The effects of P2 segment of posterior cerebral artery to thalamus blood supply pattern on gait in cerebral small vessel disease: A 7 T MRI based study.

Gait disturbance is a manifestation of cerebral small vessel disease (CSVD). The posterolateral thalamus (PL), whose blood is mainly supplied by the P2 segment of posterior cerebral artery (P2-PCA), plays pivotal roles in gait regulation. We investigated the influence of the distance between P2-PCA and PL on gait with varying CSVD burden. 71 participants were divided into low and high CSVD burden groups. The distance from P2-PCA to PL was measured using 7 T TOF-MRA and categorized into an immediate or distant PCA-to-thalamus pattern. Functional connectivity (FC) and voxel-based morphometry were assessed to evaluate functional and structural alterations. In the low CSVD burden group, immediate PCA-to-thalamus supply strongly correlates with longer step length and higher wave phase time percent, and exhibited enhanced FCs in left supplementary motor area, right precentral cortex (PreCG.R). While in the high CSVD burden group, no association between PCA-to-thalamus pattern and gait was found, and we observed reduced FC in PreCG.R with immediate PCA-to-thalamus pattern. Higher CSVD burden was associated with decreased gray matter density in bilateral thalamus. However, no significant structural thalamic change was observed between the two types of PCA-to-thalamus patterns in all patients. Our study demonstrated patients with immediate PCA-to-thalamus supply exhibited better gait performance in low CSVD burden populations, which also correlated with enhanced FCs in motor-related cortex, indicating the beneficial effects of the immediate PCA-to-thalamus supply pattern. In the higher burden CSVD populations, the effects of PCA-to-thalamus pattern on gait are void, attributable to the CSVD-related thalamic destruction and impairment of thalamus-related FC.

Whole-cerebrum guanidino and amide CEST mapping at 3 T by a 3D stack-of-spirals gradient echo acquisition.

PURPOSE: To develop a 3D, high-sensitivity CEST mapping technique based on the 3D stack-of-spirals (SOS) gradient echo readout, the proposed approach was compared with conventional acquisition techniques and evaluated for its efficacy in concurrently mapping of guanidino (Guan) and amide CEST in human brain at 3 T, leveraging the polynomial Lorentzian line-shape fitting (PLOF) method. METHODS: Saturation time and recovery delay were optimized to achieve maximum CEST time efficiency. The 3DSOS method was compared with segmented 3D EPI (3DEPI), turbo spin echo, and gradient- and spin-echo techniques. Image quality, temporal SNR (tSNR), and test-retest reliability were assessed. Maps of Guan and amide CEST derived from 3DSOS were demonstrated on a low-grade glioma patient. RESULTS: The optimized recovery delay/saturation time was determined to be 1.4/2 s for Guan and amide CEST. In addition to nearly doubling the slice number, the gradient echo techniques also outperformed spin echo sequences in tSNR: 3DEPI (193.8 ± 6.6), 3DSOS (173.9 ± 5.6), and GRASE (141.0 ± 2.7). 3DSOS, compared with 3DEPI, demonstrated comparable GuanCEST signal in gray matter (GM) (3DSOS: [2.14%-2.59%] vs. 3DEPI: [2.15%-2.61%]), and white matter (WM) (3DSOS: [1.49%-2.11%] vs. 3DEPI: [1.64%-2.09%]). 3DSOS also achieves significantly higher amideCEST in both GM (3DSOS: [2.29%-3.00%] vs. 3DEPI: [2.06%-2.92%]) and WM (3DSOS: [2.23%-2.66%] vs. 3DEPI: [1.95%-2.57%]). 3DSOS outperforms 3DEPI in terms of scan-rescan reliability (correlation coefficient: 3DSOS: 0.58-0.96 vs. 3DEPI: -0.02 to 0.75) and robustness to motion as well. CONCLUSION: The 3DSOS CEST technique shows promise for whole-cerebrum CEST imaging, offering uniform contrast and robustness against motion artifacts.

Long-term outcomes prediction in diabetic heart failure with preserved ejection fraction by cardiac MRI.

