Keywords: Probes & Targets, Tumor, Integrated diagnosis and treatment

Motivation: MnO2 combined with MONs offers potential for accurate tumor diagnosis and treatment. Our MMONs, with adjustable hardness, address issues with hard and soft nanoparticles, showing tumor responsivity and enabling MRI. Irisin loading boosts ferroptosis in drug-resistant tumors.

Goal(s): The synthesis of a stiffness-transformable nanoplatform loaded with Irisin achieves magnetic resonance imaging and induces ferroptosis in the tumor microenvironment.

Approach: MMONs and MMONs-Irisin were synthesized, characterized, and their magnetic resonance imaging and cytotoxic effects were validated at both cellular and animal levels.

Results: MMONs-Irisin is deformable, exhibits excellent magnetic resonance imaging effects, and promotes ferroptosis in tumors.

Impact: MMONs are GSH-responsive, with higher T1 and T2 relaxation rates than Magnevist at equal concentrations. They adjust stiffness for enhanced tumor uptake, loaded with Irisin, combat chemotherapy resistance through ferroptosis. MMONs-Irisin holds potential for safe, integrated cancer diagnosis and treatment.

Keywords: Biology, Models, Methods, Elastography, Preclinical, Steatohepatitis, Murine model, Viscoelasticity, Water diffusion, Fat content

Motivation: The relationship between the microstructural changes and the imaging-based biophysical properties of the liver as NASH progresses are not fully established.

Goal(s): We aim to identify quantitative imaging markers that can provide valuable insights into the microstructural progression of NASH.

Approach: We established non-alcoholic steatohepatitis in mice with a defined amino-acid high-fat diet. We performed MRI, MR elastography and histological scoring with automated fat segmentation at different times during the course of NASH.

Results: Our results shed light on liver viscosity and water diffusivity as potential quantitative markers of steatohepatitis progression in mice.

Impact: This study highlights the role of multiparametric-MRI, MR elastography and histopathology to reveal the dynamics of microstructural changes of non-alcoholic steatohepatitis in a mouse model using a clinical scanner. We identify liver viscosity and water diffusivity as reliable quantitative markers.

Keywords: Small Animals, Preclinical

Motivation: Myocarditis causes adverse ventricular remodeling. However, its early diagnosis and intervention measures remain to be explored.

Goal(s): Exploring quantitative CMR for monitoring myocarditis developments.

Approach: Cardiac T1, T2 and ECV mapping were performed in mice at two timepoints. Then the CMR parameters were compared between the control and myocarditis groups. The CMR results were validated against histology.

Results: Early acute phase of myocarditis was characterized by increased T2 and ECV. As time progressed, T2 was reduced to the normal level, while myocarditis native T1 and ECV were much higher than the control. The CMR findings agreed with histology.

Impact: Quantitative CMR parameters may serve as reliable indicators for edema, inflammation and fibrosis that are associated with the progression of myocarditis, and can be used for early diagnosis, monitoring and management of myocarditis.

Keywords: Small Animals, Cardiovascular, T1 mapping

Motivation: Preclinical cardiac T1 mapping in high field encountered a great challenge, such as rapid heart rate, B0 and B1 inhomogeneity, which affects both accuracy and precision in T1. 

Goal(s): We aim to develop an accurate, fast and reproducible T1 mapping method at 9.4 T MRI.

Approach: We adapted inversion efficiency (IE) to the segmented Look-locker sequence and validated it in a phantom, as well as in aorta banding rats.

Results: Segmented Look-Locker T1 mapping with IE is a fast and accurate T1 mapping method, which corrects the imperfection of inversion pulse in high field.

Impact: We have developed a rapid, highly precise T1 mapping technique for rat hearts using 9.4 T MRI, enabling longitudinal scans and comparisons between different animals.

Keywords: Biology, Models, Methods, Ischemia, Contrast Mechanisms, Molecular Imaging

Motivation: Studies on cardiac ischemia reperfusion injury mainly focus on events following an ischemic event.  Our focus were the initial moments during occlusion and reperfusion in a novel murine model.

Goal(s): Our goal was to characterize the dynamic processes occurring during and immediately after ischemia.

Approach: Manganese is a calcium analogue and potent T1-contrast agent for MRI that enters cardiomyocytes through active calcium channels. By exploiting this mechanism, the disruption of calcium homeostasis was monitored during and after ischemia.

Results: Studying the early phase of ischemia is feasible and data suggest a link between the final scar extent and severity of Ca²⁺ homeostasis disruption.

Impact: Preclinical ischemia-reperfusion injury studies can now be complemented with an early marker for subsequent injury. Revealing the dynamic processes occurring during and immediately after an ischemic event might help to assess the effects of applied therapeutics at an earlier stage. 

Keywords: Biology, Models, Methods, Spectroscopy, sodium, rheology, red blood cells

Motivation: Increased blood viscosity has been reported in red blood cell senescence and pathologies of decreased perfusion such as chronic kidney disease.

Goal(s):

• Rheological NMR is a powerful, although still underutilized, tool to assess the molecular-mechanical links in flowing media. This study's primary objective was to explore the dynamic alterations in Na+ interaction with glycocalyx of red blood cells exposed to the physiological shear forces experienced within the microvasculature in health and disease.

Approach:   ²³Na multiple quantum filtered (MQF) rheo-NMR in RBCs suspensions at varied haematocrit.

Results:   ²³Na MQF rheo-NMR are efficient to detect Na+ interaction with glycocalyx of red blood cells under deformation

Impact: Potential sodium “rheo-markers” reflective of blood viscosity in health and disease are proposed.

Keywords: Small Animals, Animals, cirrhosis,Cirrhotic cardiomyopathy

Motivation: As an important complication of cirrhosis, early diagnosis of cirrhotic cardiomyopathy (CCM) has a profound impact on  prognosis of patients.

Goal(s): Find in myocardial strain parameters beyond global longitudinal strain (GLS) that are relevant for early diagnosis of CCM.

Approach: The heart and liver were scanned with magnetic resonance  and multiple strain parameters were obtained from cardiac magnetic resonance to evaluate their potential diagnostic value for CCM and correlation with liver lesions. 

Results: Compared with GLS and left ventricular ejection fraction , short-axis peak diastolic radial strain rate (PDRSR-S) has an earlier time to change, better diagnostic performance, and better correlation with liver lesions.

Impact: We discoveries a myocardial strain parameter , short-axis peak diastolic radial strain rate, who showed excellent potential in the early diagnosis of cirrhotic cardiomyopathy. The discovery laid the foundation for future research and clinical applications.

Keywords: Biology, Models, Methods, Elastography, organoids, high resolution

Motivation: MR-Elastography is technology that shows promises for gauging response to therapy.

Goal(s):   It is hence of great interest to make this technology also available for the quantification of tissue organoids/spheroids. This enables the translation of the same imaging biomarkers to the pre-therapeutic regime.

Approach:  We present a system that allows for contactless quantification of organoid biomechanics at 35micron resolution and show that gauged spheroids as small as 400mm in diameter are properly quantified in terms of shear wave speed.

Results:  The concept allows to “real-word” organoid testing as they are embedded in a collagen dome with buffer solution around to enable drug exposure.

Impact: Using MRE sequence on patient derived materials to predict cancer cells response to chemotherapy, could be a lifetime saver not only for the patient but also for the clinician decision, by testing in vitro several therapies at the same time.

Keywords: Large Animals, Nonhuman Primates, Animals, CMR, pig

Motivation: Domestic pigs are frequently used as experimental animals for cardiovascular research but are subject to somatic growth.

Goal(s): To investigate the relationship of cardiac functional and volumetric parameters with animal somatic growth. 

Approach: In this retrospective CMR study in 58 female Swiss large white pigs, we correlate functional volumetric and dimensional CMR parameters to animal weight.

Results: : Left ventricular mass, left and right ventricular volumes and stroke volumes correlate with animal weight. Weight-independent parameters were left and right ejection fractions. Our findings match values found in humans.

Impact: We provide a regression analysis of clinical functional, volumetric and dimensional CMR parameters for experimental planning and refinement of animal experiments in pigs and illustrate healthy parameter ranges.

Keywords: Small Animals, Joints, CT, Osteoarthritis, Cartilage, Bone, Multimodal imaging

Motivation: This is a clinically inspired project related to Osteoarthritis which focuses on translational research to specifically enhance murine preclinical models with micro-CT and MRI. 

Goal(s): To optimize MRI methods for monitoring of longitudinal repair of a mouse model of osteochondral injury, to validate joint tissue response and assess intervention impact to the injury site.

Approach: The study design features the micro-CT and MRI imaging of the knee joint in a murine osteochondral injury model. 

Results: The optimized MRI protocol was able to demonstrate differences between groups after longitudinal assessment. This technique is an important translational step allowing the measurement of clinically relevant differences.

Impact: The developed multimodal imaging methodology to monitor tissue repair of mouse knee will extensively enhance the development of novel therapies for cartilage and bone repair, and their translatability into the clinic, whilst reducing the number of animals for preclinical research.

Keywords: Biology, Models, Methods, Bladder, Uro-dynamic MRI

Motivation: Recently developed MRI-Urodynamics methods require rigorous validation. In vitro approaches have been implemented, however lack of tissue-like mechanical properties of the in models limits their applicability. 

Goal(s): Develop and implement an ex-vivo bladder model for validation of MRI-Urodynamics.  

Approach: Porcine bladder was obtained and connected to a syringe pump to conduct MRI experiments during filling and voiding at various flow-rates. Simultaneous pressure measurements were performed during MRI.  

Results: Ex-vivo bladder MRI experiments were successfully conducted. MRI-derived flow-rates agree within 10% when compared to the flow-rates imposed by the syringe pump. Pressure-volume analysis provided means of comparison of bladder performance between filling and voiding. 

Impact: 3D dynamic MRI can assess anatomical changes in the bladder during voiding and filling. Systematic validation of this technique can enhance its clinical use.

Keywords: Small Animals, MSK, muscular dystrophy

Motivation: The frequently-used mdx model of Duchenne muscular dystrophy exhibits wide variation in disease severity, confounding detection of treatment effects.

Goal(s): We sought to design a rapid, noninvasive imaging/analysis pipeline to prescreen animals and balance disease severity across treatment groups.

Approach: Axial MR images and T₂ maps were obtained in the hindlimbs of mdx and wildtype mice. A neural network was trained to speed segmentation. The distribution of muscle T₂ values was analyzed.

Results: Semiautomated segmentation reduced image processing time ~tenfold. Pearson Skew and interdecile range of muscle T₂ distributions were repeatable indicators of muscle disease severity and correlated with Evans Blue dye uptake.

Impact: Use of this rapid, non-invasive, semi-automated MRI/analysis pipeline has the potential to improve the sensitivity of preclinical treatment studies by enabling screening of dystrophic mice prior to study enrollment to increase uniformity of muscle pathology across treatment groups.

Keywords: Preclinical Image Analysis, Quantitative Imaging

Motivation: The clinical value of newly ultrafast multiple overlapping-echo detachment T2 mapping (MOLED-T2 mapping) on common liver tumors has not yet been elucidated.

