T1 Mapping From MPRAGE Acquisitions: Application to the Measurement of the Concentration of Nanoparticles in Tumors for Theranostic Use.

BACKGROUND: The measurement of the concentration of theranostic agents in vivo is essential for the assessment of their therapeutic efficacy and their safety regarding healthy tissue. To this end, there is a need for quantitative T1 measurements that can be obtained as part of a standard clinical imaging protocol applied to tumor patients. PURPOSE: To generate T1 maps from MR images obtained with the magnetization-prepared rapid gradient echo (MPRAGE) sequence. To evaluate the feasibility of the proposed approach on phantoms, animal and patients with brain metastases. STUDY TYPE: Pilot. PHANTOM/ANIMAL MODEL/POPULATION: Solutions containing contrast agents (chelated Gd3+ and iron nanoparticles), male rat of Wistar strain, three patients with brain metastases. FIELD STRENGTH/SEQUENCE: A 3-T and 7-T, saturation recovery (SR), and MPRAGE sequences. ASSESSMENT: The MPRAGE T1 measurement was compared to the reference SR method on phantoms and rat brain at 7-T. The robustness of the in vivo method was evaluated by studying the impact of misestimates of tissue proton density. Concentrations of Gd-based theranostic agents were measured at 3-T in gray matter and metastases in patients recruited in NanoRad clinical trial. STATISTICAL TESTS: A linear model was used to characterize the relation between T1 measurements from the MPRAGE and the SR acquisitions obtained in vitro at 7-T. RESULTS: The slope of the linear model was 0.966 (R2  = 0.9934). MPRAGE-based T1 values measured in the rat brain were 1723 msec in the thalamus. MPRAGE-based T1 values measured in patients in white matter and gray matter amounted to 747 msec and 1690 msec. Mean concentration values of Gd3+ in metastases were 61.47 µmol. DATA CONCLUSION: The T1 values obtained in vitro and in vivo support the validity of the proposed approach. The concentrations of Gd-based theranostic agents may be assessed in patients with metastases within a standard clinical imaging protocol using the MPRAGE sequence. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 1.

Proton MRS on sub-microliter volume in rat brain using implantable NMR microcoils.

The use of miniaturized NMR receiver coils is an effective approach for improving detection sensitivity in studies using MRS and MRI. By optimizing the filling factor (the fraction of the coil occupied by the sample), and by increasing the RF magnetic field produced per unit current, the sensitivity gain offered by NMR microcoils is particularly interesting when small volumes or regions of interest are investigated. For in vivo studies, millimetric or sub-millimetric microcoils can be deployed in tissues to access regions of interest located at a certain depth. In this study, the implementation and application of a tissue-implantable NMR microcoil with a detection volume of 850 nL is described. The RF magnetic field generated by the microcoil was evaluated using a finite element method simulation and experimentally determined by high spatial resolution MRI acquisitions. The performance of the microcoil in terms of spectral resolution and limit of detection was measured at 7 T in vitro and in vivo in rodent brains. These performances were compared with those of a conventional external detection coil. Proton MR spectra were acquired in the cortex of rat brain. The concentrations of main metabolites were quantified and compared with reference values from the literature. In vitro and in vivo results obtained with the implantable microcoil showed a gain in sensitivity greater than 50 compared with detection using an external coil. In vivo proton spectra of diagnostic value were obtained from brain regions of a few hundred nanoliters. The similarities between spectra obtained with the implanted microcoil and those obtained with the external NMR coil highlight the minimally invasive nature of the coil implantation procedure. These implantable microcoils represent new tools for probing tissue metabolism in very small healthy or diseased regions using MRS.

Three-dimensional quantitative MRI of aerosolized gadolinium-based nanoparticles and contrast agents in isolated ventilated porcine lungs.