OBJECTIVES: We aimed to explore imaging features including tissue characterization and myocardial deformation in diabetic heart failure with preserved ejection fraction (HFpEF) patients by magnetic resonance imaging (MRI) and investigate its prognostic value for adverse outcomes. MATERIALS AND METHODS: Patients with HFpEF who underwent cardiac MRI between January 2010 and December 2016 were enrolled. Feature-tracking (FT) analysis and myocardial fibrosis were assessed by cardiac MRI. Cox proportional regression analysis was performed to determine the association between MRI variables and primary outcomes. Primary outcomes were all-cause death or heart failure hospitalization during the follow-up period. RESULTS: Of the 335 enrolled patients with HFpEF, 191 had diabetes mellitus (DM) (mean age: 58.7 years ± 10.8; 137 men). During a median follow-up of 10.2 years, 91 diabetic HFpEF and 56 non-diabetic HFpEF patients experienced primary outcomes. DM was a significant predictor of worse prognosis in HFpEF. In diabetic HFpEF, the addition of conventional imaging variables (left ventricular ejection fraction, left atrial volume index, extent of late gadolinium enhancement (LGE)) and global longitudinal strain (GLS) resulted in a significant increase in the area under the receiver operating characteristic curve (from 0.693 to 0.760, p < 0.05). After adjustment for multiple clinical and imaging variables, each 1% worsening in GLS was associated with a 9.8% increased risk of adverse events (p = 0.004). CONCLUSIONS: Diabetic HFpEF is characterized by more severely impaired strains and myocardial fibrosis, which is identified as a high-risk HFpEF phenotype. In diabetic HFpEF, comprehensive cardiac MRI provides incremental value in predicting prognosis. Particularly, MRI-FT measurement of GLS is an independent predictor of adverse outcome in diabetic HFpEF. CLINICAL RELEVANCE STATEMENT: Our findings suggested that MRI-derived variables, especially global longitudinal strain, played a crucial role in risk stratification and predicting worse prognosis in diabetic heart failure with preserved ejection fraction, which could assist in identifying high-risk patients and guiding therapeutic decision-making. KEY POINTS: • Limited data are available on the cardiac MRI features of diabetic heart failure with preserved ejection fraction, including myocardial deformation and tissue characterization, as well as their incremental prognostic value. • Diabetic heart failure with preserved ejection fraction patients was characterized by more impaired strains and myocardial fibrosis. Comprehensive MRI, including tissue characterization and global longitudinal strain, provided incremental value for risk prediction. • MRI served as a valuable tool for identifying high-risk patients and guiding clinical management in diabetic heart failure with preserved ejection fraction.

Guanidinium and amide CEST mapping of human brain by high spectral resolution CEST at 3 T.

PURPOSE: To extract guanidinium (Guan) and amide CEST on the human brain at 3 T MRI with the high spectral resolution (HSR) CEST combined with the polynomial Lorentzian line-shape fitting (PLOF). METHODS: Continuous wave (cw) turbo spin-echo (TSE) CEST was implemented to obtain the optimum saturation parameters. Both Guan and amide CEST peaks were extracted and quantified using the PLOF method. The NMR spectra on the egg white phantoms were acquired to reveal the fitting range and the contributions to the amide and GuanCEST. Two types of CEST approaches, including cw gradient- and spin-echo (cwGRASE) and steady state EPI (ssEPI), were implemented to acquire multi-slice HSR-CEST. RESULTS: GuanCEST can be extracted with the PLOF method at 3 T, and the optimum B 1 = 0.6 µ T $$ {\mathrm{B}}_1=0.6\kern0.2em \upmu \mathrm{T} $$ was determined for GuanCEST in white matter (WM) and 1.0 µT in gray matter (GM). The optimum B1  = 0.8-1 µT was found for amideCEST. AmideCEST is lower in both WM and GM collected with ssEPI compared to those by cwGRASE (ssEPI = [1.27-1.63]%; cwGRASE = [2.19-2.25]%). The coefficients of variation (COV) of the amide and Guan CEST in both WM and GM for ssEPI (COV: 28.6-33.4%) are significantly higher than those of cwGRASE (COV: 8.6-18.8%). Completely different WM/GM contrasts for Guan and amide CEST were observed between ssEPI and cwGRASE. The amideCEST was found to have originated from the unstructured amide protons as suggested by the NMR spectrum of the unfolded proteins in egg white. CONCLUSION: Guan and amide CEST mapping can be achieved by the HSR-CEST at 3 T combing with the PLOF method.

