Molecular Magnetic Resonance Imaging Research Articles

Chitosan-modified manganese oxide-conjugated methotrexate nanoparticles delivering 5-aminolevulinic acid as a dual-modal T1-T2* MRI contrast agent in U87MG cell detection.

Glioblastoma multiforme is a highly aggressive form of brain cancer, and early diagnosis plays a pivotal role in improving patient survival rates. In this regard, molecular magnetic resonance imaging has emerged as a promising imaging modality due to its exceptional sensitivity to minute tissue changes and the ability to penetrate deep into the brain. This study aimed to assess the efficacy of a novel contrast agent in detecting gliomas during MRI scans. The contrast agent utilized modified chitosan coating on manganese oxide nanoparticles. The modification included adding methotrexate and 5-aminolevulinic acid (MnO2/CS@5-ALA-MTX) to target cells with overexpressed folate receptors and breaking down excess hydrogen peroxide in tumor tissue, resulting in enhanced signal intensity in T1-weighted MR images but diminished signal intensity in T2*-weighted MR images. The nanosystem was characterized and evaluated in MR imaging, safety, and ability to target cells both in vivo and in vitro. MTX-free nanoparticles (MnO2/CS@5-ALA NPs) had no obvious cytotoxicity on cell lines U87MG and NIH3T3 after 24/48 h at a concentration of up to 160 µgr/mL (cell viability more than 80%). In this system, methotrexate enables tumor targeting and the MnO2/5-ALA improves T1-T2*-weighted MRI. In addition, MRI scans of mice with M109 carcinoma indicated significant tumor uptake and NP capacity to improve the positive contrast effect. This developed MnO2/CS@5-ALA-MTX nanoparticle system may exhibit great potential in the accurate diagnosis of folate receptor over-expressing cancers such as glioblastoma.

Synthesis, MTT assay, 99m-Technetium radiolabeling, biodistribution evaluation of radiotracer and in vitro magnetic resonance imaging study of P,N-doped graphene quantum dots as a new multipurpose imaging nano-agent

Abstract In this study, a new nano-structure, N,P-doped graphene quantum dots (N,P-GQDs), were synthesized as multipurpose imaging agent for performing scintigraphy and magnetic resonance imaging (MRI). Some standard characterization methods were used to identify the nano-structure. In vitro cytotoxicity evaluation using MTT assay revealed that N,P-GQDs nanoparticles had no significant cytotoxicity after 24 and 48 h against normal (MCF-10A) and cancerous (MCF 7) human breast cell line in concentration up to 200 μg/mL. The N,P-GQDs were radiolabeled with Technetium-99m as 99mTc-(N,P-GQDs) and the radiochemical purity was assayed by ITLC concluding RCP ≥ 95 %. The passing of 99mTc-(N,P-GQDs) through 0.1 µm filter demonstrated that 70.8 % of particles were <0.1 µm. In order to perform scintigraphy, the 99mTc-(N,P-GQDs) were injected to female healthy Wistar rats. The results showed that the radio-complex was captured and eliminated just by kidneys. Moreover, in vitro T1-weighted phantom MRI imaging showed that the N,P-GQDs have proper relaxivity in comparison to Dotarem® as a clinically available contrast agent. The results showed that the N,P-GQDs have potential to be considered as a novel and encouraging agent for both molecular MRI and nuclear medicine imagings.

Radiofrequency enhances drug release from responsive nanoflowers for hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and the third leading cause of cancer death worldwide. Most patients are diagnosed at an advanced stage, and systemic chemotherapy is the preferred treatment modality for advanced HCC. Curcumin (CUR) is a polyphenolic antineoplastic drug with low toxicity obtained from plants. However, its low bioavailability and poor solubility limit its functionality. In this study, radiofrequency- (RF) enhanced responsive nanoflowers (NFs), containing superparamagnetic ferric oxide nanoclusters (Fe3O4 NCs), – CUR layer, – and MnO2 (CUR-Fe@MnO2 NFs), were verified to have a thermal therapeutic effect. Transmission electron microscopy was used to characterize the CUR-Fe@MnO2 NFs, which appeared flower-like with a size of 96.27 nm. The in vitro experimental data showed that RF enhanced the degradation of CUR-Fe@MnO2 NFs to release Mn2+ and CUR. The cytotoxicity test results indicated that after RF heating, the CUR-Fe@MnO2 NFs significantly suppressed HCC cell proliferation. Moreover, CUR-Fe@MnO2 NFs were effective T1/T2 contrast agents for molecular magnetic resonance imaging due to the release of Mn2+ and Fe3O4 NCs.