Goal(s): To test the reliability of MOLED-T2 mapping in common hepatic tumors during clinical applications.

Approach: Total of 23 healthy subjects and 59 patients were enrolled in our study. Free breath MOLED-T2 mapping, breath hold MOLED-T2 mapping and most used breath hold GraSE T2 mapping were compared.

Results: There was no significant difference between free breath and breath hold MOLED-T2 mapping. T2 values obtained from two MOLED sequences were significantly lower than those obtained through fb-GraSE-T2 sequence.

Impact: This work will stand up the foundation for subsequent research about MOLED-T2 mapping on  abdomen quantitative MR imaging.

Keywords: Biology, Models, Methods, Diffusion Tensor Imaging, Cardiovascular

Motivation: Changes in myocardial microstructure that underlie post-myocardial infarction (MI) left ventricular (LV) remodelling may contribute to progressive deterioration in cardiac function and increased risk of adverse clinical events.

Goal(s): To assess post-MI temporal alterations of myocardial microstructure.

Approach: A longitudinal Diffusion Tensor CMR (DT-CMR) pre-clinical study was performed, including healthy, 3 days and 4 months post-MI timepoints, followed by ex-vivo imaging at low and high spatial resolution.

Results: High-resolution ex-vivo DT-CMR suggests preserved helical structure within the infarct core in this swine MI model, with endocardial layers appearing more compressed than mid and epicardial layers.

Impact: Improved understanding of temporal alteration of myocardial microstructure and its dynamics post-MI as seen by in-vivo DT-CMR may facilitate diagnosis and prognostication after MI.

Keywords: Large Animals, Nonhuman Primates, Safety, Swine, thermoregulation, temperature curves

Motivation:
Radiofrequency used during MRI exams heat tissue. The temperature increase is unknown and the thermoregulatory responses still need to be analyzed.

Goal(s): To analyse the temperatures within the thresholds. Are any changes seen. Is the biological simulation replicable in living swine.

Approach: SAR levels in the 2.mode were planned in the swine as an animal model.

Results: The thermoregulatory model (temperature going into a plateau) is only one pattern next to 3 other patterns (linear, parabolic, and sinusoidal). So these will change the  calculations of simulations for temperatures in humans receiving MRI exams.

Impact: Radiofrequency induced temperature changes in MRI exams need to be reevaluated as new thermoregulatory patterns are observed. Increased internal temperatures are subconsciously discerned causing thermoregulation to avoid tissue damage.

Keywords: Probes & Targets, Preclinical

Motivation: Early diagnosis of transplant rejection can help to improve the immune-related management of transplant recipients.

Goal(s): Developing the new methods for early and non-invasive diagnosis of acute cellular rejection to unmet clinical needs.

Approach: Develop a PET/MRI dual-model granzyme B (GzmB)  targeted probe for non-invasively detection of transplant acute cellular rejection.

Results: In preclinical heart graft models of rejection, our PET/MRI dual-model GzmB targeted probe allow noninvasive discrimination of early acute cellular rejection mediated by recipient cytotoxic CD8⁺ T cells.

Impact: In the future, this technology developed a PET/MRI dual-model probe for imaging GzmB produced by cytotoxic CD8⁺ T cells, enabling early non-invasive diagnosis of allograft rejection with high sensitivity and high spatial resolution.

Keywords: Probes & Targets, Atherosclerosis, ADAMTS4

Motivation: A precise diagnosis of atherosclerosis is of clinical importance, since cardiovascular disease remain one of the leading causes of death worldwide.

Goal(s): The goal of this study was to evaluate the feasibility of characterizing a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS4) using molecular magnetic resonance imaging in a preclnical model of atherosclerosis. 

Approach: Molecular magnetic resonance imaging using a novel probe targeted against ADAMTS4 was used in a high-fat murine model. 

Results: It was possible to image atherosclerotic lesions in a mouse model using an ADAMTS4- specific probe for magnetic resonance imaging. 

Impact: Using molecular MRI targeting ADAMTS4 is a promising method for characterization of plaque composition and could possibly impact plaque vulnerability assessment in the diagnosis and treatment of atherosclerosis in patients. 

Keywords: Preclinical Image Analysis, Quantitative Imaging, Multi-tracer, Multiparameteric, Registration

Motivation: Robust preclinical multimodal image registration must be developed to provide rich multiparametric data to noninvasively reveal biological treatment-induced tumor alterations.

Goal(s): Establish a pipeline to enable multimodal registration of semi-rigid, subcutaneous tumors in preclinical models to evaluate multi-tracer multiparametric PET/CT-MR metric alterations.

Approach: Utilizing a breast cancer murine model, a custom-designed mouse couch, augmented with an injectable liquid fiducial marker, was assessed for MR-CT co-registration, facilitating the development of a registration pipeline.

Results: Post-registration tumor segmentation performed independently across modalities yielded high Dice Similarity Coefficient scores (0.92-0.95), indicating accurate tumor alignment, and enabling preliminary multiparametric voxel-wise comparisons of multimodal imaging metrics.

Impact: Preclinical imaging with our registration pipeline enables for biological treatment-induced characterization of subcutaneous tumors through sequential multi-tracer multiparametric PET/CT-MR.

Keywords: Preclinical Image Analysis, Quantitative Susceptibility mapping, QSM , SPION, Iron concentration

Motivation: Progressing the clinical translation of QSM is important for imaging of biometal dysregulation in neurodegenerative disease but available methods for calibrating QSM sequences between systems are limited.   

Goal(s): To develop and validate a superparamagnetic iron oxide nanoparticle (SPION) phantom replicating human brain iron concentration.  

Approach: Dilutions of Ferrotrace SPION (0.1-25 $$$\mu$$$g/mL) were scanned with research application QSM gradient echo sequence using two different 3T systems and multiple analysis methods. 

Results:  A good linear fit was demonstrated between QSM values and SPION concentration across a clinically relevant interval and different QSM analysis methods. Values differed between two scanners but there was high within-scanner concordance.  

Impact: A SPION based phantom replicating in vivo iron of healthy and diseased brain could be an invaluable calibration and QA tool for QSM clinical translation, normative datasets and emerging SPION-based theranostics for brain cancer.  

Keywords: Biology, Models, Methods, Data Acquisition, EPSI, flyback readout, ghost artifacts, micro-imaging, water-fat imaging

Motivation: To assess echo-planar spectroscopic imaging (EPSI) with flyback readout gradients in preclinical MR system.

Goal(s): To demonstrate spectral ghost artifacts produced by two, three,  and four interleaved gradient echo trains and to measure water, fat, and water-fat shift artifacts free images.      

Approach: Flyback EPSI with two, three, and four interleaved gradient echo trains.  

Results: The proposed approach with four interleaved gradient echo trains and with four echoes in each train enables high spectral bandwidth in combination with narrow receiver bandwidth and a very good water/fat signals separation. It improves SNR without the undesired consequence of water-fat shift artifacts.

Impact: Echo-planar spectroscopic imaging with flyback readout enables measurement of water, fat, and water-fat shift artifact-free images. Four interleaved echo trains with four echoes in each train provide high spectral, and narrow receiver bandwidth, and a very good water-fat separation.

Keywords: Probes & Targets, Preclinical, Resonators, Transmit-Receive Coil

Motivation: High permittivity dielectric resonators for high resolution MRI are fabricated ferroelectric materials and have a large temperature coefficient, which produces a significant frequency variation in a small temperature range.

Goal(s): Reduce the temperature coefficient in dielectric resonators through a composite design.

Approach: Depending on the Curie temperature of BST, single layered dielectric resonators have positive or negative temperature dependance of resonant frequency. Bi-layered resonators combine positive and negative coefficients to create a temperature stable resonant frequency.

Results: Bi-layered resonators show on average a 75% reduction in frequency variation compared to single layers.

Impact: Bi-layered resonators are a first step in overcoming high temperature coefficients present in high permittivity dielectric resonators. With further improvements, this method can be used to significantly increase SNR in preclinical studies.

Keywords: Probes & Targets, Tumor

Motivation: Currently used Neutron capture therapy agents in clinic have low tumor targeting ability and have different structures from imaging agents that can view bio-distribution, making it difficult to determine the exact distribution of the drug in the human body.

Goal(s): Development of a new MR-image guided drugs for neutron capture therapy

Approach: Two of gadolinium complexes of porphyrin derivative were designed and synthesized. Cell uptake study was performed using normal cell and glioblastoma cells. In vivo MR images and ex vivo fluorescence images were obtained. 

Results: We found that Gd-complexes could enter into the nucleus and be further uptaken by tumor tissues.

Impact: Using the two gadolinium complexes, it is possible to compare the therapeutic efficacy of GdNCT and BNCT and expect a synergistic effect. The development of NCT treatments using small molecule substances may have the potential for clinical application.

Keywords: Other Preclinical, Reproductive, Early Embryos

Motivation: Traditional methods for early embryos assessment are often invasive or lack detail, underscoring the necessity for non-invasive, high-resolution techniques.

Goal(s): The primary goal was to test MRS as a predictive tool for embryo viability. By leveraging microchip-based probes, we analyzed the metabolic profile of early-stage bovine embryos and oocytes. This aimed at predicting developmental outcomes with high precision and accuracy.

Approach: In total, we conducted multi-channel high-throughput spectroscopy to perform a minimally invasive analysis of 1 hour on 61 single 8-cell embryos and 84 single oocytes.

Results: We found strong correlation between spectra at the 8-cell stage and subsequent development to blastocyst.

Impact: This work offers new data for MRS and embryology, laying a foundation to improve fertility treatments  by selecting viable embryos. By revealing previously inaccessible data it opens to new embryonic research, potentially revolutionizing our understanding of early developmental biology.

Keywords: Biology, Models, Methods, High-Field MRI

Motivation: The zebrafish is an important model organism for the study of vertebrate biology with its genomes showing significant parallels to human genomes.

Goal(s): To show the feasibility of in-vivo imaging at a pre-clinical 11.7T MRI without the need for dedicated hardware components.

Approach: A budget-friendly zebrafish holder was created using a syringe barrel and needle adapters, with a rotating cylinder to maintain water flow. It was positioned on a Bruker Mouse Brain Surface Coil.

Results: The use of standard imaging equipment in combination with a low-cost and easy to built animal holder is sufficient to facility high-resolution imaging of the adult zebrafish.

Impact: This research enables cost-effective, high-resolution MRI for zebrafish, enhancing its potential as a pre-clinical model for vital research in vertebrate biology, ultimately advancing our understanding of human genomics.

Keywords: Preclinical Image Analysis, Drug Development, Protein structure

Motivation: The in-cell NMR method allows direct observations of proteins in cultured human cells, to evaluate protein conformations and interactions in an intracellular environment. Currently, target proteins must be highly soluble and thermally stable.

Goal(s): A technical in-cell NMR strategy is required for proteins with poor solubility and low thermal stability.

