is characterized by an increased amount of extracellular matrix consisting of fibril-forming collagens and matrix glycoconjugates such as fibronectin, we aimed to investigate the feasibility of detecting and characterizing liver fibrosis using CLT1 peptide-targeted nanoglobular contrast agent (Gd-P) with dynamic contrast-enhanced magnetic resonance imaging in an experimental mouse model of liver fibrosis at 7 T. MATERIALS AND METHODS: Gd-P, control peptide KAREC conjugated nanoglobular contrast agent (Gd-CP), and control nontargeting nanoglobular contrast agent (Gd-C) were synthesized. Male adult C57BL/6N mice (22-25 g; N = 54) were prepared and were divided into fibrosis (n = 36) and normal (n = 18) groups. Liver fibrosis was induced in the fibrosis group through subcutaneous injection of 1:3 mixture of carbon tetrachloride (CCl(4)) in olive oil at a dose of 4 µL/g of body weight twice a week for 8 weeks. Dynamic contrast-enhanced MRI was performed in all animals. Dynamic contrast-enhanced magnetic resonance imaging was analyzed to yield postinjection ΔR(1)(t) maps for quantitative measurements. Histological analysis was also performed. RESULTS: Differential enhancements were observed and characterized between the normal and fibrotic livers using Gd-P at 0.03 mmol/kg, when compared with nontargeted controls (Gd-CP and Gd-C). For Gd-P injection, both the peak and steady-state ΔR(1) of the normal livers were significantly lower than those after 4 and 8 weeks of CCl(4) dosing. Liver fibrogenesis with increased amount of fibronectin in the extracellular space in insulted livers were confirmed by histological observations. CONCLUSIONS: These results indicated that dynamic contrast-enhanced magnetic resonance imaging with CLT1 peptide-targeted nanoglobular contrast agent can detect and stage liver fibrosis by probing the accumulation of fibronectin in fibrotic livers.

Magnetic resonance characterization of ischemic tissue metabolism.

Magnetic resonance imaging (MRI) and spectroscopy (MRS) are versatile diagnostic techniques capable of characterizing the complex stroke pathophysiology, and hold great promise for guiding stroke treatment. Particularly, tissue viability and salvageability are closely associated with its metabolic status. Upon ischemia, ischemic tissue metabolism is disrupted including altered metabolism of glucose and oxygen, elevated lactate production/accumulation, tissue acidification and eventually, adenosine triphosphate (ATP) depletion and energy failure. Whereas metabolism impairment during ischemic stroke is complex, it may be monitored non-invasively with magnetic resonance (MR)-based techniques. Our current article provides a concise overview of stroke pathology, conventional and emerging imaging and spectroscopy techniques, and data analysis tools for characterizing ischemic tissue damage.