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Advanced science (2021). doi:10.1002/advs.202100370, Published by Wiley-VCH, Weinheim

The first aim of this study was to determine how complete or perivascular loss of aquaporin-4 (AQP4) water channels affects membrane permeability for water in the mouse brain grey matter in the steady state. Time-dependent diffusion magnetic resonance imaging was performed on global Aqp4 knock out (KO) and α-syntrophin (α-syn) KO mice, in the latter perivascular AQP4 are mislocalized, but still functioning. Control animals were corresponding wild type (WT) mice. By combining in vivo diffusion measurements with the effective medium theory and previously measured extra-cellular volume fractions, the effects of membrane permeability and extracellular volume fraction were uncoupled for Aqp4 and α-syn KO. The second aim was to assess the effect of α-syn KO on cortical intermediary metabolism combining in vivo [1-13C]glucose and [1,2-13C]acetate injection with ex vivo 13C MR spectroscopy. Aqp4 KO increased the effective diffusion coefficient at long diffusion times by 5%, and a 14% decrease in membrane water permeability was estimated for Aqp4 KO compared with WT mice. α-syn KO did not affect the measured diffusion parameters. In the metabolic analyses, significantly lower amounts of [4-13C]glutamate and [4-13C]glutamine, and percent enrichment in [4-13C]glutamate were detected in the α-syn KO mice. [1,2-13C]acetate metabolism was unaffected in α-syn KO, but the contribution of astrocyte derived metabolites to GABA synthesis was significantly increased. Taken together, α-syn KO mice appeared to have decreased neuronal glucose metabolism, partly compensated for by utilization of astrocyte derived metabolites. This is the authors' accepted and refereed manuscript to the article. Locked until 30 December 2017 due to copyright restrictions. The final publication is available at link.springer.com via https://link.springer.com/article/10.1007%2Fs11064-016-2139-y

Purpose To compare experimental transverse relaxivities of iron oxide nanocrystals (IONC) as a function of clustering and magnetic field strength with different theoretical model predictions. Theory and Methods Well-defined IONC clusters in nanoemulsions (NEs) of which both size and IONC loading could be judiciously tuned were developed. Transverse relaxivities were measured as a function of NE size and IONC loading at 20 and 300 MHz and compared with four theoretical model predictions. Polydispersity of the NEs was measured and taken into account in the theoretical calculations. Results Experimentally observed relaxivities were in between theoretical predictions from the fast diffusion regime and the static dephasing regimen. NE polydispersity significantly affected the theoretical T2 relaxivity. The effect of both the number of IONCs inside each droplet as well as the radius of the droplet itself was correctly described by a fast diffusion loose aggregate model, while the effect of increased magnetic field was in agreement with a static dephasing model. Conclusion The results suggest that both fast diffusion, originating from bulk water, and static dephasing phenomena, perhaps originating from water associated with the NE, play a role in transverse relaxivities of IONC aggregates. The developed aggregate system represents a powerful tool to further study these phenomena. Magn Reson Med 74:858–867, 2015. © 2014 Wiley Periodicals, Inc.

In the past two decades advances in the development of targeted nanoparticles have facilitated their application as molecular imaging agents and targeted drug delivery vehicles. Nanoparticle-enhanced molecular imaging of the angiogenic tumor vasculature has been of particular interest. Not only because angiogenesis plays an important role in various pathologies, but also since endothelial cell surface receptors are directly accessible for relatively large circulating nanoparticles. Typically, nanoparticle targeting towards these receptors is studied by analyzing the contrast distribution on tumor images acquired before and at set time points after administration. Although several exciting proof-of-concept studies demonstrated qualitative assessment of relative target concentration and distribution, these studies did not provide quantitative information on the nanoparticle targeting kinetics. These kinetics will not only depend on nanoparticle characteristics, but also on receptor binding and recycling. In this study, we monitored the in vivo targeting kinetics of αvβ3-integrin specific nanoparticles with intravital microscopy and dynamic contrast enhanced magnetic resonance imaging, and using compartment modeling we were able to quantify nanoparticle targeting rates. As such, this approach can facilitate optimization of targeted nanoparticle design and it holds promise for providing more quantitative information on in vivo receptor levels. Interestingly, we also observed a periodicity in the accumulation kinetics of αvβ3-integrin targeted nanoparticles and hypothesize that this periodicity is caused by receptor binding, internalization and recycling dynamics. Taken together, this demonstrates that our experimental approach provides new insights in in vivo nanoparticle targeting, which may proof useful for vascular targeting in general.