Approach: Protein concentration-dependent NMR analyses revealed the self-association sites of proteins. Site-directed mutants gained higher solubility. Cell treatment conditions at lower temperature were established.

Results: We successfully constructed an in-cell NMR protocol that improves protein solubility and cell treatment conditions at 25°C, the lowest temperature established so far.

Impact: By performing experiments according to our strategy, in-cell NMR can be applicable to more types of proteins with poor solubility and low thermal stability. Furthermore, we developed an in-cell system for evaluating therapeutic candidate compounds against target proteins.

Keywords: Biology, Models, Methods, Spectroscopy, MALDI imaging, heterospectroscopy

Motivation: Combining high-resolution (HR) magnetic resonance spectroscopy (MRS) and matrix-assisted laser desorption/ionization (MALDI) imaging of tissues and cells using new workflows and data analysis approaches will further advance metabolomic and lipidomic studies.

Goal(s): The goal is to develop Statistical Heterospectroscopy (SHY) of ¹H-HR-MRS and MALDI imaging data of tissues and cells.

Approach: Phantoms, cell lines, and tumors were measured by ¹H-HR-MRS and MALDI imaging, followed by analysis with newly developed MATLAB-based software for statistical correlation of both datasets.

Results: The new MALDI-MRS-SHY software correctly generated two-dimensional spectra with cross-peaks from phantoms of pure compounds and mixtures, as well as cell lines and tumor tissues.

Impact: The newly developed MALDI-MRS-SHY software will allow for a deeper analysis of complex metabolomic and lipidomic data obtained by combined HR-MRS and MALDI imaging of cells and tissues.

Keywords: Probes & Targets, Contrast Agent

Motivation: We aim to advance biocompatible ¹⁹F-MR contrast agent to enhance imaging diagnostic in cancer.

Goal(s): Nanoparticles (NPs) internal structure impacting Gd-enhanced effect on ¹⁹F-MR signal strength, relaxation times and pH-sensitivity.

Approach: Systematic investigation using ¹H/¹⁹F-MR to understand how NPs structure affects the interaction between co-encapsulated Gd and ¹⁹F and focusing on multi-core NPs and their acidic pH-sensitivity on ¹⁹F-MR relaxation times.

Results: Our study revealed that ¹⁹F-MR signal strength is pH-dependant. After cellular uptake, multi-core NPs co-encapsulating Gd and PFCE exhibited higher T2 values and stronger signal, influenced by lysosomal acidity, highlighting pH role in MR signal modulation.

Impact: The pH-sensitive ¹⁹F-MR probe enhance NPs tracking after cell internalization and by that it holds great promise for tissue pathology imaging, as cancer diagnostics.

Keywords: Preclinical Image Analysis, Preclinical

Motivation: Radiation therapy (RT) for primary tumors triggers regression in non-irradiated metastatic lesions via the abscopal effect, can potentiate the effects of immune-checkpoint blockade on the non-treated tumors in the same animal. 

Goal(s):  To examine physiological alterations of the treated tumor linked to the abscopal effect.

Approach: We used MRI-based imaging techniques, such as EPR oximetry, DCE MRI, and ¹³C DNP MRI.

Results: After RT and PD-1 blockade, we observed improved oxygenation, permeability, perfusion, and CD8+ T cell infiltration in metastatic (untreated) tumors. Interestingly, primary tumor with increased permeability and perfusion and reduced hypoxic fraction (HF10) before treatment correlated with augmented abscopal effect post-treatment.

Impact: Metastatic tumor conditions improved with RT and ICB, enhancing oxygenation, permeability, perfusion, and CD8+ T cell infiltration. Primary tumor's elevated permeability and lower HF10 correlated with higher AE in metastatic tumors, confirmed through carbogen-enhanced perfusion.

Keywords: Biomarkers, Cancer, Multiparametric, IVIM

Motivation: IVIM MRI potentially offers non-invasive, non-contrast-based quantification of tumor perfusion parameters, which would facilitate tumor tissue characterization and longitudinal assessment of radionuclide therapy.

Goal(s): The goal was to study the feasibility of using IVIM metrics for spatiotemporal tissue characterization in the context of radionuclide therapy in a neuroendocrine tumor model. 

Approach: Mice with human neuroendocrine tumors were imaged before and repeatedly after radionuclide treatment and parametric maps of perfusion-related parameters from IVIM and DCE were compared and studied longitudinally.

Results: Interesting spatiotemporal variations that revealed similarities between techniques show promise for further in-depth analysis using spatial image registration techniques and histopathological validation.

Impact: Non-invasive, spatiotemporally resolved tumor perfusion characterization using intravoxel incoherent motion MRI would benefit preclinical optimization and understanding of radionuclide treatment with possible rapid translation into the clinics due to the widespread use of MRI in both research and clinical practice. 

Keywords: Other Preclinical, Toxicity, In vitro Pharmacometabolomics, NMR spectroscopy, Nanocomposite, Nanotoxicology

Motivation: Conventional toxicity assays generally convey the efficiency of nanomaterial, but they lack a mechanistic molecular approach to toxicity. 

Goal(s): We aimed to employ NMR-based Pharmacometabolomics to detect early metabolic alterations associated with nanomaterial developed for healthcare. 

Approach: The NMR spectroscopy technique was used on Silver nanoparticles reinforced biocomposite exposed murine fibroblast (L929) cells. 

Results: Results demonstrated that cellular metabolic profiles reset towards control upon more exposure.

Impact: Our nanomaterial-based study accentuates the role of pharmacometabolomics, which will complement the findings of conventional assays, eventually leading to efficacious clinical translation. 

Keywords: Biomarkers, Vessels, Liver, tumor, biomechanics, Elastography

Motivation: Colorectal cancer is a major global cause of cancer-related deaths, often metastasizing to the liver. Standard treatment includes chemotherapy and anti-angiogenic therapy. Quantifying therapy efficacy remains a clinical challenge.

Goal(s): We explore multifrequency MR-Elastography (MRE) for assessing vascular organization, using a murine liver metastasis model correlated with histopathology.

Approach: The study used MRE imaging of murin liver metastasis model and the corresponding histopathology to analyze vascular organization (fractal dimension), by measuring Hurst index (H-index).

Results: The H-index differs significantly between tumor and healthy liver tissue, with normal vasculature displaying a lower H-index compared to the tumoral tissue.

Impact: Our in vivo elastography study demonstrates the organization of the vascular network by matching with histological findings. This innovative approach paves the way for non-invasive evaluation of treatments targeting tumor vessels, such as bevacizumab or FOLFOX.

Keywords: Biomarkers, Molecular Imaging, Melanoma, BRAF

Motivation: We use ¹H/³¹P MRS to monitor the metabolic effects of dabrafenib therapy in four human melanoma models, an FDA-approved treatment for late-stage melanoma. 

Goal(s): Differences in relative levels of metabolites and bioenergetics between four melanoma models may produce differential therapeutic responses to BRAF inhibitors.

Approach: Intratumor variations of lactate, alanine, and bioenergetics (β-NTP/Pi) measured by in-vivo and in-vitro ¹H/³¹P MRS have the potential to become early and sensitive biomarkers of dabrafenib inhibition therapy in melanoma.

Results: Changes in lactate, alanine, and bioenergetics response to targeted dabrafenib inhibitor therapy occur rapidly and are connected to the following tumor response.

Impact: Dabrafenib blocks cell division by inhibiting the hyperactive BRAF protein. Differences in the predominance of metabolites (Lactate and Alanine) and bioenergetics may explain dabrafenib therapeutic responses in DB-1/WM983B (Sensitive mutant type), WM983BR (Resistant mutant type), and WM3918 (Wild type).

Keywords: Biomarkers, Neurodegeneration

Motivation: Robust methods are urgently needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. MRI methods hold significant promise, with quantitative Gradient Recalled Echo (qGRE) shown to provide insight into neurodegeneration in AD prior to atrophy development in humans.

Goal(s):  In this study a novel method is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD.

Approach: Histological validation of the findings is performed.

Results: A strong correlation is revealed between the MRI metric and myelin content, hence offering the explanation for the mechanism of observed contrast.

Impact: A robust method for longitudinal in-vivo quantification of neuronal density loss in a mouse model of AD is presented and validated, allowing for efficient preclinical evaluation of novel AD therapeutics and accelerated drug development in the field.

Keywords: Neurofluids, Neurofluids

Motivation: It is desirable to accurately evaluate water movement within the brain so that it can be compared with neurofluid flow observed with other tracers.

Goal(s): The aim of this study was to evaluate the motion of neurofluids in a mouse model of chronic unilateral hypoperfusion using H₂¹⁷O and Gd-DTPA as MRI tracers.   

Approach: Dynamic T2WI and T1WI were performed during and after intrathecal infusion of H₂¹⁷O and Gd-DTPA, respectively. 

Results: There was a clear difference in the distributions of H₂¹⁷O and Gd-DTPA after intrathecal injection. This suggests that different mechanisms are involved in the transport of water and other molecules in the brain. 

Impact: The difference in distribution of the tracers in the UCCAO model suggests that this method may be useful for investigating the pathological mechanism of various brain diseases. 

Keywords: fMRI Analysis, Neonatal, Synthetic Magnetic Resonance Imaging,Myelination；Brain；Relaxometry; Development

Motivation: Conventional MRI sequences used in clinical practice cannot quantitatively evaluate the development of white matter in newborns.

Goal(s): To explore the feasibility and application value of Synthetic MRI (SyMRI) in cerebral white matter myelin development of full-term neonates.

Approach: Use intra-group and inter-group comparison of quantitative relaxation metrics obtained by SyMRI to evaluate the white matter myelin development level in newborns of different gestational ages.

Results: Quantitative relaxation metrics derived by SyMRI can quantitatively evaluate the formation of myelin and brain maturity in full-term newborns. T1 and T2 values in different regions can reflect the differences in myelin sheath formation time.

Impact: SyMRI can be used in clinical practice to investigate the myelin development of white matter in full-term newborns, and provide imaging basis for early detection and diagnosis of neonatal brain developmental dysplasia and disease conditions in newborns.

Keywords: Small Animals, Brain, Asymmetry

Motivation: Exploring the mechanistic insights into the development of (altered) brain asymmetry in cognitive and psychiatric conditions requires the use of preclinical models. However, as asymmetry patterns are generally nuanced, even within human populations, substantial sample sizes are required to describe this phenomenon accurately.

Goal(s): Our goal was to explore the presence of brain asymmetry in the mouse overcoming the sample size limitations.

Approach: We leveraged a dataset encompassing MRI data from over 2000 mice.

Results: We found robust brain asymmetry in the mouse, as well as asymmetry patterns that differ from those observed in humans. 

Impact: The mouse brain is asymmetric and there are some similarities between humans and mice, but species-specific asymmetry patterns need to be taken into account for translational research, reevaluating traditional assumptions and exploring the complexities of brain function across species.