Allysine-Targeted Molecular MRI Enables Early Prediction of Chemotherapy Response in Pancreatic Cancer.

Neoadjuvant therapy (NAT) is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis allysine residues are formed on collagen proteins by the action of lysyl oxidases (LOX). Here we report the application of an allysine-targeted molecular magnetic resonance imaging (MRI) probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of NAT with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, while no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes.

Furin-Catalyzed Enhanced Magnetic Resonance Imaging Probe for Differential Diagnosis of Malignant Breast Cancers.

Molecular magnetic resonance imaging (mMRI) of biomarkers is essential for accurate cancer detection in precision medicine. However, the current clinically used contrast agents provide structural magnetic resonance imaging (sMRI) information only and rarely provide mMRI information. Here, a tumor-specific furin-catalyzed nanoprobe (NP) was reported for differential diagnosis of malignant breast cancers (BCs) in vivo. This NP with a compact structure of Fe3O4@Gd-DOTA NPs (FFG NPs) contains an "always-on" T2-weighted MR signal provided by the magnetic Fe3O4 core and a furin-catalyzed enhanced T1-weighted MR signal provided by the Gd-DOTA moiety. The FFG NPs were found to produce an activated T1 signal in the presence of furin catalysis and an "always-on" T2 signal, providing mMRI and sMRI information simultaneously. Ratiometric mMRI:sMRI intensity can be used for differential diagnosis of malignant BCs MDA-MB-231 and MCF-7, where the furin levels relatively differ. The proposed probe not only provides structural imaging but also enables real-time molecular differential visualization of BC through enzymatic activities of cancer tissues.

Intestinal MAdCAM-1 imaging as biomarker for prognostic in murine models of multiple sclerosis

IntroductionMultiple sclerosis (MS) is an autoimmune disease of the central nervous system. Recent evidence suggests that lymphocyte trafficking in the intestines could play a key role in its etiology. Nevertheless, it is not clear how intestinal tissue is involved in the disease onset nor its evolution. In the present study, we aimed to evaluate intestinal inflammation dynamic throughout the disease course and its potential impact on disease progression. MethodsWe used tissue immunophenotyping (immunohistofluorescence and flow cytometry) and a recently described molecular magnetic resonance imaging (MRI) method targeting mucosal addressin cell adhesion molecule-1 (MAdCAM-1) to assess intestinal inflammation in vivo in two distinct animal models of MS (Experimental Autoimmune Encephalomyelitis − EAE) at several time points of disease progression. ResultsWe report a positive correlation between disease severity and MAdCAM-1 MRI signal in two EAE models. Moreover, high MAdCAM-1 MRI signal during the asymptomatic phase is associated with a delayed disease onset in progressive EAE and to a lower risk of conversion to a secondary-progressive form in relapsing-remitting EAE. During disease evolution, in line with a bi-directional immune communication between the gut and the central nervous system, we observed a decrease in T-CD4+ and B lymphocytes in the ileum concomitantly with their increase in the spinal cord. ConclusionAltogether, these data unveil a crosstalk between intestinal and central inflammation in EAE and support the use of molecular MRI of intestinal MAdCAM-1 as a new biomarker for prognostic in MS patients.

