Enzymatic activity monitoring through dynamic nuclear polarization in Earth magnetic field.

Cost-effective and portable MRI systems operating at Earth-field would be helpful in poorly accessible areas or in developing nations. Furthermore Earth-field MRI can provide new contrasts opening the way to the observation of pathologies at the biochemical level. However low-field MRI suffers from a dramatic lack in detection sensitivity even worsened for molecular imaging purposes where biochemical specificity requires detection of dilute compounds. In a preliminary spectroscopic approach, it is proposed here to detect protease-driven hydrolysis of a nitroxide probe thanks to electron-nucleus Overhauser enhancement in a home-made double resonance system in Earth-field. The combination of the Overhauser effect and the specific enzymatic modification of the probe provides a smart contrast reporting the enzymatic activity. The nitroxide probe is a six-line nitroxide which lines are shifted according to its substrate/product state, which requires quantum mechanical calculations to predict EPR line frequencies and Overhauser enhancements at Earth field. The NMR system is equipped with a 13-mT prepolarization coil, a 153-MHz EPR coil and a 2-kHz NMR coil. Either prepolarized NMR or DNP-NMR without prepolarization provide NMR spectra within 3 min. The frequency dependence of Overhauser enhancement was in agreement with theoretical calculations. Protease-mediated catalysis of the nitroxide probe could only be measured through the Overhauser effect with 5 min time resolution. Future developments shall open the way for the design of new low-field DNP-MRI systems.

Age-related motor dysfunction and neuropathology in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by a progressive degeneration of the striatonigral, olivo-ponto-cerebellar, and autonomic systems. Glial cytoplasmic inclusions (GCIs) containing alpha-synuclein represent the hallmark of MSA and are recapitulated in mice expressing alpha-synuclein in oligodendrocytes. To assess if oligodendroglial expression of human wild-type alpha-synuclein in mice (proteolipid promoter, PLP-SYN) could be associated with age-related deficits, PLP-SYN and wild-type mice were assessed for motor function, brain morphometry, striatal levels of dopamine and metabolites, dopaminergic loss, and distribution of GCIs. PLP-SYN displayed age-related impairments on a beam-traversing task. MRI revealed a significantly smaller brain volume in PLP-SYN mice at 12 months, which further decreased at 18 months together with increased volume of ventricles and cortical atrophy. The distribution of GCIs was reminiscent of MSA with a high burden in the basal ganglia. Mild dopaminergic cell loss was associated with decreased dopamine turnover at 18 months. These data indicate that PLP-SYN mice may recapitulate some of the progressive features of MSA and deliver endpoints for the evaluation of therapeutic strategies.

Magnetic resonance imaging tracking of human adipose derived stromal cells within three-dimensional scaffolds for bone tissue engineering.

For bone tissue engineering, human Adipose Derived Stem Cells (hADSCs) are proposed to be associated with a scaffold for promoting bone regeneration. After implantation, cellularised scaffolds require a non-invasive method for monitoring their fate in vivo. The purpose of this study was to use Magnetic Resonance Imaging (MRI)-based tracking of these cells, labelled with magnetic agents for in vivo longitudinal assessment. hADSCs were isolated from adipose tissue and labelled with USPIO-rhodamine (Ultrasmall SuperParamagnetic Iron Oxide). USPIO internalisation, absence of toxicity towards hADSCs, and osteogenic differentiation of the labelled cells were evaluated in standard culture conditions. Labelled cells were then seeded within a 3D porous polysaccharide-based scaffold and imaged in vitro using fluorescence microscopy and MRI. Cellularised scaffolds were implanted subcutaneously in nude mice and MRI analyses were performed from 1 to 28 d after implantation. In vitro, no effect of USPIO labelling on cell viability and osteogenic differentiation was found. USPIO were efficiently internalised by hADSCs and generated a high T2* contrast. In vivo MRI revealed that hADSCs remain detectable until 28 d after implantation and could migrate from the scaffold and colonise the area around it. These data suggested that this scaffold might behave as a cell carrier capable of both holding a cell fraction and delivering cells to the site of implantation. In addition, the present findings evidenced that MRI is a reliable technique to validate cell-seeding procedures in 3D porous scaffolds, and to assess the fate of hADSCs transplanted in vivo.

Microglia used as vehicles for both inducible thymidine kinase gene therapy and MRI contrast agents for glioma therapy.