Keywords: Biomarkers, Diffusion/other diffusion imaging techniques, Idiopathic Intracranial Hypertension, DTI-ALPS

Motivation: Idiopathic intracranial hypertension (IIH) is caused by elevated intracranial pressure of unknown etiology. In recent years, growing evidence has suggested that impaired glymphatic clearance may mediate IIH pathogenesis.

Goal(s): We hypothesized that individuals with IIH would exhibit impaired glymphatic outflow, which could be directly measured using diffusion tensor imaging along the perivascular space (DTI-ALPS).

Approach: This work used DTI-ALPS to investigate glymphatic clearance in individuals with IIH, and its association with symptom severity and comorbidities.

Results: Impaired glymphatic clearance was directly related to the clinical severity of IIH, as suggested by a lower DTI-ALPS index.

Impact: We employed perivascular diffusion tensor imaging to study glymphatic flow in IIH patients. Lower ALPS index correlated with greater clinical severity, offering insights into IIH's pathomechanism and its potential for diagnosis and treatment evaluation.

Keywords: Preclinical Image Analysis, Microstructure

Motivation: High-resolution ex vivo susceptibility tensor imaging (STI) shows promise in visualizing detailed microstructural neuroanatomy related to tissue magnetic susceptibility contrast but is usually challenging with large human brain samples.

Goal(s): This work aimed to demonstrate a feasible protocol for STI on postmortem human hemibrain using a 7T human MR scanner.

Approach: De-identified human brain samples of the left hemisphere were collected, prepared, and scanned with a 3D multi-echo gradient echo sequence with 0.5 mm isotropic resolution.

Results: Multi-orientation quantitative susceptibility mapping and STI with a maximum of 12 orientations were obtained. Myelinated fibers and iron deposition in cortical substructures were visualized.

Impact: The proposed ex vivo MRI protocol is expected to be helpful to researchers interested in STI. The ex vivo STI acquired through this protocol may provide anatomical references for in vivo STI studies.

Keywords: Small Animals, Alzheimer's Disease, resting state fMRI, functional connectivity, tau

Motivation: Identifying neurological changes in Alzheimer’s Disease (AD) is critical for early intervention. Tau accumulation is a key pathological feature in AD and other neurodegenerative diseases.

Goal(s): This project investigates how tau accumulation impacts structural and functional connectivity in the brain and cognitive decline.

Approach: We use behavioral assessments of learning and memory in the rTg4510 mouse model of tauopathy with awake resting-state fMRI and diffusion tensor imaging at three timepoints during the course of tau accumulation.

Results: As tau accumulates, we identify patterns of functional connectivity changes. We plan to use machine learning to link these changes to cognitive decline.

Impact: We study how tau accumulation affects brain functional connectivity and cognitive decline in a mouse model of tauopathy. Magnetic resonance imaging may offer non-invasive tools for assessing Alzheimer's Disease pathology, potentially aiding in early diagnosis.

Keywords: Biology, Models, Methods, Validation, Axon Diameter, Diffusion-Relaxation, Relaxometry, data analysis

Motivation: Alteration of the axon radii has been previously linked with neurodevelopmental disorders and neurologic pathologies. The possibility of resolving submicrometric axon diameter yields the potential to open new diagnostic avenues.

Goal(s): Validation of the previously presented surface-based relaxation model, assessing the feasibility of estimating axon diameter based on intra-axonal transverse relaxation times.

Approach: Correlating diffusion-relaxation MRI data acquired in an ex-vivo rat sample and axon diameter measures based on histology data in the Corpus Callosum.

Results: The results confirm the previously reported linear relationship between intra-axonal T₂ and axon diameter as estimated based on histology.

Impact: This first direct validation experiment of the relationship between intra-axonal T₂ and axon diameter employing a surface-based relaxation model could pave the way for a novel biomarker in neurological disease.  

Keywords: Small Animals, Alzheimer's Disease, resting state fMRI, Functional Connectivity, Spatial Proteomics

Motivation: Alzheimer's Disease (AD) is a devastating neurodegenerative disease that affects 50 million people worldwide.

Goal(s): Advancements in neuroimaging techniques that can detect deficits prior to significant accumulation of pathology and cognitive decline would aid in early detection, diagnosis, and possible therapeutic intervention.

Approach: Resting state fMRI studies have identified early functional connectivity (FC) deficits in memory-related brain regions, preceding cognitive impairment, making it a promising clinical marker for AD.

Results: Using an AD mouse model, our study has identified unique patterns of FC changes across disease progression. Using machine learning we are working to establish relationships between neuroimaging and cognitive and proteomic changes.

Impact: This study aims to uncover dynamic alterations in functional connectivity and the link to cognitive and proteomic changes using a mouse model of Alzheimer's Disease. These findings offer potential insights for early detection and diagnostic advancements in Alzheimer's Disease research.

Keywords: Neurofluids, DSC & DCE Perfusion, Alzheimer' Disease; CSF clearance; GBCA

Motivation: Accumulation of abnormal proteins in AD has been linked with barrier breakdown between blood and tissue or CSF, and impaired clearance from the brain. 

Goal(s):  To use GBCA-induced signal changes in ventricular CSF following intravenous injection and its decay over time as indices to study the integrity of blood-CSF barrier (BCSFB) and GBCA clearance via CSF, respectively.

Approach: Dynamic-susceptibility-contrast-in-the-CSF (cDSC) MRI was performed in the 3xTg-AD mouse model. 

Results: Impaired clearance in AD mice became significant at 8 months. The amount of GBCA crossing BCSFB appeared similar between AD and WT mice at these early stages. 

Impact: Our results suggest that delayed CSF clearance may provide a more sensitive marker for AD, and parameters measured during the clearance phase may be more robust than measures obtained immediately after GBCA administration.

Keywords: Small Animals, Genetic Diseases, Volumetric

Motivation: Robust translational imaging biomarkers are needed to facilitate the development of disease-modifying treatments for Huntington’s disease (HD), a rare inherited neurodegenerative disease.

Goal(s): To determine the use of structural atrophy determined with MRI as a robust translational biomarker for testing therapeutics in mouse models prior to people with HD.

Approach: In this work, we used semi-automatic delineations and tensor-based morphometry (TBM) of 3D high-resolution anatomical MR images to assess structural anomalies in the knock-in zQ175DN model of HD at different ages.

Results: We detected progressive volumetric decrease in the zQ175DN mouse model, offering a powerful translational biomarker for the assessment of disease-modifying therapies.

Impact: We report the first brain-wide structural study of zQ175DN mice using in vivo MRI. Our work supports structural atrophy as a robust translational biomarker for testing therapeutics in mouse models prior to people with HD.

Keywords: Small Animals, Metabolism

Motivation: Large-scale brain imaging studies have shown a significant association between altered brain structure in obesity. However, the exact biological processes remain elusive. Here, we use inbred mice, fed diets with pre-determined caloric contributions to elucidate diet-specific contributions to brain structure alterations in obesity.

Goal(s): The goal of this study is to perform morphometric analysis of the brains of a commercially available mouse model of obesity. 

Approach: Mice were fed regular (5% fat), or obesogenic diets (40% fat).  After 8 weeks all mice were scanned using MRI.

Results: Obese mice show volume reduction, but not statistically significant. Neocortical volumes were larger in obese mice. 

Impact: The use of commercially available, diet-induced, obese mouse models provides an opportunity for the neuroimaging community to produce consistent structural and functional to support the assertion that obesity may be a ‘brain disease’. 

Keywords: Biology, Models, Methods, Translational Studies, Huntington's

Motivation: Suitable mouse models of Huntington's disease are crucial for the evaluation and translation of potential new treatments.

Goal(s): We studied the zQ175 heterozygous model for Huntington's disease in comparison to wildtype controls.

Approach: We compared brain MRI and behavioral readouts over a large part of the lifespan to characterize and quantify phenotypes.

Results: The model only developed a mild brain atrophy phenotype, part of the size difference was shown to be due to reduced growth rather than atrophy.

Impact: This study can help researchers to make better informed decisions on mouse model selection for evaluation of potential treatment efficacy in translational studies of Huntington's disease.

Keywords: Small Animals, Stroke

Motivation: Stroke is a serious medical condition that can lead to long-term disability and death, yet has limited treatment options. 

Goal(s): This study aims to identify effective diffusion MRI biomarkers in monitoring treatment response with a repurposed drug for stroke. 

Approach: In vivo diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI) were performed on the mouse brain with middle cerebral artery occlusion (MCAO). Mice were imaged on the 14T MR system on day 7 post-MCAO, following a 7-day treatment regimen with either Senicapoc or vehicle.

Results: Certain DTI and NODDI parameters were found to demonstrate strong treatment effect.

Impact: Both DTI and NODDI maps may provide useful information in monitoring response to repurposed Senicapoc drug treatment for stroke. 

Keywords: Biomarkers, CEST & MT

Motivation: Use MRI CEST data to predict lower back pain scores in porcine model.

Goal(s): To use a porcine model to correlate MRI-based biomarkers with backpain associated with IVD degeneration.

Approach: IVD injury was induced in the lower three lumbar discs while keeping the upper two intact. MRI scans were performed every 4 weeks upto 16 weeks post injury. Pearson Correlations were used for data analysis. 

Results: MTR and Exchange rate signal clearly separate the injured and the healthy disks. There is a positive correlation between higher exchange rate signal and higher back pain while a negative correlation between MTR and pain scores. 

Impact: The study bridges the gap between small animal models and human clinical studies by employing a clinically relevant large animal model. The development of MRI-based pain assessment biomarkers is a critical step toward advancing our understanding of lower back pain.

Keywords: Preclinical Image Analysis, Segmentation, Parcellation, atlas based volume extraction

Motivation: Manual characterization of brain regions is studied without prior knowledge to identify changes in GM/WM volume in PD. 

Goal(s): Characterisation of GM and WM changes in 6-OHDA PD model as compared to sham control

Approach: Parcellated the rat brain into predefined regions using a rat atlas and performed the Wilcoxon rank signed rank test to identify significant changes in GM/WM volume.

Results: Significant loss in GM volume of a few brain regions in PD and Sham observed in 3^rd and 7^th week. Increase in WM volume for 3^rd week is observed.

Impact: We identified GM loss and WM gain in a few brain regions without manual intervention which helps in understanding the structural changes in the whole brain in PD and Sham.

Keywords: Small Animals, Neuroscience, Neurovascular coupling;Excitatory neurons;Inhibitory neurons;Anesthesia

Motivation: Understanding hemodynamic activity is essential for blood-based brain mapping techniques like fMRI.

Goal(s): Many studies have demonstrated that excitatory activity leads to an increase in hemodynamic response. However, how inhibitory neurons regulate the brain blood’s supply is less understood. Also, how hemodynamic response is modulated by brain status induced by different anesthetic is still unclear. 

Approach: To investigate that, we used optical intrinsic signal imaging to investigate the roles of excitatory and inhibitory activity under awake and different anesthetic conditions.

Results: Our findings revealed that different conditions not only shape the response time and peak change but also causes different hemodynamic response.

Impact: We investigated the hemodynamic response of excitatory and inhibitory neurons by optogenetic stimulation under awake and 3 commonly used anesthetics. Our study may have an impact on investigating neurovascular coupling in different brain conditions.