Purpose To evaluate late gadolinium-enhanced (LGE) assessment of infarct size, a comparison with manganese-enhanced magnetic resonance imaging (MEMRI), and histology was performed in a permanent infarction model in the mouse at the acute and chronic stage. Materials and Methods In a paired fashion at the acute and chronic stage after infarction (3–4 days and 21 days, respectively), LGE and MEMRI was performed using a self-gated fast low flip angle shot (FLASH). Infarct size was evaluated as the enhanced area relative to the complete myocardial wall area in a mid-ventricular slice. Paired comparisons were made between contrast agents and between timepoints, as well as to histology. Results At the acute stage, LGE delineated a larger infarct size as compared to both MEMRI and histology. Infarct size from LGE decreased from the acute to chronic stage, a temporal development not seen with MEMRI. At the chronic stage, no significant differences in infarct size were found between the methods. Conclusion This study indicates an overenhancement of infarct size when using LGE, supported by an initial overestimation at the acute stage and a temporal decrease in infarct size from the acute to chronic stage, as compared to infarct size from MEMRI. J. Magn. Reson. Imaging 2013;38:1388–1394. © 2013 Wiley Periodicals, Inc.

Magnetic resonance imaging (MRI)-based tracking is increasingly attracting attention as a means of better understanding stem cell dynamics in vivo. Intracellular labeling with micrometer-sized particles of iron oxide (MPIOs) provides a practical MRI-based approach due to superior detectability relative to smaller iron oxide particles. However, insufficient information is available about the general utility across cell types and the effects on cell vitality of MPIO labeling of human stem cells. We labeled six human cell types from different sources: mesenchymal stem cells derived from bone marrow (MSCs), mesenchymal stem cells derived from adipose tissue (ASCs), presumptive adult neural stem cells (ad-NSCs), fetal neural progenitor cells (f-NPCs), a glioma cell line (U87), and glioblastoma tumor stem cells (GSCs), with two different sizes of MPIOs (0.9 and 2.84 μm). Labeling and uptake efficiencies were highly variable among cell types. Several parameters of general cell function were tested in vitro. Only minor differences were found between labeled and unlabeled cells with respect to proliferation rate, mitotic duration, random motility, and capacity for differentiation to specific phenotypes. In vivo behavior was tested in chicken embryos and severe combined immunodeficient (SCID) mice. Postmortem histology showed that labeled cells survived and could integrate into various tissues. MRI-based tracking over several weeks in the SCID mice showed that labeled GSCs and f-NPCs injected into the brain exhibited translocations similar to those seen for unlabeled cells and as expected from migratory behavior described in previous studies. The results support MPIO-based cell tracking as a generally useful tool for studies of human stem cell dynamics in vivo.

Labelling of olfactory ensheathing cells (OECs) with micron-sized particles of iron oxide (MPIO) and detection by MRI

The aim of the present study was to test alginate gels of different compositions as a system for controlled release of manganese ions (Mn2+) for application in manganese-enhanced MRI (MEMRI), in order to circumvent the challenge of achieving optimal MRI resolution without resorting to high, potentially cytotoxic doses of Mn2+. Elemental analysis and stability studies of Mn-alginate revealed marked differences in ion binding capacity, rendering Mn/Ba-alginate gels with high guluronic acid content most stable. The findings were corroborated by corresponding differences in the release rate of Mn2+ from alginate beads in vitro using T1-weighted MRI. Furthermore, intravitreal (ivit) injection of Mn-alginate beads yielded significant enhancement of the rat retina and retinal ganglion cell (RGC) axons 24 h post-injection. Subsequent compartmental modelling and simulation of ivit Mn2+ transport and concentration revealed that application of slow release contrast agents can achieve a significant reduction of ivit Mn2+ concentration compared with bolus injection. This is followed by a concomitant increase in the availability of ivit Mn2+ for uptake by RGC, corresponding to significantly increased time constants. Our results provide proof-of-concept for the applicability of Mn-alginate gels as a system for controlled release of Mn2+ for optimized MEMRI application. Copyright © 2012 John Wiley & Sons, Ltd.

Background The entorhinal cortex serves as an important gateway between the cerebral cortex and the hippocampus by receiving afferent information from limbic, modality sensory-specific, and multimodal association fibers from all the brain lobes. Aim To investigate whether thinning of entorhinal cortex is associated with reduced perceptual, cognitive and executive skills in very low birth weight (VLBW) adolescents. Study design Prospective, geographically based follow-up study of three year cohorts of preterm born VLBW children. Subjects Forty-nine VLBW (birth weight ≤ 1500 g) and 58 term-born control adolescents were examined at the age of 14–15 years. Outcome measures Perceptual and cognitive functions were assessed with Visual motor integration test, Grooved Pegboard test, Wechsler Intelligence Scale for Children-III and different executive function tests (Wisconsin card sorting test, Trail Making test, Knox cube test). An automated MRI technique at 1.5 T for morphometric analyses of cortical thickness was performed. Areas with cortical thinning in left and right entorhinal cortex in the VLBW group were chosen as regions of interest to look for associations between cortical thickness and clinical findings. Results Thinning of the entorhinal cortex was correlated with low performance on perceptual and cognitive scores in the VLBW adolescents, but not in controls. In addition, thinning of the entorhinal cortices correlated with reduced performance on several executive tests, including perceptual speed and aspects of working memory. Conclusions Entorhinal cortical thinning is related with low IQ and reduced perceptual and executive functions in VLBW adolescents.