MODERN IMAGING TECHNIQUES IN THE ASSESSMENT
 OF MALIGNANCY IN GLIAL BRAIN TUMORS:
 LITERATURE REVIEW

Relevance: Gliomas represent a major group of primary central nervous system tumors, accounting for approximately 80% of all
 malignant brain neoplasms. Recent advances in molecular diagnostics, including the identification of mutations in the isocitrate dehydrogenase(IDH) gene, offer new opportunities to improve the classification of gliomas and to understand the mechanisms of their development. IDH
 mutations, which are found in a large proportion of gliomas, are associated with a better prognosis and represent an important biomarker
 for the development of targeted therapeutic strategies. Diagnostic techniques, particularly magnetic resonance imaging (MRI), also play
 an important role, providing additional ways to assess the morphological and biological characteristics of gliomas, contributing to a more
 accurate determination of tumor malignancy and molecular profile, which is key to treatment decisions.
 The purpose: To study the possibilities of magnetic resonance imaging in assessing the degree of malignancy of glial brain tumors.
 Method: A literature review was performed using the keywords: glioma, IDH mutation, IDH wild-type, MRI, magnetic resonance
 spectroscopy (MRS), apparent diffusion coefficient (ADC), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI), diffusion kurtosis
 image (DKI), Susceptibility Weighted Imaging (SWI) in PubMed, BMC Medicine, and Google Scholar databases. The review includes the results
 of an analysis of 45 literature reviews on the diagnostic capabilities of molecular diagnostics and MRI to assess the malignancy of gliomas.
 Results: This review highlights the importance of current approaches to the diagnosis of gliomas, demonstrating that different grades of
 malignancy and IDH mutation status are associated with unique features on MR imaging, including differences in localization, signal, and
 enhancement patterns. DTI and DWI extend the ability of MRI to assess tissue microstructure, allowing for more precise tumor characterization.
 Studies combining MRI morphologic features, ADC and DTI parameters offer a non-invasive approach to glioma prognosis, highlighting the
 importance of integrated use of imaging modalities to improve diagnosis and therapy.
 Conclusion: The use of magnetic resonance imaging allows for more accurate morphologic and metabolic characterization of gliomas
 in assessing the degree of malignancy, allowing physicians to make more accurate prognostic assessments and select the most appropriate
 treatment strategy.
 Keywords: Glioma, IDH mutation, wild-type IDH, MRI, magnetic resonance spectroscopy, ADC, DWI, DTI, DKI, SWI

Assessment of the Efficacy of the Combination of RNAi of lncRNA DANCR with Chemotherapy to Treat Triple Negative Breast Cancer Using Magnetic Resonance Molecular Imaging.

Long noncoding RNA (lncRNA) differentiation antagonizing noncoding RNA (DANCR) is overexpressed in human triple-negative breast cancer (TNBC) and promotes cell migration and proliferation. TNBC is limited in treatment options relative to hormone-receptor-positive breast cancer and is commonly treated with chemotherapy, which is often compromised by acquired resistance. DANCR has been implicated in the development of chemoresistance across multiple cancer types. Here, we applied magnetic resonance molecular imaging (MRMI) with a targeted contrast agent, MT218, specific to extradomain-B fibronectin (EDB-FN), a marker for epithelial-to-mesenchymal transition, to assess the therapeutic efficacy of the combination of paclitaxel and ZD2-PEG-ECO/siDANCR nanoparticles (ZD2-siDANCR-ELNP) to treat TNBC. The treatment of orthotopic MDA-MB-231 TNBC in mice with paclitaxel significantly suppressed tumor growth but with a significant increase of EDB-FN in the tumor, as revealed by MRMI and immunohistochemistry. Combining ZD2-siDANCR-ELNP with paclitaxel further reduced tumor sizes, along with reduced EDB-FN expression. Interestingly, MT218-MRMI revealed a lower reduction of tumor signal enhancement with the combination treatment than that with the siDANCR treatment alone, which was supported by higher cell density in the tumors treated with the combination therapy, as shown by histochemical analysis. MT218-MRMI clearly revealed the changes of the tumor microenvironment in response to various therapies and is effective to noninvasively assess the response of TNBC tumors to the therapies. Regulating oncogenic lncRNA DANCR is an effective strategy for improving the outcomes of chemotherapy in TNBC.

A Dual-Gene Reporter-Amplifier Architecture for Enhancing the Sensitivity of Molecular MRI by Water Exchange.