Keywords: Small Animals, Preclinical

Motivation: Zero-echo time (ZTE) sequence reduces susceptibility artifacts compared to echo planar imaging (EPI). However, the feasibility of ZTE for functional MRI (fMRI) has not been fully investigated.

Goal(s): Our goal was to assess the feasibility of ZTE for fMRI. 

Approach: Time-course of ZTE, gradient echo (GE)-EPI, and spin echo (SE)-EPI signal changes by somatosensory stimulation was investigated. The functional connectivity in resting state ZTE, GE-EPI, SE-EPI was also compared.

Results: The results indicate that ZTE is useful for fMRI.

Impact: ZTE sequences realize the fMRI that is robust to susceptibility artifacts.

Keywords: Large Animals, Nonhuman Primates, Preclinical, animal models

Motivation: Functional magnetic resonance imaging is increasingly used to study brain function and cognition in domestic dogs.

Goal(s): The objective of this study was to acquire the high-quality fMRI data which dogs can be trained to remain awake and still inside MRI scanners and detect the pathway for dog’s face processing.

Approach: We use a combination of simulated and real MRI environments to train awake dogs. A visual stimulation paradigm with block design was used to compare activity elicited by human faces against objects.

Results: We successfully detect the activation of human faces against scramble objects in occipitalis, ectomarginalis, and ectosylvius medius.

Impact: This study provides a process for training dogs for fMRI acquisition while awake and introduces the temporal cortex as candidate to process human faces and dog faces.

Keywords: Neurofluids, Brain, Glymphatic System

Motivation: This study investigates the glymphatic function in awake vs. anesthetized mice by means of diffusion-weighted (DW) MRI.

Goal(s): Application of developed ‘silent’ DW-MRI protocol is presented for comparison of awake and anesthetized mice under ketamine-xylazine (K/X), and isoflurane. 

Approach:  In total, n=17 C57BL/6 mice were habituated to awake MRI setup, and successfully underwent DW-MRI with monitored body temperature and respiratory rate.

Results: Results showed that brain water mobility in awake mice was consistent, while K/X and isoflurane affected both slow and fast MR diffusivity measures differently. Awake DW-MRI offers a promising alternative to MRI under anesthesia, promoting increased biological relevance and translational potential.

Impact: This research on glymphatic function using DW-MRI underscores the importance of non-invasive MRI in awake mice, emphasizing anesthesia's impact on physiological stability. It highlights the translational potential of awake DW-MRI and is of importance to neuroscientific and biomedical research communities.

Keywords: Small Animals, Velocity & Flow, Magnetic resonance velocity mapping; Phase contrast; Velocity; Rat.

Motivation: Several human cerebral diseases are associated to neurofluids dynamics alterations and continue to require preclinical research studies. Rat models were widely used to understand these diseases but its cerebral hemodynamic is not fully elucidated. Phase contrast (PCMRI) allows noninvasive quantification of blood flow dynamics.

Goal(s): Our goal was to investigate both cerebral arterial and venous sinuses flows in rats.

Approach: Twelve Sprague-Dawley rats underwent a 7T preclinical MRI. PCMRI quantified blood flows dynamics in the internal/external carotid arteries, basilar artery and transverse sinuses during cardiac cycle.

Results: We obtained physiological references of cerebral blood flows parameters for these main cerebral vessels in rats.

Impact: This study highlights the potential of PCMRI to investigate cerebral blood flows dynamics in rats.  These findings may be important to study neurofluids dynamics interactions, pressure and compliance, to better understand human idiopathic pathologies such as hydrocephalus and intracranial hypertension.

Keywords: Small Animals, Elastography, sex differences, estrous, rat

Motivation: In rodent studies, the number of spines on hippocampal CA1 neurons decreases from proestrus to estrus, and complimentary reductions to hippocampal volume are observed in rodents and humans. It remains unknown if estrous-related changes to tissue microstructure alter the mechanical properties of CA1.

Goal(s): Evaluate the mechanical properties of CA1 between proestrus and estrus in the adult rat brain.

Approach: A novel rat Magnetic Resonance Elastography (MRE) protocol, measuring tissue deformation to determine stiffness and viscosity, was used to identify changes to the mechanical properties of CA1.

Results: CA1 stiffness increases between proestrus and estrus phases in female rats.

Impact: Results from this longitudinal study show that the stiffness of the hippocampal CA1 subregion increases between proestrus and estrus phases within-rat. We did not discover any changes to whole brain biomechanics between proestrus and estrus within-rat, consistent with the literature.

Keywords: Biology, Models, Methods, Aging, elastography

Motivation: The biomechanical signature of the aging brain and its correlation with the underlying microstructure, is poorly understood.

Goal(s): To systematically analyze the global and regional biomechanical properties of the brain during aging.

Approach: We investigated the in vivo biomechanical progression of the female mouse brain over an age range of 6 to 18 months using multifrequency MR elastography.

Results: Highly resolved elastographic atlases of the mouse brain at different ages were generated. Global and regional analysis revealed softening and reduced viscosity as dominating patters of biomechanical changes related to the structural variations of the aging brain.

Impact: This study demonstrated the use of MR elastography to track the biomechanical changes in the brains of aging healthy mice. Our study revealed softening and increased viscosity as biomechanical signature of the aging brain.

Keywords: Preclinical Image Analysis, Spectroscopy, animals, aging, spectroscopy, treatment, Rho GTPases

Motivation: RhoGTPases are involved in the pathogenesis of neurodegenerative and neurodevelopmental diseases, playing a key role in synaptic plasticity.

Goal(s): The aim is to evaluate the involvement of RhoGTPases on ageing processes, assessing effects of RhoGTPases modulation on behavior and brain metabolism (by MRS) on a healthy aging mouse model.

Approach: We pharmacologically modulated RhoGTPases pathways by administering fasudil or CNF1 in mice. Animals are subjected to behavioral tests and to MRI/MRS experiments in frontal cortex, hippocampus and cerebellum.

Results: Young mice showed apparent greater anxiolytic effect respect to old mice. We observed also age- differences in the metabolism in response to both treatments.

Impact: Dysregulation of the RhoGTPase pathway leads to: oxidative stress, inflammation, alterations in energy metabolism and reduced synaptic transmission. RhoGTPase pathway is involved in the pathogenesis of neurodegenerative diseases; RhoGTPases are here proposed as an innovative pharmacological target for their treatment.

Keywords: Neurofluids, Neurofluids, Glymphatic System

Motivation: The glymphatic system’s role in metabolic waste removal in the brain is crucial. Impairment of the flow of cerebrospinal fluid (CSF) and interstitial fluid (ISF) has been linked to several neurological conditions.

Goal(s):  Our aim is to develop a method combining contrast media administration, MRI, and postprocessing for detailed study of the glymphatic system in rats.

Approach: We investigated how administration routes with various invasiveness effect the distribution of contrast agent (CA) in the healthy rat brain and compared different data analysis methods.  

Results: Only cisterna magna application showed satisfying results. Time series cluster analysis shows patterns in the contrast agent distribution dynamic. 

Impact: A reliable MRI-based method for investigating the glymphatic system in rats will allow for the study of its role in several neurodegenerative and other diseases.

Keywords: Biology, Models, Methods, Neuroscience, Modelling, new device, hippocampus

Motivation: Virtual brains are proving quite successful for BOLD signal simulation but they still lack a specific mathematical description of individual brain regions.

Goal(s): Our goal was to develop a specific mean field model (MF) of the hippocampus CA1 microcircuit.

Approach: A bottom-up formalism recently developed for the cerebral and cerebellar cortex was adopted. It is based on a transfer function, which remaps neuronal microscale features from cellular recordings to the mean field mesoscale domain.

Results: The hippocampus CA1 MF reproduced the neuronal activity of the microcircuit and captured learning mechanisms.

Impact: The mean field of the hippocampus CA1 microcircuit enriches the growing collection of region-specific models. Its forthcoming integration into virtual brains together with other region-specific models has the potential to achieve a comprehensive and personalised BOLD signal dynamics simulation.

Keywords: Neurotransmission, Metabolism, Glucose, glutamate, GABA, Neurons, neurotransmission

Motivation: Fasting is used in weight loss but its impact on brain activity is not well understood.

Goal(s): To assess the impact of prolonged fasting on the excitatory and inhibitory neurotransmission in the brain.

Approach: Infuse [1,6-¹³C₂]glucose in mice fasted for 4h to 60h, and measure ¹³C labeling of brain metabolites by ¹H-[¹³C]-NMR spectroscopy.

Results: The glutamatergic neurometabolic activity was reduced in the cerebral cortex of mice fasted for 60 h.

Impact: These findings can be used for modifying the fasting paradigm in different interventions involving fasting.

Keywords: Large Animals, Nonhuman Primates, Animals

Motivation: Establishing standard brain images for various mammalian species may be useful in brain imaging analysis.

Goal(s): The current research aimed to establish a foundation for brain image analysis tools in a variety of mammalian species, including cats and marmosets, for which standard brain data are scarce.

Approach: For each species, we attempted to create an image of average brain using a nonrigid transformation algorithm. We also evaluated the quality of the average brain images by changing the number of subjects.

Results: We were able to create an image the average human, cat, marmoset, and mouse brain based on T1- and T2-weighted images.

Impact: This study provides an important foundation for the creation of standard brain images of various animal species and for the evaluation of individual differences. 

Keywords: Software Tools, Software Tools, preclinical, MRSI, spectroscopy

Motivation: Numerous software options exist for MRS processing, yet the preclinical domain lacks a harmonized multimodal toolbox featuring a graphical user interface (GUI).

Goal(s): Our goal was to create a harmonized toolbox tailored to preclinical MRS processing, with a special focus on addressing MRSI-related challenges.

Approach: The MRS4Brain Toolbox was designed to handle 1H and X nuclei data, and to allow brain segmentation of MRSI voxels in order to investigate brain regional differences.

Results: Fast and user-friendly brain MRSI segmentation and metabolic mapping were achieved, promoting the study of brain-regional differences.

Impact: The implementation of the open-source MRS4Brain Toolbox enables rapid and straightforward advanced preclinical MRS(I) data processing and quantification. It falls in line with the within- and across-site standardization effort launched by the MRS community. 

Keywords: Epilepsy, Hyperpolarized MR (Non-Gas)

Motivation: Thirty percent of epilepsy patients have seizures despite best medical therapies. Therefore, a non-invasive method to localize seizure onset zone (SOZ) and epilepsy network (EN) in epilepsy surgery to improve surgical outcomes is essential.  

Goal(s): The goal of this study was to apply dynamic magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized [1‑¹³C]pyruvate (Pyr) to measure lactate (Lac) release in a Pentylenetetrazol (PTZ) mouse model of epilepsy.

Approach: We hypothesize that hpMRSI of [1-¹³C]Pyr accurately measures elevated Pyr-to-Lac conversion in a PTZ mouse model of epilepsy.