Microglia are phagocytic cells that are chemoattracted by brain tumors and can represent up to 70% of the tumor cell population. To get insight into gene therapy against glioma, we decided to take advantage of those microglia properties and to use those cells as vehicles to transport simultaneously a suicide gene (under the control of a heat-sensitive promoter) and contrast agents to localize them by magnetic resonance imaging before applying any therapeutic treatment. Thymidine kinase (TK) expression and its functionality after gancyclovir administration were investigated. After the heat shock (44 degrees C and 20 min), TK was expressed in 50% of the cells. However, after gancyclovir treatment, 90% of the cells died by apoptosis, showing an important bystander effect. Then, the cells were incubated with new lanthanide contrast agents to check both their potential toxicity and their MR properties. Results indicate that the nanoparticles did not induce any cell toxicity and yield a hypersignal on MR images at 4.7 T. These in vitro experiments indicate that microglia are good candidates as vectors in gene therapy against brain tumors. Finally, microglia containing gadolinium-grafted nanoparticles were injected in the close vicinity of C6 tumor, in a mouse. The hyperintensive signal obtained on in vivo images as well as its retention time show the potential of the novel contrast agents for cellular imaging.

Muscle phosphocreatine post-exercise recovery rate is related to functional evaluation in hospitalized and community-living older people.

OBJECTIVE: to explore muscle mitochondria function with respect to age, functional status and nutrition in community-living and recovering hospitalized older subjects. MEASUREMENTS: subjects were assessed for nutrition, hand-grip strength, 10-meter gait time, a modified timed get-up-and-go test and activities of daily living score (ADL). 31P magnetic resonance spectroscopy (31P MRS) was used to assess the initial rate of post-exercise phosphocreatine recovery (ViPCr) for mitochondrial function evaluation in 25 hospitalized older subjects (86.1 + 5.3 y) and in 25 community-living younger ones (74.5 + 6.2 y). RESULTS: in multiple linear regression, longer time on the get-up-and-go test was independently associated with lower values of ViPCr (p = 0.008). For all subjects and in the 8 patients unable to perform this test, ViPCr was negatively correlated with the ADL score (respectively p < 0.001 and p = 0.025). CONCLUSION: particularly in hospitalized and frail older subjects, muscle mitochondrial function was related to the global physical functional assessment.

A standardised method for measuring magnetisation transfer ratio on MR imagers from different manufacturers--the EuroMT sequence.

Magnetisation transfer ratio (MTR) is increasingly used to evaluate neurological disorders, especially those involving demyelination. It shows promise as a surrogate marker of disease progression in treatment trials in multiple sclerosis (MS) but the value measured is highly dependent on pulse sequence parameters, making it hard to include the technique in large multi-centre clinical trials. The variations can be reduced by a normalisation procedure based on the flip angle and timing of the presaturation pulse, but correction for parameters such as saturation pulse shape, amplitude, duration and offset frequency remains problematic. We have defined a standard pulse sequence, to include a standard presaturation pulse and set of parameters, which can be implemented on scanners from both General Electric and Siemens, and has also been used on Phillips scanners. To validate the sequence and parameters, six European centres measured MTR in the frontal white matter of normal volunteers. It was possible to measure MTR values in controls which were consistent to within approximately +/-2.5 percentage units across sites. This degree of precision may be adequate in many situations. The remaining differences between sites and manufacturers are probably caused by B1 errors.

Gadolinium-enhanced small-animal TOF magnetic resonance angiography.

So far, magnetic resonance angiography (MRA) of rodents has only been performed by using time-of-flight (TOF) MRI techniques. This is because applications of first-passage contrast agents as in humans are hampered by pronounced physiologic differences (blood volume and heart beat rate). Here we describe the use of low-dose Gd-DOTA to enhance the performance of TOF MRA in rat brain. While no improvement in contrast was achieved, the measuring time could be reduced by almost a factor of three. This decrease in total acquisition time has been used to study the impact of a model of ligatured common carotid on the upper part of the blood system of the rat.

Can magnetic resonance imaging be the key technique to visualize and investigate endovascular biomaterials?