PURPOSE: The objective of this study is to evaluate the suitability and performance of ultra-short echo time (UTE) sequences for imaging and quantifying the deposition of nebulized MRI contrast agents in human-sized lungs. METHODS: Nebulization of clinically used contrast agent or gadolinium-based nanoparticles were performed using a commercial jet nebulizer in isolated and ventilated porcine lungs connected to a 3D-printed human upper airways replica. MR images of isolated lungs were acquired on a 3T clinical MR scanner using 3D UTE sequences at different flip angles. RESULTS: 3D acquisitions with isotropic millimetric resolution were obtained in less than 4 min. Images exhibit homogeneous and large MR signal enhancement (above 200%) following nebulization of both types of aerosols. Deposition of aerosol down to the level of the bronchi of secondary lobules was visualized. T1 values and the concentration of nanoparticles obtained by MRI were found to correlate with the amount of nebulized gadolinium3+ ions. CONCLUSION: The distribution of aerosolized gadolinium-based contrast agent or nanoparticles can be visualized and quantified using UTE MRI in large animal ventilated lung model on a clinical MRI scanner. This protocol can be used for assessing and quantifying aerosol regional deposition with high spatial resolution (1 mm 3D isotropic) without ionizing radiation and could be applied in the future for diagnostic or therapeutic applications in patients.

Online 1 H-MRS measurements of time-varying lactate production in an animal model of glioma during administration of an anti-tumoral drug.

The aims of this study were to implement a magnetic resonance spectroscopy (MRS) protocol for the online profiling of subnanomolar quantities of metabolites sampled from the extracellular fluid using implanted microdialysis and to apply this protocol in glioma-bearing rats for the quantification of lactate concentration and the measurement of time-varying lactate concentration during drug administration. MRS acquisitions on the brain microdialysate were performed using a home-built, proton-tuned, microsolenoid with an active volume of 2 µL. The microcoil was placed at the outlet of the microdialysis probe inside a preclinical magnetic resonance imaging (MRI) scanner. C6-bearing rats were implanted with microdialysis probes perfused with artificial cerebrospinal fluid solution and the lactate dehydrogenase (LDH) inhibitor oxamate. Microcoil magnetic resonance spectra were continuously updated using a single-pulse sequence. Localized in vivo spectra and high-resolution spectra on the dialysate were also acquired. The limit of detection and limit of quantification per unit time of the lactate methyl peak were determined as 0.37 nmol/√min and 1.23 nmol/√min, respectively. Signal-to-noise ratios (SNRs) of the lactate methyl peak above 120 were obtained from brain tumor microdialysate in an acquisition time of 4 min. On average, the lactate methyl peak amplitude measured in vivo using the nuclear magnetic resonance (NMR) microcoil was 193 ± 46% higher in tumor dialysate relative to healthy brain dialysate. A similar ratio was obtained from high-resolution NMR spectra performed on the collected dialysate. Following oxamate addition in the perfusate, a monotonic decrease in the lactate peaks was observed in all animals with an average time constant of 4.6 min. In the absence of overlapping NMR peaks, robust profiling of extracellular lactate can be obtained online using a dedicated sensitive NMR microcoil. MRS measurements of the dynamic changes in lactate production induced by anti-tumoral drugs can be assessed accurately with temporal resolutions on the order of minutes. The MRS protocol can be readily transferred to the clinical environment with the use of suitable clinical microdialysis probes.

Orotracheal manganese-enhanced MRI (MEMRI): An effective approach for lung tumor detection.