The development of genetic reporters for magnetic resonance imaging (MRI) is essential for investigating biological functions in vivo. However, current MRI reporters have low sensitivity, making it challenging to create significant contrast against the tissue background, especially when only a small fraction of cells express the reporter. To overcome this limitation, we developed an approach for amplifying the sensitivity of molecular MRI by combining a chemogenetic contrast mechanism with a biophysical approach to increase water diffusion through the co-expression of a dual-gene construct comprising an organic anion transporting polypeptide, Oatp1b3, and a water channel, Aqp1. We first show that the expression of Aqp1 amplifies MRI contrast in cultured cells engineered to express Oatp1b3. We demonstrate that the contrast amplification is caused by Aqp1-driven increase in water exchange, which provides the gadolinium ions internalized by Oatp1b3-expressing cells with access to a larger water pool compared with exchange-limited conditions. We further show that our methodology allows cells to be detected using approximately 10-fold lower concentrations of gadolinium than that in the Aqp1-free scenario. Finally, we show that our approach enables the imaging of mixed-cell cultures containing a low fraction of Oatp1b3-labeled cells that are undetectable on the basis of Oatp1b3 expression alone.

Advances in nanoprobes for molecular MRI of Alzheimer's disease.

Alzheimer's disease is the most common cause of dementia and a leading cause of mortality in the elderly population. Diagnosis of Alzheimer's disease has traditionally relied on evaluation of clinical symptoms for cognitive impairment with a definitive diagnosis requiring post-mortem demonstration of neuropathology. However, advances in disease pathogenesis have revealed that patients exhibit Alzheimer's disease pathology several decades before the manifestation of clinical symptoms. Magnetic resonance imaging (MRI) plays an important role in the management of patients with Alzheimer's disease. The clinical availability of molecular MRI (mMRI) contrast agents can revolutionize the diagnosis of Alzheimer's disease. In this article, we review advances in nanoparticle contrast agents, also referred to as nanoprobes, for mMRI of Alzheimer's disease. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease.

Magnetic-optical dual-modality imaging monitoring chemotherapy efficacy of pancreatic ductal adenocarcinoma with a low-dose fibronectin-targeting Gd-based contrast agent.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal hypovascular tumor surrounded by dense fibrosis. Albumin-bound paclitaxel and gemcitabine (AG) chemotherapy is the mainstay of PDAC treatment through depleting peritumoral fibrosis and killing tumor cells; however, it remains challenging due to the lack of a noninvasive imaging method evaluating fibrotic changes during AG chemotherapy. In this study, we developed a dual-modality imaging platform that enables noninvasive, dynamic, and quantitative assessment of chemotherapy-induced fibrotic changes through near-infrared fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI) using an extradomain B fibronectin (EDB-FN)-targeted imaging probe (ZD2-Gd-DOTA-Cy7). The ZD2-Gd-DOTA-Cy7 probe was constructed by conjugating a peptide (Cys-TVRTSAD) to Gd-DOTA and the near-infrared dye Cy7. PDAC murine xenograft models were intravenously injected with ZD2-Gd-DOTA-Cy7 at a Gd concentration of 0.05 mmol/kg or free Cy7 and Gd-DOTA as control. The normalized tumor background ratio (TBR) on FMI and the T1 reduction ratio on MRI were quantitatively analyzed. For models receiving AG chemotherapy or saline, MRI/FMI was performed before and after treatment. Histological analyses were performed for validation. The ZD2-Gd-DOTA-Cy7 concentration showed a linear correlation with the fluorescence intensity and T1 relaxation time in vitro. The optimal imaging time was 30min after injection of the ZD2-Gd-DOTA-Cy7 (0.05 mmol/kg), only half of the clinic dosage of gadolinium. Additionally, ZD2-Gd-DOTA-Cy7 generated a 1.44-fold and 1.90-fold robust contrast enhancement compared with Cy7 (P < 0.05) and Gd-DOTA (P < 0.05), respectively. For AG chemotherapy monitoring, the T1 reduction ratio and normalized TBR in the fibrotic tumor areas were significantly increased by 1.99-fold (P < 0.05) and 1.78-fold (P < 0.05), respectively, in the control group compared with those in the AG group. MRI/FMI with a low dose of ZD2-Gd-DOTA-Cy7 enables sensitive imaging of PDAC and the quantitative assessment of fibrotic changes during AG chemotherapy, which shows potential clinical applications for precise diagnosis, post-treatment monitoring, and disease management.