Objective DynaCT® is a method for obtaining computed tomography (CT)-like images using a C-arm system. Our aim was to compare the accuracy of these images to multidetector CT (MDCT) images prior to endovascular aortic repair (EVAR). Methods A non-consecutive group of 20 elective patients were prospectively exposed to MDCT and one additional DynaCT before EVAR. Six arterial measurements and nine anatomical areas were chosen to: (1) visualise the peri-aortic soft tissue and assess the possibility to diagnose a potential haemorrhage from a ruptured aneurysm and (2) make the pre-treatment measurements before insertion of stent graft. Differences between modalities and readers were statistically compared using a linear mixed model. Results For maximum aortic diameter, a significant difference of 1.3 mm was found between techniques (p = 0.043). Visibility scores were significantly better for all areas in MDCT data. Pre-treatment evaluation with DynaCT before EVAR was possible for all areas; evaluation of the iliac arteries were suboptimal due to a limited imaging volume size. Significant inter-reader differences were found for all anatomical areas. Conclusion The result indicates that DynaCT gives sufficient information to determine the correct treatment and for selecting the proper stent graft before EVAR. A limited volume size reduces the evaluation of the iliac arteries.

The purpose of the present study was to use magnetic resonance imaging (MRI) as a tool for monitoring transplant-mediated repair of the adult rat visual pathway. We labelled rat olfactory ensheathing cells (OECs) using micron-sized particles of iron oxide (MPIO) and transplanted them by: i) intravitreal injection (ivit) and ii) intra-optic nerve (ON) injection (iON) in adult rats with ON crush (ONC) injury. We applied T(2)-weighted MRI and manganese-enhanced MRI (MEMRI) to visualise transplanted cells and ON axons at specific times after injury and cell engraftment. Our findings demonstrate that ivit MPIO-labelled OECs are unequivocally detected by T(2)-weighted MRI in vivo and that the T(1)-weighted 3D FLASH sequence applied for MEMRI facilitates simultaneous visualisation of Mn(2+-) enhanced regenerating retinal ganglion cell (RGC) axons and MPIO-labelled OEC grafts. Furthermore, analysis of MRI data and ultrastructural findings supports the hypothesis that iON OEC transplants mediate regeneration and remyelination of RGC axons post injury.

Purpose 1) To evaluate a novel theoretical model for in vivo axonal Mn(2+) transport with MRI data from the rat optic nerve (ON); and 2) to compare predictions from the new model with previously reported experimental data. Materials and methods Time-resolved in vivo T(1)-weighted magnetic resonance imaging (MRI) of adult female Sprague-Dawley rat (n = 9) ON was obtained at different timepoints after intravitreal MnCl(2) injection. A concentration-dependent and a rate-dependent function for the Mn(2+) retinal ganglion cell (RGC) axon entrance was convolved with three different transport functions and each model system was optimized to fit the ON data. Results The rate-limited input function gave a better fit to the data than the concentration-limited input. Simulations showed that the rate-limited input leads to a semilogarithmic relationship between injected dose and Mn(2+) concentration in the ON, which is in agreement with previously reported in vivo experiments. A random walk transport model and an anterograde predominant slow model gave a similar fit to the data, both better than an anterograde predominant fast model. Conclusion The results indicate that Mn(2+) input into RGC axons is limited by a maximum entrance rate into the axons. Also, a wide range of apparent Mn(2+) transport rates seems to be involved, different from synaptic vesicle transport rates, meaning that manganese does not depict synaptic vesicle transport rates directly.

The aim of this study was to investigate any structural-functional relationship between changes in white matter microstructure seen on diffusion tensor imaging and results of an executive function test in adolescents with very low birth weight (VLBW). Thirty-four VLBW adolescents were examined at 15 years of age. Executive function was assessed by the Wisconsin Card Sorting Test. Diffusion tensor imaging scans were performed at 1.5 T for calculation of individual fractional anisotropy maps. Through a voxel-wise regression analysis, correlations were found between the results on Wisconsin Card Sorting Test and fractional anisotropy values in the left cingulum and both inferior fronto-occipital fascicles. We speculate that impairments in executive function in VLBW children may be influenced by disturbed connectivity between posterior brain regions and the prefrontal cortex.