OBJECTIVE: Magnetic resonance imaging (MRI) is an established modality in clinical use but may be potentially underutilized to visualize and investigate biomaterials. As its use is totally contraindicated only for ferromagnetic devices, it was employed to visualize deployment, biofonctionality, healing, and biodurability of a commercially available endovascular device, namely the Medtronic-AVE AneuRx. The quality of the observations coupled with the absence of ionizing radiations are likely to make this technique an attractive imaging modality in the future. METHOD: The potential benefits of the MRI technique were investigated in a GE Vectra-MR 0.5T MRI for the Medtronic-AVE AneuRx endovascular prosthesis, under different conditions: undeployed i.e., inserted in the delivery cartridge as received from the manufacturer (step 1), deployed in a mock glass-aneurysm tube (step 2), and as a pathological explant harvested at the autopsy of a patient (step 3). The device was submitted to X-rays for examination in addition to MRI. At step 3, the device was further investigated with light microscopy and scanning electron microscopy (SEM) together with X-ray diffraction. RESULTS: The device which was inserted and pleated in the delivery cartridge did not demonstrate any significant observation either in MRI or in X-rays. When it was deployed in the mock aneurysmal glass tube, light artefacts were associated with the T2 weighed FSE images around the Nitinol whereas X-rays gave images of indisputable interest. Similar results were noted using the explanted device. Very high contrasts were obtained with T1 whereas T2 images were almost defect free. The X-rays allowed to accurate imaging of the Nitinol skeleton but were poor to discriminate between the different tissues. Pathology observations using light microscopy were not really challenged, as the magnetic resonance imaging was performed using a 0.5T machine. DISCUSSION: The benefits of magnetic resonance imaging as a quality control technique to examine an endovascular device within its cartridge remains ill defined. Similarly, the role of conventional X-rays is unknown. The observation of devices fully deployed in a mock aneurysmal glass-tube under MRI are potentially useful but X-rays images allowed better definition. The MRI examination of the explanted device does permit observations related to the healing of the device that might be obtained in vivo and, thus offers new avenues for the follow-up of implanted devices. The pathological investigations brought additional informations about the tissues and the corrosion of the Nitinol. However, it is unlikely that MRI will permit detailed analysis of the biomaterials and in particular the corrosion process of the stents. CONCLUSION: These early observations of the follow-up of devices using MRI warrant further investigation. The absence of ionizing radiation with MRI makes this technique particularly attractive. As there is no emission of ionizing radiation associated with magnetic resonance, it is recommended that further investigation using this environment friendly technique for the follow-up of devices made of biomaterials that are MRI compatible.

[Comparative assessment of helical CT-angiography, 2D TOF MR-angiography and 3D gadolinium enhanced MRA in aorto-iliac occlusive disease]. / Evaluation comparative de l'angio-TDM spiralée, de l'angio-IRM 2D temps de vol et 3d gadolinium en pathologie athéromateuse aorto-iliaque.

PURPOSE: To compare helical CT-angiography (CTA) and two techniques of MR angiography (MRA) to conventional angiography in aorto-iliac occlusive disease. MATERIALS AND METHODS: The abdominal aorta and iliac arteries in 22 patients (4 for preoperative assessment of abdominal aortic aneurysm and 18 for peripheral vascular disease) were imaged using four techniques: digital subtraction angiography ("gold standard"), 2D TOF MR angiography, 3D Gd-enhanced MR angiography and helical CT angiography. Source (CTA and 2D TOF MRA) and MIPed images (after subtraction measures before and after gadolinium injection for 3D Gd-MRA) were reviewed. RESULTS: Sensitivity, specificity and accuracy for the detection of significant (>50%) stenosis and occlusion of aorto-iliac arteries were respectively: 38%, 89%, 77% for 2D TOF MRA; 75%, 71%, 72% for 3D Gd-MRA and 95%, 90%, 92% for CTA. Excluding the internal iliac arteries, results were 54%, 96%, 88% for 2D TOF MRA; 96%, 80%, 83% for 3D Gd-MRA and 92%, 93%, 95% for CTA. CONCLUSION: 3D Gd-MRA, a technique with potential for further improvement, is superior to 2D TOF MRA for detecting significant stenosis and occlusion of aorto-iliac arteries. Results at Gd-MRA are nearly similar to those at CTA (after excluding internal iliac arteries). Results at Gd-MRA are not affected by calcified plaque.

A new fast and unsynchronized method for MRI of viscoelastic properties of soft tissues.

Quantitative measurement of mechanical properties of biologic tissues may have several applications for diagnosis or biomechanic modeling in sports medicine, traumatology, or computer-guided surgery. The magnetic resonance imaging (MRI) methods previously tested for these applications all required synchronization between MRI acquisition pulses and the mechanical stimulation. A new unsynchronized method operating with no prior knowledge of intensity, direction, and frequency of the mechanical waves is proposed. A specifically modified SPAMM (SPAtial Modulation of Magnetization) sequence has been used, operating on a 0.2-T MRI system. The experimental results obtained on test objects fit well with theoretical calculations. The new proposed method is very fast (a less than 5-second acquisition time) for routine clinical use.