Hyperpolarized Xenon-129 Chemical Exchange Saturation Transfer (HyperCEST) Molecular Imaging: Achievements and Future Challenges.

Molecular magnetic resonance imaging (MRI) is an emerging field that is set to revolutionize our perspective of disease diagnosis, treatment efficacy monitoring, and precision medicine in full concordance with personalized medicine. A wide range of hyperpolarized (HP) 129Xe biosensors have been recently developed, demonstrating their potential applications in molecular settings, and achieving notable success within in vitro studies. The favorable nuclear magnetic resonance properties of 129Xe, coupled with its non-toxic nature, high solubility in biological tissues, and capacity to dissolve in blood and diffuse across membranes, highlight its superior role for applications in molecular MRI settings. The incorporation of reporters that combine signal enhancement from both hyperpolarized 129Xe and chemical exchange saturation transfer holds the potential to address the primary limitation of low sensitivity observed in conventional MRI. This review provides a summary of the various applications of HP 129Xe biosensors developed over the last decade, specifically highlighting their use in MRI. Moreover, this paper addresses the evolution of in vivo applications of HP 129Xe, discussing its potential transition into clinical settings.

J Coupling Constants of

Observing pyruvate metabolism in vivo has become a focal point of molecular magnetic resonance imaging. Signal amplification by reversible exchange (SABRE) has recently emerged as a versatile hyperpolarization technique. Tuning of the spin order transfer (SOT) in SABRE is challenging as the small 1H-13C J couplings, in the 13C-pyruvate case, result in SOT being not readily discernible. We demonstrate an experimental method using frequency-selective excitation of parahydrogen-derived polarization SOT sequence (SEPP-SPINEPT); its application led to up to 5700-fold 13C signal gain. In this way, we estimated the lifetime of two Ir-pyruvate SABRE complexes alongside the individual probing of eight small 1H-13C J couplings that connect the hydride protons in these complexes to 1- and 2-13C pyruvate spins, affording values between 0 and 2.69 Hz. Using electronic structure calculations, we define the low-energy structure of the corresponding complexes. Hence, this study demonstrates a novel approach to analyzing the spin topology of short-lived organometallic complexes.

Molecular magnetic resonance imaging of myeloperoxidase activity identifies culprit lesions and predicts future atherothrombosis.

Unstable atherosclerotic plaques have increased activity of myeloperoxidase (MPO). We examined whether molecular magnetic resonance imaging (MRI) of intraplaque MPO activity predicts future atherothrombosis in rabbits and correlates with ruptured human atheroma. Plaque MPO activity was assessed in vivo in rabbits (n = 12) using the MPO-gadolinium (Gd) probe at 8 and 12 weeks after induction of atherosclerosis and before pharmacological triggering of atherothrombosis. Excised plaques were used to confirm MPO activity by liquid chromatography-tandem mass spectrometry (LC-MSMS) and to determine MPO distribution by histology. MPO activity was higher in plaques that caused post-trigger atherothrombosis than plaques that did not. Among the in vivo MRI metrics, the plaques' R1 relaxation rate after administration of MPO-Gd was the best predictor of atherothrombosis. MPO activity measured in human carotid endarterectomy specimens (n = 30) by MPO-Gd-enhanced MRI was correlated with in vivo patient MRI and histological plaque phenotyping, as well as LC-MSMS. MPO-Gd retention measured as the change in R1 relaxation from baseline was significantly greater in histologic and MRI-graded American Heart Association (AHA) type VI than type III-V plaques. This association was confirmed by comparing AHA grade to MPO activity determined by LC-MSMS. We show that elevated intraplaque MPO activity detected by molecular MRI employing MPO-Gd predicts future atherothrombosis in a rabbit model and detects ruptured human atheroma, strengthening the translational potential of this approach to prospectively detect high-risk atherosclerosis.