A snapshot of the vast array of diamagnetic CEST MRI contrast agents.

Since the inception of CEST MRI in the 1990s, a number of compounds have been identified as suitable for generating contrast, including paramagnetic lanthanide complexes, hyperpolarized atom cages and, most interesting, diamagnetic compounds. In the past two decades, there has been a major emphasis in this field on the identification and application of diamagnetic compounds that have suitable biosafety profiles for usage in medical applications. Even in the past five years there has been a tremendous growth in their numbers, with more and more emphasis being placed on finding those that can be ultimately used for patient studies on clinical 3 T scanners. At this point, a number of endogenous compounds present in tissue have been identified, and also natural and synthetic organic compounds that can be administered to highlight pathology via CEST imaging. Here we will provide a very extensive snapshot of the types of diamagnetic compound that can generate CEST MRI contrast, together with guidance on their utility on typical preclinical and clinical scanners and a review of the applications that might benefit the most from this new technology.

A novel cardiac magnetic resonance-based personalized risk stratification model in dilated cardiomyopathy: a prospective study.

OBJECTIVES: To explore individual weight of cardiac magnetic resonance (CMR) metrics to predict mid-term outcomes in patients with dilated cardiomyopathy (DCM), and develop a risk algorithm for mid-term outcome based on CMR biomarkers. MATERIALS AND METHODS: Patients with DCM who underwent CMR imaging were prospectively enrolled in this study. The primary endpoint was a composite of heart failure (HF) death, sudden cardiac death (SCD), aborted SCD, and heart transplantation. RESULTS: A total of 407 patients (age 48.1 ± 13.8 years, 331 men) were included in the final analysis. During a median follow-up of 21.7 months, 63 patients reached the primary endpoint. NYHA class III/IV (HR = 2.347 [1.073-5.133], p = 0.033), left ventricular ejection fraction (HR = 0.940 [0.909-0.973], p < 0.001), late gadolinium enhancement (LGE) > 0.9% and ≤ 6.6% (HR = 3.559 [1.020-12.412], p = 0.046), LGE > 6.6% (HR = 6.028 [1.814-20.038], p = 0.003), and mean extracellular volume (ECV) fraction ≥ 32.8% (HR = 5.922 [2.566-13.665], p < 0.001) had a significant prognostic association with the primary endpoints (C-statistic: 0.853 [0.810-0.896]). Competing risk regression analyses showed that patients with mean ECV fraction ≥ 32.8%, LGE ≥ 5.9%, global circumferential strain ≥ - 5.6%, or global longitudinal strain ≥ - 7.3% had significantly shorter event-free survival due to HF death and heart transplantation. Patients with mean ECV fraction ≥ 32.8% and LGE ≥ 5.9% had significantly shorter event-free survival due to SCD or aborted SCD. CONCLUSION: ECV fraction may be the best independently risk factor for the mid-term outcomes in patients with DCM, surpassing LVEF and LGE. LGE has a better prognostic value than other CMR metrics for SCD and aborted SCD. The risk stratification model we developed may be a promising non-invasive tool for decision-making and prognosis. CLINICAL RELEVANCE STATEMENT: "One-stop" assessment of cardiac function and myocardial characterization using cardiac magnetic resonance might improve risk stratification of patients with DCM. In this prospective study, we propose a novel risk algorithm in DCM including NYHA functional class, LVEF, LGE, and ECV. KEY POINTS: • The present study explores individual weight of CMR metrics for predicting mid-term outcomes in dilated cardiomyopathy. • We have developed a novel risk algorithm for dilated cardiomyopathy that includes cardiac functional class, ejection fraction, late gadolinium enhancement, and extracellular volume fraction. • Personalized risk model derived by CMR contributes to clinical assessment and individual decision-making.

Quantitative cerebrovascular reactivity MRI in mice using acetazolamide challenge.