Lung cancer is a primary cause of cancer deaths worldwide. Timely detection of this pathology is necessary to delay or interrupt lung cancer progression, ultimately resulting in a possible better prognosis for the patient. In this context, magnetic resonance imaging (MRI) is especially promising. Ultra-short echo time (UTE) MRI sequences, in combination with gadolinium-based contrast agents, have indeed shown to be especially adapted to the detection of lung neoplastic lesions at submillimeter precision. Manganese-enhanced MRI (MEMRI) increasingly appears to be a possible effective alternative to gadolinium-enhanced MRI. In this work, we investigated whether low-dose MEMRI can effectively target non-small-cell lung cancer in rodents, whilst minimizing the potential toxic effect of manganese. Both systemic and orotracheal administration modalities allowed the identification of tumors of submillimeter size, as confirmed by bioluminescence imaging and histology. Equivalent tumor signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using 20 times lower doses compared with the more conventional systemic route. This finding is of crucial importance as it supports the observation that higher performances of contrast agents can be obtained using an orotracheal administration route when targeting lung diseases. As a consequence, lower concentrations of contrast media can be employed, reducing the dose and potential safety issues. The non-detectable accumulation of ionic manganese in the brain and liver following orotracheal administration observed in vivo is extremely encouraging with regard to the safety of the orotracheal protocol with low-dose Mn2+ administration. To our knowledge, this is the first time that a study has clearly allowed the high-precision detection of lung tumor and its contours via the synergic employment of a strongly T1 -weighted MRI UTE sequence and ionic manganese, an inexpensive contrast agent. Overall, these results support the growing interest in drug and contrast agent delivery via the airways to target and diagnose several diseases of the lungs.

Targeting and in vivo imaging of non-small-cell lung cancer using nebulized multimodal contrast agents.

One of the main reasons for the dismal prognosis of lung cancer is related to the late diagnosis of this pathology. In this work, we evaluated the potential of optimized lung MRI techniques and nebulized ultrasmall multimodal gadolinium-based contrast agents [ultrasmall rigid platforms (USRPs)] as a completely noninvasive approach for non-small-cell lung cancer (NSCLC) in vivo detection. A mouse model of NSCLC expressing the luciferase gene was developed. Ultrashort echo-time free-breathing MRI acquisitions were performed before and after i.v. or intrapulmonary administration of the nanoparticles to identify and segment the tumor. After orotracheal or i.v. administration of USRPs, an excellent colocalization of the position the tumor with MRI, bioluminescence and fluorescence reflectance imaging, and histology was observed in all mice. Significantly higher signal enhancements and contrast-to-noise ratios were observed with orotracheal administration using lower doses, reducing the toxicity issues and the interobserver variability in tumor detection. The observations suggested the existence of an unknown original mechanism (different from the enhanced permeability and retention effect) responsible for this phenomenon. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify, and longitudinally monitor the development of submillimetric NSCLCs. The absence of ionizing radiation and high resolution MRI, along with the complete noninvasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge this is the first time that the advantages of an orotracheal administration route are demonstrated for the investigation of the pathomorphological changes due to NSCLCs.

Morphological and quantitative evaluation of emphysema in chronic obstructive pulmonary disease patients: A comparative study of MRI with CT.

PURPOSE: To further validate the ability of ultrashort echo-time (UTE) magnetic resonance imaging (MRI) in quantifying lung density in patients diagnosed with chronic obstructive pulmonary disease (COPD) and to develop an MRI-based emphysema index (EI). MATERIALS AND METHODS: Ten subjects clinically diagnosed with COPD (5M/5F, age 62.6 ± 8.5 years) and ten healthy subjects (2M/8F, age 48.9 ± 19.2 years) were imaged via UTE MRI at 3T (4 mm slices, 1.39 × 1.39 mm2 pixels). Chest computed tomography (CT) images (generally 5 mm slices, ≈0.55 × 0.55 mm2 pixels), acquired retrospectively, were compared to UTE MRI. CT lung densities, MR lung-signal density, and EI were quantified from both CT and UTE MR images via a quantitative automated analysis and compared to the percent predicted forced expiratory volume in 1 second (FEV1 % predicted). RESULTS: EI quantified in controls via CT and UTE MRI was 0.23 ± 0.78% and 2.40 ± 1.50%, respectively; in COPD subjects it was 13.3 ± 14.9% (P = 0.021) and 12.0 ± 9.8% (P = 0.013), respectively. Bland-Altman determined the mean differences and 95% limits of agreement for COPD subjects and healthy controls were 0.06 (12.50 to -12.38). Strong correlation (R2 = 0.79, P < 0.0001) existed between EIs quantified from both CT and UTE MRI. There was a slightly higher correlation between FEV1 % predicted and the UTE MRI EI (R2 = 0.65, P < 0.0001) compared to CT EI (R2 = 0.49, P < 0.0001). CONCLUSION: Our results demonstrate a significant positive correlation between lung density and EI assessed with CT and MRI. Furthermore, UTE MRI exhibits its potential as a diagnostic alternative to CT for assessing the extent and the severity of emphysema, particularly for longitudinal studies. J. Magn. Reson. Imaging 2016;44:1656-1663.