Gadolinium-enhanced MR imaging of normal renal transplants. An evaluation of a T1-weighted dynamic echo-planar sequence.

PURPOSE: To evaluate the potential usefulness of dynamic MR with echoplanar imaging (EPI) in assessing the renal function in patients with renal allografts. MATERIAL AND METHODS: Using a T1-weighted sequence, EPI was performed after injection of a Gd-chelate in 17 patients with normally functioning renal allografts. Time-intensity curves were plotted from the signal intensity (SI) measurements of the cortex and the medulla. RESULTS: The pattern of corticomedullar differentiation (CMD) observed after contrast enhancement was divided into four phases using the T1-EPI. After a rapid decrease in the SI of cortical structures, and a subsequent return to precontrast levels, a gradual fall in the SI of the medulla was observed. The average time between the two periods of signal loss was 60 s. CONCLUSION: This study illustrated the potential use of dynamic T1-EPI to demonstrate contrast-induced CMD in renal allografts.

A multicenter measurement of magnetization transfer ratio in normal white matter.

To assess the importance of intercenter variations when measuring magnetization transfer ratio (MTR) in the brain, six European centers measured MTR in normal white matter. MTR ranged from 9 to 51 percent units (25 sequences). The effective flip angle of the saturating pulse divided by the pulse repetition time (ENRsat degrees/msec) was a good predictor of MTR (MTR = 3.25 ENRsat).

[Fast imaging sequences]. / Séquences d'imagerie rapide.

Although conventional spin echo and gradient echo sequences are still in general use, the need to improve the temporal resolution of MRI and to study organ function has prompted to develop fast imaging techniques. These techniques are based on different approaches, but present common underlying principles which allow optimize k space fitting. As a result, both contrast and spatial resolution may be improved aside from the capability to reduce scan time. The selection of the most appropriate fast imaging technique will depend on the needed temporal resolution, spatial resolution and contrast. The aim of this paper is to review and explain the basic principles of fast imaging techniques, with emphasis on their advantages, limitations, and clinical applications.

Cinematic study of temporomandibular joint motion using ultra-fast magnetic resonance imaging.

Magnetic Resonance Images (MRI) of the temporomandibular joint (TMJ) are usually performed to study the opening/closing movements of the mandible and have up to now been pseudodynamic step-by-step images simulating condylar motion by post-processing reconstruction. The aim of this study was: 1. to optimize a TMJ cine-imaging method to give a better clinical result than the step-by-step methods; 2. to develop an ultra-fast MRI Gradient Echo (GE) sequence for this purpose; and 3. to analyze condylar movements in the sagittal, coronal and para-axial planes during border mandibular displacements and chewing. Both TM joints were studied in six asymptomatic volunteers. The method involved a compromise between in-plane resolution, slice thickness, signal-to-noise ratio and time resolution. Routine clinical use was found to be a GE pulse sequence providing three images per second with an isometric voxel resolution of approximately two millimeters in ridge. This did not allow visualization of the disk. Using this sequence enabled real and simultaneous condylar displacement observation in the three planes of space and therefore contributed to a better functional diagnosis of pathologic TMJ motions.

A validation of a flow quantification by MR phase mapping software.

AIM: We evaluated a Siemens software of flow quantification (FQ) by MR phase mapping, in the framework of a common practical use. METHODS: Experiments with a laminar flow phantom and in vivo pulsatile flow were performed. In particular, FQ in ascending aorta was investigated in healthy volunteers. RESULTS AND CONCLUSION: Flow phantom experiments reveal that the FQ slightly underestimates (8% on the average) actual velocities (mean velocities over a vessel area), and also that velocity uncertainties are related to the encoding velocity value, whatever the measured velocity. Furthermore, using well characterized working criteria, we found low intraobserver variability and negligible interobserver variability in ascending aorta FQs. The role played by the choice of reference area in FQ accuracy is emphasized. When recording several cardiac cycles during the same acquisition, it is shown that the FQ software may provide erroneous results. Several comments for FQ software use in the ascending aorta are added.

Auditory cortex activation in deaf subjects during cochlear electrical stimulation. Evaluation by functional magnetic resonance imaging.