PURPOSE: To develop a quantitative MRI method to estimate cerebrovascular reactivity (CVR) in mice. METHODS: We described an MRI procedure to measure cerebral vasodilatory response to acetazolamide (ACZ), a vasoactive agent previously used in human clinical imaging. Vascular response was determined by cerebral blood flow (CBF) measured with phase-contrast or pseudo-continuous arterial spin labeling MRI. Vasodilatory input intensity was determined by plasma ACZ level using high-performance liquid chromatography. We verified the source of the CVR MRI signal by comparing ACZ injection to phosphate-buffered saline injection and noninjection experiments. Dose dependence and feasibility of regional CVR measurement were also investigated. RESULTS: Cerebral blood flow revealed an exponential increase following intravenous ACZ injection, with a time constant of 1.62 min. In contrast, phosphate-buffered saline or noninjection exhibited a slow linear CBF increase, consistent with a gradual accumulation of anesthetic agent, isoflurane, used in this study. When comparing different ACZ doses, injections of 30, 60, 120, and 180 mg/kg yielded a linear increase in plasma ACZ concentration (p < 0.0001). On the other hand, CBF changes under these doses were not different from each other (p = 0.50). The pseudo-continuous arterial spin labeling MRI with multiple postlabeling delays revealed similar vascular responses at different postlabeling delay values. There was a regional difference in CVR (p = 0.005), with isocortex (0.81 ± 0.17%/[µg/ml]) showing higher CVR than deep-brain regions. Mice receiving multiple ACZ injections lived for a minimum of 6 months after the study without noticeable aberrant behavior or appearance. CONCLUSIONS: We demonstrated the proof-of-principle of a new quantitative CVR mapping technique in mice.

Deep learning-based classification of preclinical breast cancer tumor models using chemical exchange saturation transfer magnetic resonance imaging.

Chemical exchange saturation transfer (CEST) magnetic resonance imaging has shown promise for classifying tumors based on their aggressiveness, but CEST contrast is complicated by multiple signal sources and thus prolonged acquisition times are often required to extract the signal of interest. We investigated whether deep learning could help identify pertinent Z-spectral features for distinguishing tumor aggressiveness as well as the possibility of acquiring only the pertinent spectral regions for more efficient CEST acquisition. Human breast cancer cells, MDA-MB-231 and MCF-7, were used to establish bi-lateral tumor xenografts in mice to represent higher and lower aggressive tumors, respectively. A convolutional neural network (CNN)-based classification model, trained on simulated data, utilized Z-spectral features as input to predict labels of different tissue types, including MDA-MB-231, MCF-7, and muscle tissue. Saliency maps reported the influence of Z-spectral regions on classifying tissue types. The model was robust to noise with an accuracy of more than 91.5% for low and moderate noise levels in simulated testing data (SD of noise less than 2.0%). For in vivo CEST data acquired with a saturation pulse amplitude of 2.0 µT, the model had a superior ability to delineate tissue types compared with Lorentzian difference (LD) and magnetization transfer ratio asymmetry (MTRasym ) analysis, classifying tissues to the correct types with a mean accuracy of 85.7%, sensitivity of 81.1%, and specificity of 94.0%. The model's performance did not improve substantially when using data acquired at multiple saturation pulse amplitudes or when adding LD or MTRasym spectral features, and did not change when using saliency map-based partial or downsampled Z-spectra. This study demonstrates the potential of CNN-based classification to distinguish between different tumor types and muscle tissue, and speed up CEST acquisition protocols.

Dynamic contrast-enhanced CEST MRI using a low molecular weight dextran.

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

Furin-mediated intracellular self-assembly of olsalazine nanoparticles for enhanced magnetic resonance imaging and tumour therapy.

Among the strategies used for enhancement of tumour retention of imaging agents or anticancer drugs is the rational design of probes that undergo a tumour-specific enzymatic reaction preventing them from being pumped out of the cell. Here, the anticancer agent olsalazine (Olsa) was conjugated to the cell-penetrating peptide RVRR. Taking advantage of a biologically compatible condensation reaction, single Olsa-RVRR molecules were self-assembled into large intracellular nanoparticles by the tumour-associated enzyme furin. Both Olsa-RVRR and Olsa nanoparticles were readily detected with chemical exchange saturation transfer magnetic resonance imaging by virtue of exchangeable Olsa hydroxyl protons. In vivo studies using HCT116 and LoVo murine xenografts showed that the OlsaCEST signal and anti-tumour therapeutic effect were 6.5- and 5.2-fold increased, respectively, compared to Olsa without RVRR, with an excellent 'theranostic correlation' (R2 = 0.97) between the imaging signal and therapeutic response (normalized tumour size). This furin-targeted, magnetic resonance imaging-detectable platform has potential for imaging tumour aggressiveness, drug accumulation and therapeutic response.