To evaluate manganese (Mn(2+))-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) as tools for detection of axonal injury and regeneration after intravitreal peripheral nerve graft (PNG) implantation in the rat optic nerve (ON).In adult Fischer rats, retinal ganglion cell (RGC) survival was evaluated in Flurogold (FG) back-filled retinal whole mounts after ON crush (ONC), intravitreal PNG, and intravitreal MnCl(2) injection (150 nmol) at 0 and 20 days post lesion (dpl). MEMRI and echo-planar DTI (DTI-EPI) was obtained of noninjured ON one day after intravitreal MnCl(2) injection, and at 1 and 21 dpl after ONC, intravitreal PNG, and intravitreal MnCl(2) injections given at 0 and 20 dpl. GAP-43 immunohistochemistry was performed after the last MRI.ONC reduced RGC density in retina by 94% at 21 dpl compared to noninjured ON without MnCl(2) injections. Both intravitreal PNG and intravitreal MnCl(2) injections improved RGC survival in retina, which was reduced by 90% (ONC+MnCl(2)), 82% (ONC+PNG), and 74% (ONC+PNG+MnCl(2)) compared to noninjured ON. DTI-derived parameters (fractional anisotropy [FA], mean diffusivity, axial diffusivity lambda( parallel), and radial diffusivity lambda( perpendicular)) were unaffected by the presence of Mn(2+) in the ON. At 1 dpl, CNR(MEMRI) and lambda( parallel) were reduced at the injury site, while at 21 dpl they were increased at the injury site compared to values measured at 1 dpl. GAP-43 immunoreactive axons were present in the ON distal to the ONC injury site.MEMRI and DTI enabled detection of functional and structural degradation after rat ON injury, and there was correlation between the MRI-derived and immunohistochemical measures of axon regeneration.

The aim of this study was to establish a robust set of motor tasks that could be used to functionally delineate the motor cortex with blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) at 3 T and produce precise functional maps for pre-operative planning and functional neuronavigation.Twelve male and four female control subjects were recruited for this study which examined six different motor tasks. Finger-, tongue-, lip- and toe-movements, as well as isometric upper arm- and thigh-contraction tasks were conducted during separate scans on a 3 T MRI scanner. Furthermore, patients that previously had undergone similar motor tasks were reviewed, to evaluate whether this set of tasks was able to be adopted for use in a population of patients with brain lesions.The results of this study indicated that the finger-, toe- and tongue-motor tasks were the most robust in identifying their respective primary motor area. Moreover, all three tasks activated regions at regular intervals along the convexity of the hemisphere, making it possible to functionally delineate the primary motor cortex in both healthy subjects and patients.The motor tasks described in this study (toe, finger and tongue) were effective at localizing the primary motor cortex for the purposes of neurosurgical planning. These three tasks produced the highest success rate and resulted in activations at regular intervals along the convexity of the hemisphere, allowing the delineation of the entire motor strip even in the presence of edema and anatomical distortions.

To provide dose-response data for the safe and effective use of MnCl(2) for manganese (Mn(2+)) -enhanced MRI (MEMRI) of the visual pathway.Retinal ganglion cell (RGC) toxicity, CNR in MEMRI, axon density resolution for MEMRI, mode of axonal transport and clearance of Mn(2+) from the vitreous after ivit were investigated. After 0, 30, 150, 300, 1500, and 3000 nmol ivit MnCl(2), neural toxicity was measured by counting surviving RGC back-filled with FluroGold (FG), CNR of the vitreous body and visual pathway by three-dimensional (3D) MEMRI, resolution of ON axon density by correlating CNR with axon density, and axonal transport of Mn(2+) by studying CNR in 3D MEMRI of the ON after ion of 200 nmol MnCl(2).There were no changes in RGC density after ivit MnCl(2)or= 150 nmol, and reductions of 12%, 57%, and 94% occurred after 300, 1500, and 3000 nmol MnCl(2). CNR increased in the visual pathway with MnCl(2)or= 300 nmol, and decreased when the dose was raised further. Minimum detectable ON axon densities were 125,000/mm(2). After 200 nmol ion MnCl(2), CNR0 were recorded distally from the ion site, but there was no signal in the retina. At ivit doses1500 nmol, clearance from the vitreous body was impaired.The optimal dose for MEMRI of the rat visual pathway was found to be 150-300 nmol ivit MnCl(2). Higher doses are toxic, causing RGC death, impair active clearance from the vitreous, and loss of Mn(2+) enhancement throughout the visual pathway. Mn(2+) traffic within RGC axons is mediated mainly by anterograde transport.

Purpose To develop a method for the measurement of brain perfusion based on dynamic contrast-enhanced T1-weighted MR imaging. Materials and Methods Dynamic imaging of the first pass of a bolus of a paramagnetic contrast agent was performed using a 3T whole-body magnet and a T1-weighted fast field echo sequence. The input function was obtained from the internal carotid artery. An initial T1 measurement was performed in order to convert the MR signal to concentration of the contrast agent. Pixelwise and region of interest (ROI)-based calculation of cerebral perfusion (CBF) was performed using Tikhonov's procedure of deconvolution. Seven patients with acute optic neuritis and two patients with acute stroke were investigated. Results The mean perfusion value for ROIs in gray matter was 62 mL/100g/min and 21 mL/100g/min in white matter in patients with acute optic neuritis. The perfusion inside the infarct core was 9 mL/100g/min in one of the stroke patients. The other stroke patient had postischemic hyperperfusion and CBF was 140 mL/100g/min. Conclusion Absolute values of brain perfusion can be obtained using dynamic contrast-enhanced MRI. These values correspond to expected values from established PET methods. Furthermore, at 3T pixelwise calculation can be performed, allowing construction of CBF maps. J. Magn. Reson. Imaging 2008;27:754–762. © 2008 Wiley-Liss, Inc.