RATIONALE AND OBJECTIVES: The authors detect activation in the auditory cortex during cochlear electrical stimulation in deaf patients using functional magnetic resonance (MR) imaging. METHODS: Stimulating electrode was inserted gently under local anesthesia close to the round window membrane of the cochlea in seven cochlear implant candidates. These patients suffered from postlingual-acquired deafness. Four patients were stimulated above the electrical perception threshold and three below the electrical discomfort threshold. Functional scans (fast low-angle shot 91 mseconds/60 mseconds) were acquired in an oblique axial plane running parallel to the sylvian fissure. Four consecutive series of six images were obtained in 6 minutes. The acquisition time of each image was 15 seconds. RESULTS: During electrical cochlear stimulation below the discomfort threshold, the three patients described "auditory" sensations with activation of the superior temporal regions. In two patients with electrical stimulation of the left ear, the maximum signal intensity increased by 8.42% in the right auditory cortex and 5.69% in the left. In one patient with a right electrical stimulation only the left cortex was activated. Electrical cochlear stimulation above the perception threshold induces no significant activation in the auditory cortex. CONCLUSION: Functioning MR imaging can detect activation in the auditory cortex during cochlear electrical stimulation in deaf patients using a conventional 1.5-tesla system in a routine hospital environment. Further studies are needed to investigate its usefulness in clinical practice.

[Progressive multifocal leukoencephalopathy. Study of the demyelination by magnetization transfer]. / Leucoencéphalopathie multifocale progressive. Etude de la démyélinisation par transfert de magnétisation.

PURPOSE: magnetization transfer imaging (MT) has been used to study the degree of demyelination in progressive multifocal leukoencephalopathy (PML). MATERIAL AND METHOD: two groups were studied: a group of 10 HIV + patients with clinical, MR features, biological and/or biopsy proven PML, and a group of 11 normal volunteers with matched age. MT ratio (MTR) were obtained from the center of the PML lesions and 11 areas of normal appearing white matter (NAWM) in the control group. RESULTS: the mean MTR of NAWM in the control group was 46.6% (SD = 2,3). PML lesions demonstrated a strong and significant (p = 0) decreased of the MTR with mean MTR value of 22.4% (SD = 2,3). CONCLUSION: MT characterized the demyelinating process in PML, and can be used to improve diagnosis. Furthermore, MT allowed a quantification of the degree of demyelination which can be helpful in other demyelinating process of CNS such as multiple sclerosis.

Magnetization transfer with echo planar imaging.

The aim of magnetization transfer is to saturate the protons of the macromolecule pool with a radiofrequency (RF) pulse leading to differences in free water pool signal. Magnetization transfer (MT) contrast is difficult to achieve with the echo planar imaging (EPI) technique, although its short acquisition time would be most beneficial. Indeed, the RF saturation pulses can only be applied once before sampling the whole k-space in a single-short sequence. A possible solution to improve the sensitivity of EPI to magnetization transfer consists in applying a train of several saturation RF pulses before image acquisition. The different parameters of a RF pulse train and their influence on the MT rate have been tested to optimize an EPI clinical sequence. Our experimental procedure makes it possible to obtain a MT map in about 1 second. The technique is evaluated by multiple sclerosis lesion characterization.

Lateralization of prefrontal activation during internal mental calculation: a functional magnetic resonance imaging study.

1. Functional magnetic resonance imaging (fMRI) at 1.5 T was used to investigate the lateralization of prefrontal cortex activity during internal mental calculation in 16 human volunteers (8 right-handed and 8 left-handed). Subjects were asked to perform two different tasks: 1) a serial subtraction of prime numbers and 2) a control task in which they mentally recited numbers. 2. Signal modifications were regularly observed in the prefrontal cortex (Brodmann's area 46) during the serial subtraction of prime numbers, whereas the number listing task poorly activated the same areas. 3. In right-handed subjects, activation was clearly lateralized in the left dorsolateral prefrontal cortex, whereas a frequent bilateral activation was found in left-handed subjects. 4. We conclude that prefrontal activation during mental calculation is lateralized in a manner similar to that reported during linguistic tasks, i.e., a clear lateralization in right- but not in left-handed subjects.

Activation of association auditory cortex demonstrated with functional MRI.

Activations in the temporal lobes previously observed using positron emission tomography and auditory stimuli were partially reproduced with functional MRI and echo-planar imaging at 1.5 T in six volunteers performing tone and phoneme monitoring tasks. Verbal processing compared to a tone recognition task significantly activated a cortical area located in the left anterior temporal region (P < 0.02).