Nebulized gadolinium-based nanoparticles: a theranostic approach for lung tumor imaging and radiosensitization.

Lung cancer is the most common and most fatal cancer worldwide. Thus, improving early diagnosis and therapy is necessary. Previously, gadolinium-based ultra-small rigid platforms (USRPs) were developed to serve as multimodal imaging probes and as radiosensitizing agents. In addition, it was demonstrated that USRPs can be detected in the lungs using ultrashort echo-time magnetic resonance imaging (UTE-MRI) and fluorescence imaging after intrapulmonary administration in healthy animals. The goal of the present study is to evaluate their theranostic properties in mice with bioluminescent orthotopic lung cancer, after intrapulmonary nebulization or conventional intravenous administration. It is found that lung tumors can be detected non-invasively using fluorescence tomography or UTE-MRI after nebulization of USRPs, and this is confirmed by histological analysis of the lung sections. The deposition of USRPs around the tumor nodules is sufficient to generate a radiosensitizing effect when the mice are subjected to a single dose of 10 Gy conventional radiation one day after inhalation (mean survival time of 112 days versus 77 days for irradiated mice without USRPs treatment). No apparent systemic toxicity or induction of inflammation is observed. These results demonstrate the theranostic properties of USRPs for the multimodal detection of lung tumors and improved radiotherapy after nebulization.

Ultrasmall Nanoplatforms as Calcium-Responsive Contrast Agents for Magnetic Resonance Imaging.

The preparation of ultrasmall and rigid platforms (USRPs) that are covalently coupled to macrocycle-based, calcium-responsive/smart contrast agents (SCAs), and the initial in vitro and in vivo validation of the resulting nanosized probes (SCA-USRPs) by means of magnetic resonance imaging (MRI) is reported. The synthetic procedure is robust, allowing preparation of the SCA-USRPs on a multigram scale. The resulting platforms display the desired MRI activity­i.e., longitudinal relaxivity increases almost twice at 7 T magnetic field strength upon saturation with Ca(2+). Cell viability is probed with the MTT assay using HEK-293 cells, which show good tolerance for lower contrast agent concentrations over longer periods of time. On intravenous administration of SCA-USRPs in living mice, MRI studies indicate their rapid accumulation in the renal pelvis and parenchyma. Importantly, the MRI signal increases in both kidney compartments when CaCl2 is also administrated. Laser-induced breakdown spectroscopy experiments confirm accumulation of SCA-USRPs in the renal cortex. To the best of our knowledge, these are the first studies which demonstrate calcium-sensitive MRI signal changes in vivo. Continuing contrast agent and MRI protocol optimizations should lead to wider application of these responsive probes and development of superior functional methods for monitoring calcium-dependent physiological and pathological processes in a dynamic manner.

Orotracheal administration of contrast agents: a new protocol for brain tumor targeting.

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs.

In vivo MRI for effective non-invasive detection and follow-up of an orthotopic mouse model of lung cancer.