Mesial temporal lobe epilepsy is associated with structural and functional abnormalities, such as hippocampal sclerosis and axonal reorganization. The temporal evolution of these changes remains to be determined, and there is a need for in vivo imaging techniques that can uncover the epileptogenic processes at an early stage. Manganese-enhanced magnetic resonance imaging may be useful in this regard. The aim of this study was to analyze the temporospatial changes in manganese enhancement in rat brain during the development of epilepsy subsequent to systemic kainate application (10 mg/kg i.p.). MnCl(2) was given systemically on day 2 (early), day 15 (latent), and 11 weeks (chronic phase) after the initial status epilepticus. Twenty-four hours after MnCl(2) injection T1-weighted 3D MRI was performed followed by analysis of manganese enhancement. In the medial temporal lobes, there was a pronounced decrease in manganese enhancement in CA1, CA3, dentate gyrus, entorhinal cortex and lateral amygdala in the early phase. In the latent and chronic phases, recovery of the manganese enhancement was observed in all these structures except CA1. A significant increase in manganese enhancement was detected in the entorhinal cortex and the amygdala in the chronic phase. In the latter phase, the structurally intact cerebellum showed significantly decreased manganese enhancement. The highly differentiated changes in manganese enhancement are likely to represent the net outcome of a number of pathological and pathophysiological events, including cell loss and changes in neuronal activity. Our findings are not consistent with the idea that manganese enhancement primarily reflects changes in glial cells.

Very low birth weight (VLBW) children are at high risk of perinatal white matter injury, which, when subtle, may not be seen using conventional magnetic resonance imaging. The relationship between clinical findings and fractional anisotropy (FA) measurements in white matter of adolescents born prematurely with VLBW was studied in 34 subjects (age = 15 years, birth weight

Diabetes mellitus (DM) increases the risk of heart failure after myocardial infarction (MI), and aggravates ventricular arrhythmias in heart failure patients. Although exercise training improves cardiac function in heart failure, it is still unclear how it benefits the diabetic heart after MI. To study the effects of aerobic interval training on cardiac function, susceptibility to inducible ventricular arrhythmias and cardiomyocyte calcium handling in DM mice after MI (DM-MI). Male type 2 DM mice (C57BLKS/J Lepr (db) /Lepr (db) ) underwent MI or sham surgery. One group of DM-MI mice was submitted to aerobic interval training running sessions during 6 weeks. Cardiac function and structure were assessed by echocardiography and magnetic resonance imaging, respectively. Ventricular arrhythmias were induced by high-frequency cardiac pacing in vivo. Protein expression was measured by Western blot. DM-MI mice displayed increased susceptibility for inducible ventricular arrhythmias and impaired diastolic function when compared to wild type-MI, which was associated with disruption of cardiomyocyte calcium handling and increased calcium leak from the sarcoplasmic reticulum. High-intensity exercise recovered cardiomyocyte function in vitro, reduced sarcoplasmic reticulum diastolic calcium leak and significantly reduced the incidence of inducible ventricular arrhythmias in vivo in DM-MI mice. Exercise training also normalized the expression profile of key proteins involved in cardiomyocyte calcium handling, suggesting a potential molecular mechanism for the benefits of exercise in DM-MI mice. High-intensity aerobic exercise training recovers cardiomyocyte function and reduces inducible ventricular arrhythmias in infarcted diabetic mice.

The potential for detecting fluorinated compounds in a 2.35 T nuclear magnetic resonance system was assessed to evaluate the possibility for in vivo monitoring of fluorinated drugs applied to the eye. Time‐share proton decoupled 19F NMR spectroscopy was implemented for signal enhancement in an experimental eye model. Signal‐to‐noise in 19F NMR spectra of dexamethasone phosphate was enhanced by 56%. However, decoupling did not enhance S/N for ciprofloxacin. The obtained detection limit of 0.1–0.2 µmol did not enable detection of drugs at therapeutic concentrations in the eye. Higher magnetic field and improved coil and detection technology might enable future in vivo monitoring of drugs in the eye.