Non-contrast-enhanced abdominal MRA at 3 T using velocity-selective pulse trains.

PURPOSE: Most existing non-contrast-enhanced methods for abdominal MR arteriography rely on a spatially selective inversion (SSI) pulse with a delay to null both static tissue and venous blood, and are limited to small spatial coverage due to the sensitivity to slow arterial inflow. Velocity-selective inversion (VSI) based approach has been shown to preserve the arterial blood inside the imaging volume at 1.5 T. Recently, velocity-selective saturation (VSS) pulse trains were applied to suppress the static tissue and have been combined with SSI pulses for cerebral MR arteriography at 3 T. The aim of this study is to construct an abdominal MRA protocol with large spatial coverage at 3 T using advanced velocity-selective pulse trains. METHODS: Multiple velocity-selective MRA protocols with different sequence modules and 3D acquisition methods were evaluated. Sequences using VSS only as well as SSI+VSS and VSI+VSS preparations were then compared among a group of healthy young and middle-aged volunteers. Using MRA without any preparations as reference, relative signal ratios and relative contrast ratios of different vascular segments were quantitatively analyzed. RESULTS: Both SSI+VSS and VSI+VSS arteriograms achieved high artery-to-tissue and artery-to-vein relative contrast ratios above aortic bifurcation. The SSI+VSS sequence yielded lower signal at the bilateral iliac arteries than VSI+VSS, reflecting the benefit of the VSI preparation for imaging the distal branches. CONCLUSION: The feasibility of noncontrast 3D MR abdominal arteriography was demonstrated on healthy volunteers using a combination of VSS pulse trains and SSI or VSI pulse.

N-Aryl Amides as Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agents.

Chemical exchange saturation transfer (CEST) MRI has recently emerged as a versatile molecular imaging approach in which diamagnetic compounds can be utilized to generate an MRI signal. To expand the scope of CEST MRI applications, herein, we systematically investigated the CEST properties of N-aryl amides with different N-aromatic substitution, revealing their chemical shifts (4.6-5.8 ppm) and exchange rates (up to thousands s-1 ) are favorable to be used as CEST agents as compared to alkyl amides. As the first proof-of-concept study, we used CEST MRI to detect the enzymatic metabolism of the drug acebutolol directly by its intrinsic CEST signal without any chemical labeling. Our study implies that N-aryl amides may enable the label-free CEST MRI detection of the metabolism of many N-aryl amide-containing drugs and a variety of enzymes that act on N-aryl amides, greatly expanding the scope of CEST MR molecular imaging.

The role of imaging in 2019 novel coronavirus pneumonia (COVID-19).

Almost the entire world, not only China, is currently experiencing the outbreak of a novel coronavirus that causes respiratory disease, severe pneumonia, and even death. The outbreak began in Wuhan, China, in December of 2019 and is currently still ongoing. This novel coronavirus is highly contagious and has resulted in a continuously increasing number of infections and deaths that have already surpassed the SARS-CoV outbreak that occurred in China between 2002 and 2003. It is now officially a pandemic, announced by WHO on the 11th of March. Currently, the 2019 novel coronavirus (SARS-CoV-2) can be identified by virus isolation or viral nucleic acid detection; however, false negatives associated with the nucleic acid detection provide a clinical challenge and thus make the imaging examination crucial. Imaging exams have been a main clinical diagnostic criteria for the 2019 novel coronavirus disease (COVID-19) in China. Imaging features of multiple patchy areas of ground glass opacity and consolidation predominately in the periphery of the lungs are characteristic manifestations on chest CT and extremely helpful in the early detection and diagnosis of this disease, which aids prompt diagnosis and the eventual control of this emerging global health emergency. Key Points • In December 2019, China, an outbreak of pneumonia caused by a novel, highly contagious coronavirus raised grave concerns and posed a huge threat to global public health. • Among the infected patients, characteristic findings on CT imaging include multiple, patchy, ground-glass opacity, crazy-paving pattern, and consolidation shadows, mainly distributed in the peripheral and subpleural areas of both lungs, which are very helpful for the frontline clinicians. • Imaging examination has become the indispensable means not only in the early detection and diagnosis but also in monitoring the clinical course, evaluating the disease severity, and may be presented as an important warning signal preceding the negative RT-PCR test results.