One of the main reasons for the dismal prognosis of lung cancer is related to the late diagnosis of this pathology. In this study, we evaluated the potential of optimized lung MRI techniques as a completely non-invasive approach for non-small-cell lung cancer (NSCLC) MRI in vivo detection and follow-up in a mouse model of lung adenocarcinoma expressing the luciferase gene. Bioluminescent lung tumour cells were orthotopically implanted in immuno-deficient mice. Ultra-short echo-time (UTE) MRI free-breathing acquisitions were compared with standard gradient-echo lung MRI (FLASH) using both respiratory-gated and free-breathing protocols. The MRI findings were validated against bioluminescence imaging (BLI) and gold-standard histopathology analysis. Adenocarcinoma-like pathological tissue was successfully identified in all the mice with gated-FLASH and non-gated UTE MRI, and good tumour co-localization was found between MRI, BLI and histological analyses. An excellent or good correlation was found between the measured bioluminescent signal and the total tumour volumes quantified with UTE MRI or gated-FLASH MRI, respectively. No significant correlation was found when the tumours were segmented on non-gated MR FLASH images. MRI was shown to be a powerful imaging tool able to detect, quantify and longitudinally monitor the development of sub-millimetric NSCLCs. To our knowledge, this is the first study which proves the feasibility of a completely non-invasive MRI quantitative detection of lung adenocarcinoma in freely breathing mice. The absence of ionizing radiation and the high-resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed non-gated protocol, make this imaging tool ideal for direct translational applications.

Three-dimensional assessment of lung tissue density using a clinical ultrashort echo time at 3 tesla: a feasibility study in healthy subjects.

PURPOSE: To implement and assess the performance of three-dimensional (3D) ultra-short echo (UTE) time for evaluating lung tissue density changes induced by gravity dependence and lung inflation. MATERIALS AND METHODS: Twelve healthy volunteers were imaged by 3D UTE at 3 Tesla, during free-breathing and breathholding of the subjects. MR signal intensities were measured in lung tissue and muscle regions. The variations of MR lung signal intensity and lung water content were evaluated as a function of lung inflation and anterior/posterior position. RESULTS: SNR in lung tissue ranged between 35 for free-breathing acquisitions and 7 for breathhold acquisitions at functional residual capacity. Lung-to-muscle signal ratios decreased from 0.58 in posterior areas to 0.34 in anterior areas. The average water content measured in lungs was equal to 34% and 58% in gravitationally nondependent and dependent regions of interest. CONCLUSION: The 3D UTE lung MRI provides signal within lung parenchyma and can be used to assess lung tissue density.

Quantitative biodistribution and pharmacokinetics of multimodal gadolinium-based nanoparticles for lungs using ultrashort TE MRI.

OBJECTIVE: To study the biodistribution and lung pharmacokinetics of tracheally administered gadolinium-based contrast agents [gadoteric acid and multimodal ultra-small rigid platforms (USRPs)], to validate their pharmacokinetics against optical imaging of fluorescent USRPs, and to test their short-term toxicity. MATERIALS AND METHODS: Ultrashort echo-time (UTE) lung proton magnetic resonance imaging (MRI) was performed at 4.7-Tesla (T) after the intratracheal instillation of different concentrations of contrast agent solutions in mice. Pharmacokinetic models were implemented on the absolute concentration calculated from the MRI signal enhancement measurements. Fluorescent USRPs were used to obtain optical images with the same protocol. Bronchoalveolar lavage inflammatory cell count and serum creatinine measurement were performed on four groups of instilled mice (sham, saline, USRPs, lipopolysaccharide). RESULTS: MR and optical imaging showed similar kinetics of the USRPs, passing from the airways to the lung tissue and to the kidneys, with negligible hepatic clearance. No significant increase of lung and renal inflammation markers were observed in USRP-instilled animals. CONCLUSION: A T 1-weighted radial UTE sequence was found to be valuable in quantitatively monitoring the biodistribution and pharmacokinetics of nanoparticles in the lungs of mice. The observed favorable pharmacokinetics, which was validated by fluorescence imaging, ensures the negligible toxicity of the nanoprobes, making the USRPs and the developed protocol good candidates for applications on selected lung diseases.

Implantable theranostic device for in vivo real-time NMR evaluation of drug impact in brain tumors.