Blood-Oxygenation-Level-Dependent functional Magnetic-Resonance-Imaging (BOLD fMRI) and Diffusion Tensor Imaging (DTI) are specialized MRI-techniques for imaging of eloquent cortices and neural tracts in gray and white matter, respectively. By processing of the BOLD fMRI images, it is possible to map eloquent cortices and visualize them as statistical parametric color coded maps to be overlain on for instance anatomical MRI-images. Processing of the DTI images using a technique called Diffusion Tensor Tractography (DTT), makes it possible to map important neural tracts and visualize them as fiber bundles. The results from these examinations may be helpful during planning and resection of brain lesions, by providing information on functional eloquent cortices and important white matter tracts in close proximity to the lesion, as the goal of surgery is to maximize resection without inflicting new neurological deficits. This functional information may also be incorporated into neuronavigation systems and utilized during surgery. The overall aim of this thesis was to develop, implement, and evaluate BOLD fMRI and DTT at 3 Tesla for routine use in preoperative planning and 3D ultrasound-guided functional neuronavigation combined with minimal invasive neurosurgery. Obtaining normative functional data in healthy subjects is a first step in the development of clinical useful tasks. Thus, we investigated different motor tasks in a group of healthy subjects to evaluate which combination was best suited for functional mapping and delineation of the primary motor cortex. Movement of fingers, toes, and tongue yielded the highest success rates in healthy subjects and proved equally successful in patients with brain lesions. We also investigated a set of language tasks and the reproducibility of the activation size and location for these. We found that a word-generation task and a responsive naming task should be preferred for mapping of the frontal and temporal language area, respectively. A novel language task with the potential to map both the frontal and temporal language areas was also established. This task has the advantage of being more engaging, which may help the subjects to maintain concentration and stay motivated throughout the scanning session. We have also evaluated the use of BOLD fMRI and DTT in 3D ultrasound-guided functional neuronavigation by retrospectively reviewing patients operated during a threeyear period. We found that surgery gave an overall significant improvement in clinical status compared to preoperatively, and for gliomas we found a median residual tumor volume of 11%. We also found a significant correlation between decreasing lesion-toeloquent- area distance and increasing residual tumor percentage in gliomas, indicating that the resections were performed as a compromise between removing as much tumor tissue as possible without jeopardizing eloquent areas. Furthermore, some glioma patients with lesion-to-eloquent-area distance less than 2 mm also had radical resections without post-operative neurological deficits. Thus indicating that guided functional neuronavigation with updated anatomical information using 3D ultrasound gives the surgeon an advantage when resecting brain lesions, as well as facilitates maximal tumor resection with minimal deficit. The challenges ahead lie in establishing standardized tasks and analysis for processing of these investigations, as well as carrying out prospective outcome studies or clinical randomized trials in order to produce evidence for effect of presurgical BOLD fMRI and DTT on morbidity and mortality in patients with brain lesions.

Object Conflicting results have been reported concerning the antitumor efficacy of the angiogenesis inhibitor endostatin. This may be due to differences in the biological distribution of endostatin between studies or to the varying biological efficacies of the different protein forms that were examined. To address this issue, the authors used a local delivery approach in which each tumor cell secreted endostatin, providing uniform endostatin levels throughout the tumors. This allowed a direct assessment of the biological efficacy of soluble endostatin in vivo. Methods The authors genetically engineered BT4C gliosarcoma cells so that they would stably express and secrete either the human or murine form of endostatin. Endostatin-producing cells or mock-infected cells were implanted intracerebrally in syngeneic BD-IX rats. The antitumor efficacy of endostatin was evaluated on the basis of survival data and tumor volume comparisons. In addition, microvascular parameters were assessed. The authors confirmed the continuous release of endostatin by the BT4C cells. A magnetic resonance imaging–assisted comparison of tumor volumes revealed that local production of murine endostatin significantly inhibited tumor growth. Notably, 40% of the animals in this treatment group experienced long-term survival without histologically verifiable tumors 7 months after cell implantation. After local treatment with murine endostatin, tumor blood plasma volumes were reduced by 71%, microvessel density counts by 84%, and vascular area fractions by 75%. In contrast, human endostatin did not inhibit tumor growth significantly in this model. Centrally located regions of necrosis were present in tumors secreting both the human and the murine species-specific form of endostatin. Conclusions The results suggest that endostatin inhibits tumor angiogenesis in vivo in a species-specific manner.

Purpose To assess magnitude and duration of changes in myocardial longitudinal relaxation rate (R1) in humans following infusion of the manganese (Mn) releasing contrast agent MnDPDP (Mn-dipyridoxyl-diphosphate). Materials and methods Fifteen healthy volunteers were divided into three groups. After initial myocardial and liver R1 measurements using an inversion recovery (IR) turbo fast low-angle shot (FLASH) sequence at 1.5 Tesla, the groups were given different doses of intravenous MnDPDP: 5, 10 and 15 micromol/kg body weight, respectively, over 30 minutes. R1 measurements were then repeated at 1, 2, 4, 8, and 24 hours after the infusion ended. Results The left ventricular wall R1 prevalue was 0.98 second(-1) (+/-0.04). R1 increased on average (all 15 subjects) 0.41 second(-1) (+/-0.09). The increase was present one hour after the end of the infusion, remained relatively constant the next two hours, and then declined gradually. After 24 hours, there was still a moderate R1 elevation present, with an average R1-value of 1.16 (+/-0.05). There were only small differences in myocardial R1 responses between the three doses investigated, which was contrasted by a marked dose-response in liver tissue. Conclusion MnDPDP gave a significant and prolonged rise in myocardial R1 even at a dose of 5 micromol/kg. The R1-values in the myocardium did not increase linearly with higher doses.