Results: Significant increase in Pyr-to-Lac conversion has been measured in PTZ kindled mice compared to control mice.

Impact: Epilepsy surgery outcomes depend on correctly identifying SOZ and EN. We utilized hpMRSI of [1-¹³C]Pyr to accurately identify elevated Lac release in PTZ mouse model of epilepsy. These results support its potential application to identify epileptic focus in epilepsy patients.

Keywords: Small Animals, Spectroscopy, X-nuclei, dynamic 13C, mice brain, cerebral metabolism

Motivation: Dynamic ¹³C MRS is a powerful tool for the investigation of brain metabolism in vivo. Due to its low SNR, it is typically constrained to big voxel sizes covering almost the whole brain in mice. Thus, making region specific research questions difficult.

Goal(s): Investigating the feasibility of acquiring ¹³C spectra from a distinct brain region (bilateral hippocampi) in the mouse brain at 9.4T.

Approach: We applied a combination of polarization transfer, a CryoProbe, frequency correction and ‘SVD denoising’ for the acquisition of ¹³C spectra.

Results: We achieved sufficient spectral quality to quantify even small metabolite pools like GABA in the bilateral hippocampus.

Impact: 13C MRS of distinct brain regions in the mouse brain paves the way for more specific research questions.

Keywords: Biology, Models, Methods, Neuroscience, fMRI Analysis, brain connectivity, preclinical

Motivation: We do not yet know where zona incerta (ZI) neural activity is distributed in central pathways despite extensive knowledge of incertal projections and functions.

Goal(s): We aim to reveal the long-range functional pathways of ZI neural activity to bridge the knowledge gap between known anatomical projections and implicated functions.

Approach: We deployed optogenetic fMRI to directly initiate neural activity at ZI and computational approaches to characterize the downstream central pathways involved.

Results: The propagation of neural activity from ZI are not restricted to monosynaptic projections within known subcortical structures, but along multi-synaptic, long-range central pathways.

Impact: Characterization of ZI functional pathways is of tremendous value to neuroscientists and clinicians for future in-depth investigations of key/previously undefined incertal regions and for designing more effective therapeutic measures such as deep brain stimulation, where ZI is a key target.

Keywords: Probes & Targets, Tumor, Spleen

Motivation: Metastasis is the leading cause of cancer-related mortality worldwide. We must pave new avenues for cancer treatment by interrogating the pro-tumorigenic properties of the tumor macroenvironment. 

Goal(s): We seek to investigate how tumorigenesis metabolically impacts the spleen microenvironment and how it contributes to immune evasion. 

Approach: Proton magnetic resonance spectroscopy was used to identify aqueous spleen metabolites during tumorigenesis. Flow cytometric analyses were conducted to immunophenotype splenic CD8⁺ T cells and to quantify MDSC and T-cell frequencies. 

Results: Tumorigenesis induced common, distinct metabolite changes in mouse spleens. Flow cytometric analyses revealed splenic CD8-T-cell exhaustion and reduced cytotoxic T-cell effector function.

Impact: Tumors drive metabolic spleen alterations that may contribute to reduced CD8⁺ T cells and their exhaustion even before reaching the tumor, contributing to immune suppression and poor prognosis. This may provide metabolism-targeted strategies to improve immune surveillance and immunotherapy.

Keywords: Preclinical Image Analysis, Preclinical, Prostate Imaging for Recurrence Reporting; Prostate cancer; Recurrence; Interreader agreement.

Motivation: PI-RR assessment is not universally validated and has not yet been extensively studied for diagnostic accuracy and interreader variability.

Goal(s): To evaluate the performance of PI-RR for detecting local recurrence in PCa patients with BCR after radiation therapy (RT) or radical prostatectomy (RP).

Approach: 110 patients who underwent MRI and FDG PET/CT were included. A group of four radiologists with varying experience was recruited for recurrence evaluation.

Results: With a PI-RR of 3 as a cutoff, the AUCs ranged from 0.56 to 0.83 after RT and 0.73 to 0.90 after RP across the four readers. The ICC values were 0.54 and 0.68, respectively.

Impact: PI-RR may serve as a clinical guide to improve the management of recurrent PCa by achieving good diagnostic performance and interreader agreement.

Keywords: Preclinical Image Analysis, Tumor, prostate cancer

Motivation: The combination of MRI imaging and PSMA PET/CT imaging has attracted more and more attention. 

Goal(s): Therefore, this study will compare the diagnostic value of ¹⁸F-PSMA-1007 PET/CT imaging and multi-parameter MRI alone and in combination with prostate cancer.

Approach: This study retrospectively collected the clinical, imaging and pathological data of 50 patients with prostate disease who underwent mp-MRI and ¹⁸F-PSMA-1007PET/CT examination in our hospital.

Results: We found that the combination of ¹⁸F-PSMA-1007 PET/CT and multi-parameter MRI can improve the diagnostic efficiency of prostate cancer. ADC value, SUV_max and SUV_max/ADC can distinguish between low-risk and medium-high-risk prostate cancer.

Impact: The diagnostic efficacy of combined multi-parameter MRI (ADC) and ¹⁸F-PSMAPET/CT (SUVmax) is better than that of ADC, SUV_max and SUV_max/ADC with higher sensitivity and specificity. The combination of these two imaging modalities can complement each other and improve the accuracy.

Keywords: Biology, Models, Methods, Whole Body, compressed sensing; metastasis; fluorescence tomography

Motivation: Cancer metastasis  involves multiple organs and traditional bioluminescent imaging lacks spatial resolution to locate metastatic foci.  New MRI imaging protocols need to be developed to image metastasis distribution over the whole mouse body.

Goal(s):

1. Acquire high resolution 3D volumes in an acceptable time frame.
2. Validate findings using cryo-fluorescence tomography (CFT).

Approach:

1. An 8-channel array coil was used to acquire whole body isotropic volumes with compressed sensing.
2. Post imaging CFT datasets were acquired for validation.
   

Results:

1. High contrast volumes of mouse body were acquired at 200x200x200 μm  in 16 minutes.
2. Liver metastatic foci observed.
3. Correspondence of mouse anatomy with MRI and CFT achieved.

Impact: Whole body imaging with 8-channel array coil permits longitudinal visualization of major organs in normal and diseased states.  Compressed sensing optimizes workflow for high throughput screening, and Cryo-Fluorescence tomography can then be used as gold standard for validation of MRI.

Keywords: Other Preclinical, Molecular Imaging, Prostate Cancer Models, Lonidamine, mito-Lonidamine, 1H and 31P MRS, Seahorse, oxygen consumption rate, pH

Motivation: When prostate cancer is treated with external beam radiation therapy (RT) with doses up to 78 Gy, gastrointestinal and genitourinary toxicities are often observed.

Goal(s): Tumor sensitization by mito-lonidamine (mito-LND) will lower RT doses reducing the risk of adverse effects.

Approach: The effects were assessed in vitro and in vivo in prostate cancer models using Seahorse, ¹H and ³¹P MRS respectively.

Results: Our findings showed a sustained and tumor-selective decrease in intracellular pH, bioenergetics, oxygen consumption rate and lactate. Selective tumor acidification, deenergization and oxygenation induced by mito-LND may improve the radiation response in prostate cancer.
 

Impact: Exploiting the modulation of tumor metabolism and microenvironment for improving therapeutic efficacy of radiation therapy (RT) in early stage prostate cancer will lead to improved outcomes in prostate cancer patients.

Keywords: Preclinical Image Analysis, Quantitative Imaging, hypoxia

Motivation: Heterogeneous distributions of hypoxic tissues lead to divergent radiotherapy response. Thus, developing a practical, accurate, and reproducible method of quantifying hypoxia is of great interest.

Goal(s): Establish a repeatable, multiparametric MRI protocol for quantifying hypoxia.

Approach: We induced C6 brain tumors in rats and conducted test-retest TOLD-MRI, DCE-MRI, and DW-MRI exams on each rat. We then analyzed the MRI data to identify spatially distinct physiological clusters within the tumor. 

Results: An initial assessment of repeatability of hypoxia, normoxia, and necrotic tissue localization within a tumor.

Impact: Developing a quantitative and repeatable protocol for quantifying tumor hypoxia will have immediate applications in studies seeking to design, assess, and optimize radiotherapy regimens.

Keywords: Biology, Models, Methods, Cancer, Glioblastoma, hypoxia, vasculature, metabolism, chick embryo CAM model

Motivation: Understanding vasculature, hypoxia and glycolysis in GBM is paramount towards understanding its resistance to therapies, but cannot be done in vitro. The CAM model is attractive as it provides the interaction between host vasculature and the tumour.  

Goal(s): Optimise MRI and MRS to assess hypoxia, tumour-host vasculature and glycolytic metabolism in the GBM-CAM.

Approach: GBM-CAM xenografts were created under normoxic- and hypoxic-conditions. Imaging was performed using microscopy and MRI, and lactate detection via MRS.

Results: Distinct morphological differences in vasculature were identified between conditions. MRI revealed vessel penetration, MRS detected lactate levels, which were significantly higher in hypoxic tumours than in the CAM.

Impact: Developing tools to characterise vascular morphology and quantify lactate levels in the CAM GBM model can shed light on fundamental biological mechanisms, and support the development of therapeutic strategies for the clinic. 

Keywords: Biology, Models, Methods, Cancer, Preclinical; CEST & MT

Motivation: The diffuse growth of paediatric-type diffuse high grade glioma (PDHGG) precludes complete delineation with conventional MRI. 

Goal(s): Molecular imaging with CEST may improve tumour detection.

Approach: Three orthotopic models of PDHGG were assessed using inverse Z-spectrum analysis of CEST data.

Results: Clear distinction between tumour and contralateral normal-appearing brain in ssMT and rNOE maps, which relate to macromolecular content, was observed in two well-defined tumour models when analysed using MTR_Rex and AREX. Similar CEST contrast was also apparent in a third more diffuse model, inconspicuous on T₂w-MRI. This CEST approach can successfully stratify PDHGG tumours in vivo.

Impact: Relaxation compensated CEST metrics provide novel biochemical contrasts in three orthotopic models of paediatric-type diffuse high grade glioma, enabling detection of diffuse disease, highlighting the clinical potential of CEST contrasts to stratifying tumours.

Keywords: Tumors (Post-Treatment), Animals

Motivation: What is the specific efficacy of carbon ion radiation in the treatment of brain gliomas?

Goal(s): To assess the specific effect of carbon ion irradiation in inhibiting the growth and peritumor infiltration of gliomas.

Approach: Establishment of a rat C6 brain glioma model with carbon ion irradiation and assessment of the efficacy response of brain glioma after carbon ion irradiation using MRI multiparametric imaging

Results: MRI multiparametric imaging can reflect the inhibitory effect of carbon ion irradiation on the growth and invasion of gliomas.

Impact: CIRT for glioma is still in the stage of clinical trials, the number of subjects is limited, and its specific efficacy still needs to be explored. Our study provides an experimental basis for the clinical application of CIRT for gliomas.