The evaluation of the efficacy of a drug is a fundamental step in the development of new treatments or in personalized therapeutic strategies and patient management. Ideally, this evaluation should be rapid, possibly in real time, easy to perform and reliable. In addition, it should be associated with as few adverse effects as possible for the patient. In this study, we present a device designed to meet these goals for assessing therapeutic response. This theranostic device is based on the use of magnetic resonance imaging and spectroscopy for the diagnostic aspect and on the application of the convection-enhanced delivery technique for the therapeutic aspect. The miniaturized device is implantable and can be used in vivo in a target tissue. In this study, the device was applied to rodent glioma models with local administration of choline kinase inhibitor and acquisition of magnetic resonance images and spectra at 7 Tesla. The variations in the concentration of key metabolites measured by the device during the administration of the molecules demonstrate the relevance of the approach and the potential of the device.

Quantifying gadolinium-based nanoparticle uptake distributions in brain metastases via magnetic resonance imaging.

AGuIX, a novel gadolinium-based nanoparticle, has been deployed in a pioneering double-blinded Phase II clinical trial aiming to assess its efficacy in enhancing radiotherapy for tumor treatment. This paper moves towards this goal by analyzing AGuIX uptake patterns in 23 patients. A phantom was designed to establish the relationship between AGuIX concentration and longitudinal ( T 1 ) relaxation. A 3T MRI and MP2RAGE sequence were used to generate patient T 1 maps. AGuIX uptake in tumors was determined based on longitudinal relaxivity. AGuIX (or placebo) was administered to 23 patients intravenously at 100 mg/kg 1-5 hours pre-imaging. Each of 129 brain metastases across 23 patients were captured in T 1 maps and examined for AGuIX uptake and distribution. Inferred AGuIX recipients had average tumor uptakes between 0.012 and 0.17 mg/ml, with a mean of 0.055 mg/ml. Suspected placebo recipients appeared to have no appreciable uptake. Tumors presented with varying spatial AGuIX uptake distributions, suspected to be related to differences in accumulation time and patient-specific bioaccumulation factors. This research demonstrates AGuIX's ability to accumulate in brain metastases, with quantifiable uptake via T 1 mapping. Future analyses will extend these methods to complete clinical trial data (~ 134 patients) to evaluate the potential relationship between nanoparticle uptake and possible tumor response following radiotherapy.Clinical Trial Registration Number: NCT04899908.Clinical Trial Registration Date: 25/05/2021.

Contrast enhanced lung MRI in mice using ultra-short echo time radial imaging and intratracheally administrated Gd-DOTA-based nanoparticles.

PURPOSE: To investigate the in vivo T1 -enhancement of the lung parenchyma in free-breathing healthy mice following intratracheal administration of Gd-DOTA-based nanoparticles, to assess the enhancement kinetics of the instilled contrast medium and to identify its elimination pathways. METHODS: Ultrashort Echo Time (276 µs) proton MRI of the lung was performed (N = 14) at 4.7 T after the intratracheal instillation of 50 µL of seven different concentrations of contrast agent solution (from 2 to 100 mM of Gd(3+) ). The signal enhancement (SE) in lungs, blood, liver, kidneys, and bladder was assessed (N = 3) for a 50 mM concentration solution at different time points. RESULTS: The largest SE in lungs (266 ± 14%) was observed for a 50 mM solution of Gd(3+) . In lungs, the SE was observed to decay exponentially with a time constant of 149 ± 51 min. The passage of the nanoparticles from lung tissue to blood and kidneys, and ultimately to the bladder, was observed. No significant hepatic enhancement was measured. CONCLUSION: This study demonstrates the feasibility of large SEs of lung tissue using intratracheally administrated solutions of Gd-based contrast agents. In future applications, the SE in lungs could be used to image the biodistribution of coadministrated drug aerosols or to selectively enhance lung diseased tissues.

Ultrashort-TE MRI longitudinal study and characterization of a chronic model of asthma in mice: inflammation and bronchial remodeling assessment.