PURPOSE: To compare perfusion magnetic resonance imaging (MRI) and ventilation-perfusion scintigraphy (V-P scan) in the study of perfusion abnormalities in pulmonary embolism (PE) and to compare the PE results to the findings previously reported for pneumonia and chronic obstructive pulmonary disease (COPD), in terms of perfusion abnormalities. MATERIALS AND METHODS: Dynamic contrast-enhanced MR images and V-P scans of 20 patients with PE, 11 patients with acute pneumonia, and 13 patients with exacerbation of COPD were studied. Five categories of perfusion abnormalities within each imaging modality were defined. Intra- and inter-modality agreement (kappa values) in the evaluation of perfusion abnormalities were calculated, based on the two observers of each imaging modality (all blinded to each other and true diagnosis). Finally, three categories of perfusion MRI diagnosis (PE, pneumonia, and COPD) were also defined and the inter-observer agreement (kappa value) was calculated. RESULTS: For PE, the intra-modality agreement (kappa value) in the evaluation of perfusion abnormalities was 0.77 for MRI and 0.65 for V-P scan. The inter-modality agreement varied from 0.52 to 0.57, respectively, and was observer-dependent. For the pooled group of PE, pneumonia, and COPD, the intra-modality agreement of perfusion abnormalities was 0.76 for MRI and 0.65 for V-P scan, and the inter-modality agreement varied from 0.51 to 0.56. The kappa value for inter-observer agreement for MRI diagnosis was 0.92. CONCLUSION: Evaluation of perfusion abnormalities in PE, pneumonia, and COPD using perfusion MRI and V-P scan showed a high intra-modality agreement that was higher than the inter-modality agreement. Further studies are now needed in patients presenting with possible PE to evaluate the sensitivity and specificity of the method. (Less)

To compare experimental transverse relaxivities of iron oxide nanocrystals (IONC) as a function of clustering and magnetic field strength with different theoretical model predictions.Well-defined IONC clusters in nanoemulsions (NEs) of which both size and IONC loading could be judiciously tuned were developed. Transverse relaxivities were measured as a function of NE size and IONC loading at 20 and 300 MHz and compared with four theoretical model predictions. Polydispersity of the NEs was measured and taken into account in the theoretical calculations.Experimentally observed relaxivities were in between theoretical predictions from the fast diffusion regime and the static dephasing regimen. NE polydispersity significantly affected the theoretical T2 relaxivity. The effect of both the number of IONCs inside each droplet as well as the radius of the droplet itself was correctly described by a fast diffusion loose aggregate model, while the effect of increased magnetic field was in agreement with a static dephasing model.The results suggest that both fast diffusion, originating from bulk water, and static dephasing phenomena, perhaps originating from water associated with the NE, play a role in transverse relaxivities of IONC aggregates. The developed aggregate system represents a powerful tool to further study these phenomena.

There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 761 and 1762 days posttreatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p,0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p,0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+ mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy. (c) 2014 Rygh et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Astrocytes are intimately involved in both glutamate and γ-aminobutric acid (GABA) synthesis, and ischemia-induced disruption of normal neuroastrocytic interactions may have important implications for neuronal survival. The effects of middle cerebral artery occlusion (MCAO) on neuronal and astrocytic intermediary metabolism were studied in rats 30, 60, 120, and 240 minutes after MCAO using in vivo injection of [1-13C]glucose and [1,2-13C]acetate combined with ex vivo13C magnetic resonance spectroscopy and high-performance liquid chromatography analysis of the ischemic core (lateral caudoputamen and lower parietal cortex) and penumbra (upper frontoparietal cortex). In the ischemic core, both neuronal and astrocytic metabolism were impaired from 30 minutes MCAO. There was a continuous loss of glutamate from glutamatergic neurons that was not replaced as neuronal glucose metabolism and use of astrocytic precursors gradually declined. In GABAergic neurons astrocytic precursors were not used in GABA synthesis at any time after MCAO, and neuronal glucose metabolism and GABA-shunt activity declined with time. No flux through the tricarboxylic acid cycle was found in GABAergic neurons at 240 minutes MCAO, indicating neuronal death. In the penumbra, the neurotransmitter pool of glutamate coming from astrocytic glutamine was preserved while neuronal metabolism progressively declined, implying that glutamine contributed significantly to glutamate excitotoxicity. In GABAergic neurons, astrocytic precursors were used to a limited extent during the initial 120 minutes, and tricarboxylic acid cycle activity was continued for 240 minutes. The present study showed the paradoxical role that astrocytes play in neuronal survival in ischemia, and changes in the use of astrocytic precursors appeared to contribute significantly to neuronal death, albeit through different mechanisms in glutamatergic and GABAergic neurons.