Protein aggregation linked to Alzheimer's disease revealed by saturation transfer MRI.

The goal of this study was to develop a molecular biomarker for the detection of protein aggregation involved in Alzheimer's disease (AD) by exploiting the features of the water saturation transfer spectrum (Z-spectrum), the CEST signal of which is sensitive to the molecular configuration of proteins. A radial-sampling steady-state sequence based ultrashort echo time (UTE) readout was implemented to image the Z-spectrum in the mouse brain, especially the contributions from mobile proteins at the frequency offsets for the composite protein amide proton (+3.6 ppm) and aliphatic proton (-3.6 ppm) signals. Using a relatively weak radiofrequency (RF) saturation amplitude, contributions due to strong magnetization transfer contrast (MTC) from solid-like macromolecules and direct water saturation (DS) were minimized. For practical measure of the changes in the mobile protein configuration, we defined a saturation transfer difference (ΔST) by subtracting the Z-spectral signals at ±3.6 ppm from a control signal at 8 ppm. Phantom studies of glutamate solution, protein (egg white) and hair conditioner show the capability of the proposed scheme to minimize the contributions from amine protons, DS, and MTC, respectively. The ST signal at ±3.6 ppm of the cross-linked bovine serum albumin (BSA) solutions demonstrated that the ΔST signal can be used to monitor the aggregation process of the mobile proteins. High-resolution ΔST images of AD mouse brains at ±3.6 ppm of mouse brains showed significantly reduced ΔST (-3.6) signal compared to the age-matched wild-type (WT) mice. Thus, this signal has potential to serve as a molecular biomarker for monitoring protein aggregation in AD.

The effect of the mTOR inhibitor rapamycin on glucoCEST signal in a preclinical model of glioblastoma.

PURPOSE: The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up-regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment. METHODS: A human U87-EGFRvIII xenograft model in mice was studied. The mice were treated with a mammalian target of Rapamycin inhibitor, rapamycin. The effect of the treatment was evaluated in vivo with dynamic glucose CEST MRI. RESULTS: Rapamycin treatment led to significant increases (P < 0.001) in dynamic glucose-enhanced signal in both the tumor and contralateral brain as compared to the no-treatment group, namely a maximum enhancement of 3.7% ± 2.3% (tumor, treatment) versus 1.9% ± 0.4% (tumor, no-treatment), 1.7% ± 1.1% (contralateral, treatment), and 1.0% ± 0.4% (contralateral, no treatment). Dynamic glucose-enhanced contrast remained consistently higher in treatment versus no-treatment groups for the duration of the experiment (17 min). This was confirmed with area-under-curve analysis. CONCLUSION: Increased glucose CEST signal was found after mammalian target of Rapamycin inhibition treatment, indicating potential for dynamic glucose-enhanced MRI to study tumor response to glucose deprivation treatment.

GlucoCEST imaging with on-resonance variable delay multiple pulse (onVDMP) MRI.

PURPOSE: To examine the detection sensitivity for the rapidly exchanging hydroxyl protons of D-glucose using the recently developed on-resonance variable delay multi-pulse (onVDMP) chemical exchange saturation transfer (CEST) technique. METHODS: The onVDMP method was applied for the detection of water signal changes upon venous D-glucose infusion in mice with 9L glioma xenografts. The effect size of onVDMP MRI during infusion was compared with that of conventional continuous wave (CW) CEST MRI. RESULTS: Both methods highlighted the tumor and the blood vessels on D-glucose infusion. In interleaved studies, the mean signal changes detected by onVDMP were found to be 1.8 times higher than those by CW-CEST, attributed to its high labeling efficiency for fast exchanging protons and the labeling of the OH protons over a larger frequency range. CONCLUSIONS: The onVDMP method is a more sensitive technique for the detection of exogenous CEST agents with fast-exchanging protons compared to CW-CEST MRI.

CEST MRI monitoring of tumor response to vascular disrupting therapy using high molecular weight dextrans.