Asthma is a chronic disease characterized by bronchial hyperresponsiveness (BHR), bronchial inflammation and remodeling. The great improvements in (1)H MRI ultrashort-TE (UTE) sequences in the last decade have allowed lung images with high-resolution and good signal-to-noise ratio to be obtained in parenchymal tissues. In this article, we present a UTE (1)H MRI high-resolution study of a chronic model of asthma in mice with the aim to longitudinally assess the main features of asthma using a fully noninvasive approach. Balb/c mice (n = 6) were sensitized with ovalbumin over a period of 75 days. The control group (n = 3) received normal saline on the same days. MRI acquisitions were performed on days 0, 38 and 78 to study the inflammatory volumes and bronchial remodeling (peribronchial signal intensity index, PBSI). Plethysmographic studies were performed on days 0, 39 and 79 to assess BHR to methacholine using the enhanced pause (Penh) ratio. The average inflammatory volume measured by MRI in the ovalbumin group (15.6 ± 2.4 µL) was increased significantly relative to control mice (-0.3 ± 0.7 µL) on day 38. The inflammatory volume was larger (34.2 ± 3.1 µL) on day 78 in the ovalbumin group. PBSI was significantly higher in the ovalbumin group on day 78 (1.53 ± 0.08) relative to the control group (1.16 ± 0.10), but not on day 38. After sensitization, asthmatic mice presented BHR to methacholine on days 39 and 79. Penh ratios correlated significantly with the inflammatory volume on day 39 and with the PBSI on day 79. This study shows, for the first time, that high-resolution UTE (1)H MRI of the lungs may allow the noninvasive quantification of peribronchial eosinophilic inflammation with airways occlusion by mucus and of bronchial remodeling in a murine asthma model that correlates with functional parameters.

Longitudinal and noninvasive assessment of emphysema evolution in a murine model using proton MRI.

Ultrashort echo time (550 µs) MR imaging was implemented to track the emphysema development in mice lung challenged with elastase. Two parameters, namely, signal intensity and T 2, were used to monitor the disease evolution. Nine mice were imaged before and at 24 h as well as at 3 and 8 weeks after elastase instillation. Five mice instilled with saline served as controls. At week 8, the mean normalized signal intensity ± SD was 0.89 ± 0.20 for healthy controls and 0.64 ± 0.10 for animals with emphysema. Similarly, a reduced value of T 2 (1.27 ± 0.35 ms vs 0.96 ± 0.18 ms) was found in the emphysema group. The mean signal intensity drop and the reduction of T 2 were prominent at 3 weeks following elastase instillation and stabilized between 3 and 8 weeks. The results indicated an excellent agreement between MR findings and histological morphometry (signal intensity, r = -0.78, P = 0.004; T 2, r = -0.78, P = 0.001). This result shows that proton MRI allows structural changes at alveolar level to be monitored longitudinally. This technique, applied routinely in preclinical trials will represent a valuable tool for assessment of drug therapy efficacy.

Implantable NMR Microcoils in Rats: A New Tool for Exploring Tumor Metabolism at Sub-Microliter Scale?

The aim of this study was to evaluate the potential of a miniaturized implantable nuclear magnetic resonance (NMR) coil to acquire in vivo proton NMR spectra in sub-microliter regions of interest and to obtain metabolic information using magnetic resonance spectroscopy (MRS) in these small volumes. For this purpose, the NMR microcoils were implanted in the right cortex of healthy rats and in C6 glioma-bearing rats. The dimensions of the microcoil were 450 micrometers wide and 3 mm long. The MRS acquisitions were performed at 7 Tesla using volume coil for RF excitation and microcoil for signal reception. The detection volume of the microcoil was measured equal to 450 nL. A gain in sensitivity equal to 76 was found in favor of implanted microcoil as compared to external surface coil. Nine resonances from metabolites were assigned in the spectra acquired in healthy rats (n = 5) and in glioma-bearing rat (n = 1). The differences in relative amplitude of choline, lactate and creatine resonances observed in glioma-bearing animal were in agreement with published findings on this tumor model. In conclusion, the designed implantable microcoil is suitable for in vivo MRS and can be used for probing the metabolism in localized and very small regions of interest in a tumor.