Keywords: Preclinical Image Analysis, Electron Paramagnetic Resonance

Motivation: Renal tumors in patients affected by Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) are aggressive and metastasize early. The high expression of NAD(P)H quinone oxidoreductase 1 (NQO1) in HLRCC could be a therapeutic target.

Goal(s): Our goal was to determine if NQO1-activated substrates can be used as a therapeutic approach for HLRCC renal tumors.

Approach: In vitro experiments and EPR, DCE, and photoacoustic imaging were performed to study the effect of NQO1-activated substrates on oxygen levels and tumor growth in HLRCC.

Results: Our study demonstrated by EPR imaging that oxygen consumption is induced by NQO1-activated substrates, resulting in ROS production and tumor cytotoxicity.

Impact: We found that NQO1-activated substrates induced non-mitochondrial oxygen consumption in FH-deficient renal tumor cells, triggering oxidative stress-induced cancer cell death. Our results suggest a promising path for NQO1-targeted therapy in HLRCC, necessitating further research and treatment development.

Keywords: Preclinical Image Analysis, Electron Paramagnetic Resonance

Motivation: In the previous study, EPR oximetry unveiled physiological responses to a VEGF inhibitor, but the potential of EPR oximetry in upstream inhibition of the HIF pathway remained unclear.

Goal(s): To determine if Belzutifan, a HIF-2α inhibitor, affects tumor oxygenation as measured by EPR oximetry and to offer a non-invasive biomarker of its therapeutic efficacy.

Approach: Three xenograft models of clear cell carcinoma were treated with Belzutifan and changes in tumor oxygen levels were assessed using EPR oximetry.

Results: We observed significant alterations in tumor oxygenation exclusively in responding tumors, which we attributed to diminished VEGF expression.

Impact: This research underlines the significance of EPR oximetry as a non-invasive tool to detect early responses to HIF-2α inhibitors like Belzutifan, which could profoundly affect the management and therapeutic approach for cancer treatment, guiding personalized medicine.

Keywords: Preclinical Image Analysis, Modelling, Breast, Cancer, Vascular, Image Reconstruction

Motivation: Metronomic chemotherapy shows promise as a cost-effective therapy for vascular normalization. However, it is unclear how to determine the optimal biological dose (OBD). 

Goal(s): Our goal is to use dynamic contrast-enhanced (DCE) MRI and pharmacokinetic analysis for non-invasive measurements of the heterogenous tumor treatment response toward determining the OBD.

Approach: The 4T1 murine orthotopic triple negative breast cancer models were assessed longitudinally using two different dosing schemes, daily and intermittent, using cyclophosphamide. Pharmacokinetic and histological analysis (CD31, Ki67) were conducted. 

Results: The intermittent dosing schedule showed higher V_p, F_p, and K^trans in all tumor regions indicating possible vascular normalization.

Impact: The proposed 3D-UTE-GRASP DCE-MRI method provides a non-invasive platform to assess for optimal biological dose in metronomic chemotherapy. By accurately determining the heterogenous tumor vessel dynamical changes, this platform can be used to enhance treatment response over time. 

Keywords: Biology, Models, Methods, Breast, Vascular, Image Reconstruction, Cancer

Motivation: Breast cancer molecular subtype may affect therapeutic efficacy of metronomic chemotherapy, which currently has not been investigated with non-invasive methods. 

Goal(s): This study is to utilize DCE-MRI for quantitative measurement of treatment response in different breast cancer subtypes. 

Approach: Preclinical orthotopic models 67NR(ER+) and 4T1(triple negative) of breast cancer were treated with the same metronomic chemotherapy, while the heterogenous treatment response was evaluated using DCE-MRI. 

Results:  In both tumor models, treatment induced higher V_p, F_p, and K^trans. The 67NR tumors had higher vascular measures with slower growth rates than the 4T1 tumors.

Impact: The preliminary data in this study suggest that the tumor volume alone does not provide adequate information about the changes induced by treatment, and the treatment response differs substantially between breast cancer subtypes as observed by DCE-MRI parameters. 

Keywords: Small Animals, Cancer, Treatment Response

Motivation: KRAS mutations occur in 90% of pancreatic ductal adenocarcinoma(PDA) with G12Dmutation being the most common.Recent KRAS(G12D) inhibitors have unraveled an exciting therapeutic opportunity for this deadly cancer,as they are being tested in clinical trials. 

Goal(s): However, the prior use of KRAS(G12C)inhibitors in lung cancer treatment showed mere 50% patient response,despite the accurate genetic mutation,calling for biomarkers which can assess the drug-target engagement early on and predict treatment outcome. 

Approach: To test the utility of translational MRI markers in a clinically relevant PDA model for early responses to KRAS(G12D) inhibitor,MRTX1133.

Results: ADC,K^trans and MTR captured MRTX1133 induced early cancer cell death and stroma change.

Impact: Our study in genetically engineered mouse model of pancreatic cancer supports that clinical translatable MRI metrics (ADC, Ktrans and MTR) are promising for capturing early pharmacodynamic responses to KRAS inhibitor MRTX1133.

Keywords: Biology, Models, Methods, Head & Neck/ENT

Motivation: The low specificity of many Thyroid Imaging Reporting and Data Systems (TI-RADSs)  lead to a large number of unnecessary biopsies. 

Goal(s): This study developed and validated a predictive model based on MRI morphological features to improve the specificity.

Approach: A retrospective analysis was conducted on 825 thyroid nodules pathologically confirmed postoperatively. Univariate and multivariate logistic regression was used to obtain β coefficients, construct predictive models and nomogram incorporating MRI morphological features in the training cohort, and validated in a validation cohort. 

Results: Compared with the TI-RADSs, predictive models have better specificity along with a high sensitivity and can reduce unnecessary biopsies.

Impact: predictive models have better specificity along with a high sensitivity and may avoid numerous invasive needle biopsies

Keywords: Probes & Targets, Cancer

Motivation: Only 15-20% of patients with advanced head and neck squamous cell carcinoma (HNSCC) benefit from immunotherapy, with no reliable strategies to quickly predict or determine a patient’s response to treatment.

Goal(s): We aim to evaluate a therapeutic monitoring strategy using MRI by targeting extradomain B fibronectin (EDB-FN) in the tumor stroma.

Approach: Using mouse models bearing HNSCC allografts, we treated and monitored therapeutic efficacy of anti-PDL1 immunotherapy with MRI using MT218, our EDB-FN-targeted contrast agent.

Results: Treatment-responsive tumors exhibited unique expression patterns of EDB-FN compared to controls that were visualized with MT218 MRI, demonstrating the potential for predicting and monitoring HNSCC immunotherapy response.

Impact: We demonstrate that EDB-FN is a potential biomarker for immunotherapy response in HNSCC, and our MRI strategy targeting EDB-FN offers clinicians a potential method for predicting or monitoring immunotherapeutic outcomes to improve the clinical management of HNSCC.

Keywords: Biology, Models, Methods, Modelling

Motivation: Isotope exchange at equilibrium complicates interpretation hyperpolarized [1-¹³C]pyruvate MR. Modelling this phenomenon could help to quantify the effect of exchange on HP MR signal.

Goal(s): Investigate how isotope exchange (compensatory backward conversion of unlabeled lactate concurrent with labeled lactate production) occurs and affects hyperpolarized [1-¹³C]pyruvate MR.

Approach: Develop a realistic computational model of pyruvate-lactate interconversion and apply it to characterize how different levels of endogenous lactate influence metabolic reaction kinetics and exchange.

Results: Elevation of unlabeled lactate increases isotope exchange at equilibrium. Net production of lactate occurs unless total lactate exceeds its equilibrium ratio with total pyruvate.

Impact: This in silico model of isotope exchange in hyperpolarized [1-13C]pyruvate MR realistically replicates spectroscopic measurements, with particle-level data for a range of conditions providing insight into metabolic dynamics relevant to complex cellular architectures with different local equilibria.

Keywords: Probes & Targets, Hyperpolarized MR (Non-Gas), Fumarate, meglumine, hyperpolarization, gluconeogenesis, solubility

Motivation: Clinical translation of many hyperpolarized substrates, including ¹³C-fumarate, has been obstructed by its low solubility in water, causing rapid precipitation of the substrates after dissolution when prepared in conventional glassing solvents. 

Goal(s): The goal of this study was to enhance water solubility and glassing properties of fumarate. 

Approach: We introduced a new formulation of fumarate for DNP by using meglumine as a counterion.

Results: Meglumine significantly improved the polarization performance of fumarate with excellent solubility and glassing properties and previously invisible products along gluconeogenesis were observed in rat kidneys in vivo. 

Impact: The solubilizing and vitrifying effect of meglumine counterion is not limited to fumarate. It is applicable to other 13C- and 15N-labeled compounds such as carboxylic acids and amino acids that have poor solubility and can form meglumine salts or adducts. 

Keywords: Small Animals, Oxygenation

Motivation: T2* MRI and photoacoustic imaging (PAI) offer non-invasive oxygenation measures, but their comparative effectiveness for placental study remains untested.

Goal(s): Our goal was to directly compare T2* MRI and PAI's ability and effectiveness to assess placental and fetal organ oxygenation responses under normoxic hypercapnia challenge.

Approach: Using pregnant rats, the study involved sequential scans of fetoplacental units with T2* MRI and PAI under normoxic hypercapnia challenge.

Results: We found discrepancies between MRI and PAI in detecting oxygenation changes. MRI displayed a marked response in placental oxygenation, not as prominently reflected in PAI measurements.

Impact: T2* MRI could accurately captures fetoplacental responses to hypercapnia, outperforming photoacoustic imaging. Investigating this performance gap is essential before combining these techniques in preeclampsia and fetal growth restriction studies.

Keywords: Small Animals, Quantitative Imaging

Motivation: Intravoxel incoherent motion (IVIM) imaging can evaluate tissue microperfusion and diffusion information respectively, which can more accurately evaluate renal fibrosis (RF) in chronic kidney disease. 

Goal(s): IVIM can reflect the occurrence and development of RF from two aspects of perfusion and diffusion respectively. It has a great application prospect for the evaluation of RF.

Approach: The dynamic changes of renal cortical and medullary signal with the progression of fibrosis were monitored by IVIM, and the compensatory effect of the contralateral kidney was analyzed. 

Results: Some IVIM parameters of the renal cortex and medulla were moderately or strongly negatively correlated with RF.

Impact: Early detection and dynamic evaluation of the process of RF are crucial for reversing renal function damage. IVIM can reflect the development of RF from two aspects of perfusion and diffusion, which has a great application prospect for evaluating RF.

Keywords: Small Animals, CEST & MT

Motivation: There is lack of a comprehensive MRI technique to comprehensively detect the acute kidney injury (AKI) induced by ischemia reperfusion injury (IRI).

Goal(s): We aimed to develop the mpMRI for diagnosis of AKI induced by ischemia reperfusion IRI.

Approach: The IRI-AKI model of 40-minutes ischemia in rats were established, and mpMRI is conducted at 0, 1, 3, 7, 14, and 28 days. Several MRI indexes signal and their diagnosis performance were compare, respectively.