PURPOSE: Vascular disrupting therapy of cancer has become a promising approach not only to regress tumor growth directly but also to boost the delivery of chemotherapeutics in the tumor. An imaging approach to monitor the changes in tumor vascular permeability, therefore, has important applications for monitoring of vascular disrupting therapies. METHODS: Mice bearing CT26 subcutaneous colon tumors were injected intravenously with 150 kD dextran (Dex150, diameter, d~ 20 nm, 375 mg/kg), tumor necrosis factor-alpha (TNF-α; 1 µg per mouse), or both (n = 3 in each group). The Z-spectra were acquired before and 2 h after the injection, and the chemical exchange saturation transfer (CEST) signals in the tumors as quantified by asymmetric magnetization transfer ratio (MTRasym ) at 1 ppm were compared. RESULTS: The results showed a significantly stronger CEST contrast enhancement at 1 ppm (∆MTRasym = 0.042 ± 0.002) in the TNF-α-treated tumors than those by Dex150 alone (∆MTRasym = 0.000 ± 0.005, P = 0.0229) or TNF-α alone (∆MTRasym = 0.002 ± 0.004, P = 0.0264), indicating that the TNF-α treatment strongly augmented the tumor uptake of 150 kD dextran. The MRI findings were verified by fluorescence imaging and immunofluorescence microscopy. CONCLUSIONS: High molecular weight dextrans can be used as safe and sensitive CEST MRI contrast agents for monitoring tumor response to vascular disrupting therapy and, potentially, for developing dextran-based theranostic drug delivery systems.

Extradomain-B Fibronectin-Targeted Dextran-Based Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Probe for Detecting Pancreatic Cancer.

A dextran-peptide conjugate was developed for magnetic resonance (MR) molecular imaging of pancreatic ductal adenocarcinoma (PDAC) through its overexpressed microenvironment biomarker, extradomain-B fibronectin (EDB-FN). This new agent consists of diamagnetic and biocompatible dextran and a targeting peptide. Dextrans can be directly detected by chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) without the need for radionuclide or metallic labeling. In addition, large molecular weight dextran, dextran 10 (MW ∼ 10 kDa), provides an approximately 50 times higher sensitivity per molecule than a single glucose unit. The potential of this highly biocompatible diamagnetic probe is demonstrated in a murine syngeneic allograft PDAC tumor model. The biocompatibility and sensitivity of this new agent clearly show potential for a path to clinical translation.

High-resolution creatine mapping of mouse brain at 11.7 T using non-steady-state chemical exchange saturation transfer.

The current study aims to optimize the acquisition scheme for the creatine chemical exchange saturation transfer weighted (CrCESTw) signal on mouse brain at 11.7 T, in which a strong magnetization transfer contrast (MTC) is present, and to further develop the polynomial and Lorentzian line-shape fitting (PLOF) method for quantifying CrCESTw signal with a non-steady-state (NSS) acquisition scheme. Studies on a Cr phantom with cross-linked bovine serum albumin (BSA) as well as on mouse brain demonstrated that the maximum CrCESTw signal was reached with a short saturation time determined by the rotating frame relaxation time of the MTC pool instead of the steady-state saturation. The saturation power for the maximal signal was around 1-1.5 µT for Cr with 20% cross-linked BSA and in vivo applications, but 2 µT was found to be most practical for signal stability. For the CrCEST acquisition with strong MTC interference, the optimal saturation power and length are completely different from those on Cr solution alone. This observation could be explained well using R1ρ theory by incorporating the strong MTC pool. Finally, a high-resolution Cr map was obtained on mouse brain using the PLOF method with the NSS CEST acquisition and a cryogenic coil. The Cr map obtained by CEST showed homogenous intensity across the mouse brain except for regions with cerebrospinal fluid.

Carbon Dots as a New Class of Diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI Contrast Agents.

While carbon dots (C-dots) have been extensively investigated pertaining to their fluorescent, phosphorescent, electrochemiluminescent, optoelectronic, and catalytic features, their inherent chemical exchange saturation transfer magnetic resonance imaging (CEST MRI) properties are unknown. By virtue of their hydrophilicity and abundant exchangeable protons of hydroxyl, amine, and amide anchored on the surface, we report here that C-dots can be adapted as effective diamagnetic CEST (diaCEST) MRI contrast agents. As a proof-of-concept demonstration, human glioma cells were labeled with liposomes with or without encapsulated C-dots and implanted in mouse brain. In vivo CEST MRI was able to clearly differentiate labeled cells from non-labeled cells. The present findings may encourage new applications of C-dots for in vivo imaging in deep tissues, which is currently not possible using conventional fluorescent (near-infrared) C-dots.