Molecular MRI Identifies Sexually Dimorphic AD Pathology in 3x Tg‐AD Mice

AbstractBackgroundWomen exhibit higher prevalence of Alzheimer’s disease (AD) with faster cognitive decline compared to men, but the mechanisms of this dimorphism remain understudied. Astrocyte function and morphology is distinct in some regions of male and female adult brains which may reflect different courses taken by the neurodegenerative process. Additionally, the p‐tau levels are higher in females than in males. The 3xTg AD mouse model, which manifests amyloid and tau pathology, has been reported to exhibit similar sexual dimorphism. In this work, we investigated whether molecular MRI using a targeted agent that detects hyperphosphorylative cells expressing cell‐surface vimentin predominantly on neurons and the disease associated astrocytes in early states of tau pathology can be used for in vivo imaging of sexual dimorphism in AD pathology.MethodLiposomal Withaferin nanoparticles (WNP) that contain Gd/DOTA for an MRI readout were injected in 3xTg AD mice, at 2‐,5‐,7‐ 9‐ and 12‐ months of age. Animals (n = 14/timepoint, 7 males and 7 females) underwent contrast enhanced magnetic resonance imaging (MRI) using T1 weighted sequences to visualize hyperphosphorylative cells expressing cell surface vimentin. Animals were euthanized after the final time point and brains were harvested for histology and immunofluorescence analysis. CE‐MR images were analyzed for signal enhancement.ResultIn this study, we report the sexually dimorphic nature of the cell surface vimentin expressed by the hyperphosphorylative cells in the brain using the 3xTg AD mice. Both sexes were imaged at 2‐,5‐,7‐ and 9‐ months of age to reveal significant differences in the expression of VIM in males and . Signal enhancement in post‐contrast MRI scans over the baseline scans showed significantly higher enhancement in the females compared with the males (p&lt;0.05) Simultaneously, we also investigate the plasma concentrations of total tau, ptau181, amyloid beta 40 and 42.ConclusionFemale mice expressed higher vimentin in comparison with males, thus reflecting changes in the neurodegenerative processes in the brains of females and males of this strain. Sexually dimorphic molecular changes were successfully visualized by molecular MRI.

Dynamic and rapid deep synthesis of chemical exchange saturation transfer and semisolid magnetization transfer MRI signals

Model-driven analysis of biophysical phenomena is gaining increased attention and utility for medical imaging applications. In magnetic resonance imaging (MRI), the availability of well-established models for describing the relations between the nuclear magnetization, tissue properties, and the externally applied magnetic fields has enabled the prediction of image contrast and served as a powerful tool for designing the imaging protocols that are now routinely used in the clinic. Recently, various advanced imaging techniques have relied on these models for image reconstruction, quantitative tissue parameter extraction, and automatic optimization of acquisition protocols. In molecular MRI, however, the increased complexity of the imaging scenario, where the signals from various chemical compounds and multiple proton pools must be accounted for, results in exceedingly long model simulation times, severely hindering the progress of this approach and its dissemination for various clinical applications. Here, we show that a deep-learning-based system can capture the nonlinear relations embedded in the molecular MRI Bloch–McConnell model, enabling a rapid and accurate generation of biologically realistic synthetic data. The applicability of this simulated data for in-silico, in-vitro, and in-vivo imaging applications is then demonstrated for chemical exchange saturation transfer (CEST) and semisolid macromolecule magnetization transfer (MT) analysis and quantification. The proposed approach yielded 63–99% acceleration in data synthesis time while retaining excellent agreement with the ground truth (Pearson’s r > 0.99, p < 0.0001, normalized root mean square error < 3%).

Research status and progress of cardiovascular magnetic resonance molecular imaging

Research status and progress of cardiovascular magnetic resonance molecular imaging

Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

PH-Weighted amine chemical exchange saturation transfer echo planar imaging visualizes infiltrating glioblastoma cells.