Results: Multi-parametric MRI may shows comprehensive variations in IRI-AKI, and amine-CEST may exhibits the highest accuracy for diagnosis of IRI-AKI.

Impact: This may provide guideline for clinical application of renal mpMRI.

Keywords: Electron Paramagnetic Resonance, Oxygenation, EPR oximetry, Ox071

Motivation: EPR oximetry using Ox071 holds promise in detecting chemotherapy-induced acute kidney injury by monitoring pO₂ distribution. 

Goal(s): Using EPR, our study assessed the ability to discern pO₂ variations between healthy kidneys and kidney injury models induced by intraperitoneal cyclophosphamide treatment. 

Approach: To validate these changes, we performed ex vivo histological assessments with pimonidazole staining, comparing these results with EPR based pO₂ maps. 

Results: Analysis of the hypoxic fraction in tumor tissues via pimonidazole staining revealed a transient reduction at 2 days post-treatment, followed by recovery at 30 days. EPR oximetry results consistently mirrored these trends, affirming its reliability as a non-invasive method.

Impact: Historically, EPR oximetry focused on tumor hypoxia due to Ox063's limitations in well-oxygenated tissues. Using Ox071, a deuterated analog, current research extends oximetry to normoxic tissues, notably the kidneys.

Keywords: Biomarkers, Cancer, ITPP, EPRI, Immunotherapy, Radiosensitizer, Breast Cancer

Motivation: We showed previously that multispectral optoacoustic tomography (MSOT) measures oxygen saturation (%sO₂) of intravascular hemoglobin which can indirectly evaluate the effect of a radiosensitizer, inositol tripyrophosphate (ITPP), on tumor oxygenation. Electron paramagnetic resonance imaging (EPRI) could serve as a more direct biomarker by measuring the extravascular, extracellular oxygen pressure (pO₂) in pre-clinical tumor models.

Goal(s): Validate prior MSOT results showing decrease in hemoglobin saturation with ITPP.

Approach: Use EPRI to observe extracellular oxygenation before and after treatment with ITPP compared with vehicle control.

Results: Tumors treated with ITPP demonstrated lower extracellular oxygenation compared to pretreatment levels (p = 0.003).

Impact: An imaging biomarker to determine how much a radiosensitizer improves tumor pO2 would dramatically impact clinical care by potentially improving response to radiotherapy and immunotherapy.  EPRI could evaluate the effect of a radiosensitizer allowing for more personalized treatment approaches. 

Keywords: Small Animals, Cancer

Motivation: Many cancer studies concentrate in isolated markers like oxygenation, pH or relaxivity measurements. We believe studying all biomarkers and its interactions as microenvironments is the key.

Goal(s): Our goal is to build a library of multiparametric data with pH-derived habitats to aid treatment response in the future.

Approach: Mice with flank implanted pancreatic tumors were imaged to estimate tumor volume, pH, R₂* and susceptibility maps. All maps were compared using one-way ANOVA between two pH-derived habitats.

Results: Significant differences in susceptibility and R₂* were found between pH-derived habitats for large tumors. The same trend, without significant differences, was found in smaller tumors. 

Impact: The study of different tumor microenvironments defined by CEST-derived pH habitats was demonstrated. A larger subset of animals with different tumor volumes and other multiparametric data will help understand tumor microenvironment better and aid treatment response in the future.

Keywords: Biomarkers, Cancer, Hyperpolarized MRI, Immunotherapy, Melanoma, CEST, Esomeprazole

Motivation: Biomarkers to predict immunotherapy response are needed. AcidoCEST MRI and hyperpolarized magnetic resonance spectroscopy (HP-MRS) may predict response.

Goal(s):

1. Establish baseline pHe and lactate to pyruvate ratio in tumors with varying immunotherapy response.
2. Observe changes after combination treatment with esomeprazole and immune checkpoint blockade (ICB).

Approach: AcidoCEST MRI and HP-MRS were used to measure extracellular pH (pHe) and lactate to pyruvate ratio. Imaging was performed on treated and untreated groups.

Results: Baseline lactate to pyruvate ratio and pHe were higher in the most resistant model compared to other models, but were unchanged in treatment vs control groups for the most resistant model.

Impact: Robust clinical tools are sorely needed to predict immunotherapy response. Development of a non-invasive clinical imaging tool would allow for less wasted time trying ineffective medications and more personalized treatment plans tailored so treatment is as effective as possible.

Keywords: Small Animals, Preclinical, Quantitative Imaging

Motivation: The project assessed the glucose uptake in brown adipose tissue (BAT) without using ionizing radiation since current methods, such as PET, have safety risks.

Goal(s): In a preclinical study we investigated whether chemical exchange saturation transfer MRI (CEST-MRI) could quantify the uptake of exogenous glucose in BAT.

Approach: We utilized CEST-MRI to monitor and analyze the glucose uptake in 6 mice following intravenous (i.v.) and intraperitoneal (i.p.) administration of glucose.

Results: GlucoCEST MRI successfully detected glucose uptake in BAT and revealed distinct glucose kinetics after i.v. and i.p. administration.

Impact: GlucoCEST is a promising radiation-free technique to measure relative glucose uptake in BAT, which can be used to investigate BAT activity e.g. in metabolic diseases. Additionally, it can provide further insight into BAT function and pharmacological activation.

Keywords: Biomarkers, Hyperpolarized MR (Gas), Dynamic Gas Exchange Spectroscopy, Look-locker, Chemical Shift Saturation Recovery, Rapid Acquisition

Motivation: Hyperpolarized ¹²⁹Xe Chemical Shift Saturation Recovery (CSSR), commonly employed for assessing pulmonary physiological function, is time-consuming and prone to weak signals and potential errors at short exchange times.

Goal(s): To accelerate the acquisition of CSSR while ensuring the precise physiological parameter extraction.

Approach: Techniques of inversion recovery (IR) and look-locker (LL) were combined with conventional CSSR (refer to as IR-LL-CSSR), and the results were compared with that obtained by conventional CSSR and IR-CSSR.

Results: By using the proposed method (IR-LL-CSSR), the acquisition could be accelerated for eight times, and meanwhile preserve the accuracy of the extracted physiological parameters.

Impact: IR-LL-CSSR substantially accelerates CSSR acquisition with ¹²⁹Xe MRS and also ensures a precise physiological parameter assessment, showing promise for improving the pulmonary assessment in clinic.

Keywords: Biology, Models, Methods, Head & Neck/ENT, Oxygen-enhanced MRI, Hypoxia, Radiation, Biomarker

Motivation: Tumour hypoxia is associated with radioresistance and is a negative factor in the prognosis of oral cavity squamous cell carcinoma. Non-invasive methods to rapidly quantify the extent and heterogeneity of tumour hypoxia would offer clinical benefit in treatment planning.

Goal(s): To assess the utility of oxygen-enhanced (OE-) MRI to image hypoxia and provide predictive imaging biomarkers of radiation response.

Approach: OE-MRI was performed in murine oral carcinoma allografts prior to 8Gy irradiation, and relationships with subsequent overall tumour response sought.

Results: Tumours exhibiting voxels with a marked hyperoxia-induced reduction in R₂* yet negligible ΔR₁ were more radiosensitive.

Impact: OE-MRI revealed extensive hypoxia in murine oral carcinoma allografts, and have the potential to predict tumour radiosensitivity based on the combined degree of hypoxia and haemodynamic vasculature.

Keywords: Probes & Targets, Hyperpolarized MR (Non-Gas)

Motivation: Investigating metabolic changes in glycolysis within Tramp C1 cells due to photon irradiation, focusing on the role of HP ${}^{}$13C pyruvate.

Goal(s): To determine how photon irradiation affects pyruvate-to-lactate flux in vitro, indicating metabolic reprogramming.

Approach: Utilizing benchtop NMR to monitor HP ${}^{}$13C dynamics in irradiated versus control cells, targeting lactate production.

Results: Photon irradiation elevated ${}^{}$¹³C lactate production by two-fold on Day 0, with persistently higher levels observed on Day 3, signifying altered metabolic flux post-irradiation.

Impact: This study's findings reveal photon irradiation's potent effect on cellular metabolism, potentially influencing radiation therapy strategies. It opens avenues for targeted metabolic interventions and underscores the metabolic resilience in Tramp C1 cells, crucial for cancer treatment optimization.

Keywords: Other Preclinical, CEST & MT, hydrogel

Motivation: Biocompatible materials with detectable APT effects are lacking for biomedical applications.  

Goal(s): To validate the APT properties of a new synthesised biocompatible copolymer p(MPC-AE)₅₅ hydrogel which has potential exchange between its MPC and AE cross-linkage.  

Approach: An experimental phantom with variable copolymer concentration and existing egg protein model was imaged with a research application APT-CEST sequence at 3T and analysed both inline and using CEST-EVAL software.

Results: APT of the new hydrogel increased accordingly with its concentration and this was validated by results for egg protein which agreed with previous work. Both analysis methods were in agreement.  

Impact: Understanding the properties of newly synthesized copolymer hydrogel extends its value in biomedical applications including potential for phantoms that could support translation of APT-CEST.

Keywords: Atherosclerosis, Atherosclerosis

Motivation: The molecular imaging and relationship between the brain and atherosclerosis are poorly understood.

Goal(s): To study the brain during atherosclerosis development and the association of atherosclerosis and brain using CEST MRI.

Approach: 3 months old ApoE –/– and C57BL/6 mouse brains were imaged using 3T preclinical MRI and CEST was applied, then three offsets, 3.5, –1.6 and –3.5 ppm, were extracted for post-processing.

Results: ApoE –/–  mouse showed higher APT and rNOE signals than WT in thalamus, hippocampus and cortex, which are associated with neuroinflammation and cholesterol deposition during atherosclerosis development. 

Impact: The underlying molecular changes of the brain during atherosclerosis development could enhance the identification of diseases at early stage using CEST MRI.

Keywords: Biology, Models, Methods, Metabolism

Motivation: NMR-based analyses of lipids can reveal the sources and pathways contributing to lipid biosynthesis in cells grown in the presence of ¹³C-labeled tracers. 

Goal(s): Our goal was to determine whether treatment of FLCN-deficient renal cell carcinoma (RCC) cells with the Complex I inhibitor metformin modulated cellular biosynthesis of lipids.

Approach: We utilized ¹H-¹³C HSQC NMR analysis of cellular lipids in FLCN-deficient tumor cells to assess incorporation of acetyl groups derived ¹³C₆-glucose or ¹³C₅¹⁵N₂-L-glutamine into cellular lipids during treatment with metformin.

Results: We observed a sharp decrease in incorporation of ¹³C-glucose-derived carbon into lipid acyl chains and cholesterol methyl groups following metformin treatment.

Impact: We found that metformin decreased synthesis of lipids from glucose while enhancing lipid synthesis from glutamine in renal tumor cells. These findings demonstrate that targeting Complex I may be a promising therapeutic avenue for treatment and prevention of FLCN-deficient RCC.