Given the invasive nature of glioblastoma, tumor cells exist beyond the contrast-enhancing (CE) region targeted during treatment. However, areas of non-enhancing (NE) tumors are difficult to visualize and delineate from edematous tissue. Amine chemical exchange saturation transfer echo planar imaging (CEST-EPI) is a pH-sensitive molecular magnetic resonance imaging technique that was evaluated in its ability to identify infiltrating NE tumors and prognosticate survival. In this prospective study, CEST-EPI was obtained in 30 patients and areas with elevated CEST contrast ("CEST+" based on the asymmetry in magnetization transfer ratio: MTRasym at 3 ppm) within NE regions were quantitated. Median MTRasym at 3 ppm and volume of CEST + NE regions were correlated with progression-free survival (PFS). In 20 samples from 14 patients, image-guided biopsies of these areas were obtained to correlate MTRasym at 3 ppm to tumor and non-tumor cell burden using immunohistochemistry. In 15 newly diagnosed and 15 recurrent glioblastoma, higher median MTRasym at 3ppm within CEST + NE regions (P = .007; P = .0326) and higher volumes of CEST + NE tumor (P = .020; P < .001) were associated with decreased PFS. CE recurrence occurred in areas of preoperative CEST + NE regions in 95.4% of patients. MTRasym at 3 ppm was correlated with presence of tumor, cell density, %Ki-67 positivity, and %CD31 positivity (P = .001; P < .001; P < .001; P = .001). pH-weighted amine CEST-EPI allows for visualization of NE tumor, likely through surrounding acidification of the tumor microenvironment. The magnitude and volume of CEST + NE tumor correlates with tumor cell density, degree of proliferating or "active" tumor, and PFS.

Molecular magnetic resonance imaging of liver inflammation using an oxidatively activated probe

Many liver diseases are driven by inflammation, but imaging to non-invasively diagnose and quantify liver inflammation has been underdeveloped. The inflammatory liver microenvironment is aberrantly oxidising owing in part to reactive oxygen species generated by myeloid leucocytes. We hypothesised that magnetic resonance imaging using the oxidatively activated probe Fe-PyC3A will provide a non-invasive biomarker of liver inflammation. A mouse model of drug-induced liver injury was generated through intraperitoneal injection of a hepatoxic dose of acetaminophen. A mouse model of steatohepatitis was generated via a choline-deficient, l-amino acid defined high-fat diet (CDAHFD). Images were acquired dynamically before and after intravenous injection of Fe-PyC3A. The contrast agent gadoterate meglumine was used as a non-oxidatively activated negative control probe in mice fed CDAHFD. The (post-pre) Fe-PyC3A injection change in liver vs. muscle contrast-to-noise ratio (ΔCNR) recorded 2min post-injection was correlated with liver function test values, histologic scoring assigned using the NASH Clinical Research Network criteria, and intrahepatic myeloid leucocyte composition determined by flow cytometry. For mice receiving i.p. injections of acetaminophen, intrahepatic neutrophil composition correlated poorly with liver test values but positively and significantly with ΔCNR (r= 0.64, p <0.0001). For mice fed CDAHFD, ΔCNR generated by Fe-PyC3A in the left lobe was significantly greater in mice meeting histologic criteria strongly associated with a diagnosis NASH compared to mice where histology was consistent with likely non-NASH (p= 0.0001), whereas no differential effect was observed using gadoterate meglumine. In mice fed CDAHFD, ΔCNR did not correlate strongly with fractional composition of any specific myeloid cell subpopulation as determined by flow cytometry. Magnetic resonance imaging using Fe-PyC3A merits further evaluation as a non-invasive biomarker for liver inflammation. Non-invasive tests to diagnose and measure liver inflammation are underdeveloped. Inflammatory cells such as neutrophils release reactive oxygen species which creates an inflammatory liver microenvironment that can drive chemical oxidation. We recently invented a new class of magnetic resonance imaging probe that is made visible to the scanner only after chemical oxidation. Here, we demonstrate how this imaging technology could be applied as a non-invasive biomarker for liver inflammation.