Recent studies have demonstrated the potential of dynamic contrast-enhanced magnetic resonance imaging (MRI) describing pulmonary perfusion. However, breathing motion, susceptibility artifacts, and a low signal-to-noise ratio (SNR) make automatic pixel-by-pixel analysis difficult. In the present work, we propose a novel method to compensate for breathing motion. In order to test the feasibility of this method, we enrolled 53 patients with pulmonary embolism (N = 24), chronic obstructive pulmonary disease (COPD) (N = 14), and acute pneumonia (N = 15). A crucial part of the method, an automatic diaphragm detection algorithm, was evaluated in all 53 patients by two independent observers. The accuracy of the method to detect the diaphragm showed a success rate of 92%. Furthermore, a Bayesian noise reduction technique was implemented and tested. This technique significantly reduced the noise level without removing important clinical information. In conclusion, the combination of a motion correction method and a Bayesian noise reduction method offered a rapid, semiautomatic pixel-by-pixel analysis of the lungs with great potential for research and clinical use. J. Magn. Reson. Imaging 2001;13:577–587. © 2001 Wiley-Liss, Inc.

Metastatic involvement of axillary lymph nodes is one of the most important prognostic variables in breast cancer. The aim of our work was to study the value of dynamic contrast-enhanced MR imaging in revealing axillary lymph node metastases from breast cancer. A total of 65 patients with invasive breast cancer treated with axillary lymph node dissection were preoperatively evaluated by MRI. T1-weighted dynamic contrast-enhanced 3D images were acquired using a coil covering the breast and the axilla. The dynamic contrast enhancement, size, and morphology of the axillary lymph nodes were registered. Histopathological examination revealed axillary lymph node metastases in 24 patients. When using a signal intensity increase in the lymph nodes of > 100 % during the first postcontrast image as a threshold for malignancy, 57 of 65 patients were correctly classified (sensitivity 83 %, specificity 90 %, accuracy 88 %). These results were not improved when lymph node size and morphology were used as additional criteria. Axillary lymph nodes can be evaluated as a part of an MR-mammography study without substantial increase in examination time, and provide the surgeon with knowledge about the localization of possible metastatic lymph nodes.

RATIONALE AND OBJECTIVES: To establish a pig model suitable for imitating pulmonary emboli to facilitate research in the diagnosis of pulmonary embolism. METHODS: Thirteen animals were anesthetized, mechanically ventilated, and subjected to pulmonary artery catheterization initiated from the right external jugular vein. With the use of a Swan-Ganz catheter, repetitive occlusion/reperfusion maneuvers were done at different locations of the pulmonary arterial tree. Conventional pulmonary angiography, MR angiography, and perfusion MR imaging were performed. RESULTS: The model remained hemodynamically stable throughout the 13 experiments, without any significant difference between the blood pressure measurements at the start and at the end of the right-heart and pulmonary artery catheterizations. In each of the nine animal experiments that investigated MR imaging, four of four using perfusion MR imaging (proximal and distal occlusions) and five of five using MR angiography (larger pulmonary artery occlusions), all repeated pulmonary artery occlusions were successfully performed (reproducibility of 100%). CONCLUSIONS: The closed-chest pulmonary artery occlusion/reperfusion model in the pig allowed repetitive, controlled imitations of pulmonary emboli at different levels of the pulmonary artery in the same experiment. MR angiography and perfusion MR imaging were adequate to detect the pulmonary artery occlusions and the nonperfused lung regions, respectively. The model may be a helpful tool for future research in this field. (Less)

In order to address the question whether lactate in blood can serve as a precursor for cerebral metabolites, fully awake rats were injected intravenously with [U-13C]lactate or [U-13C]glucose followed 15 min later by decapitation. Incorporation of label from [U-13C]glucose was seen mainly in glutamate, GABA, glutamine, aspartate, alanine and lactate. More label was found in glutamate than glutamine, underscoring the predominantly neuronal metabolism of pyruvate from [U-13C]glucose. It was estimated that the neuronal metabolism of acetyl CoA from glucose accounts for at least 66% and the glial for no more than 34% of the total glucose consumption. When [U-13C]lactate was the precursor, label incorporation was similar to that observed from [U-13C]glucose, but much reduced. Plasma analysis revealed the presence of approximately equal amounts of [1,2,3-13C]- and [1,2-13C]glucose, showing gluconeogenesis from [U-13C]lactate. It was thus possible that the labeling seen in the cerebral amino acids originated from labeled glucose, not [U-13C]lactate. However, the presence of significantly more label in [U-13C]- than in [2,3-13C]alanine demonstrated that [U-13C]lactate did indeed cross the blood-brain barrier, and was metabolized further in the brain. Furthermore, contributions from pyruvate carboxylase (glial enzyme) were detectable in glutamine, glutamate and GABA, and were comparatively more pronounced in the glucose group. This indicated that relatively more pyruvate from lactate than glucose was metabolized in neurons. Surprisingly, the same amount of lactate was synthesized via the tricarboxylic acid cycle in both groups, indicating transfer of neurotransmitters from the neuronal to the astrocytic compartment, as previous studies have shown that this lactate is synthesized primarily in astrocytes. Taking into consideration that astrocytes take up glutamate more avidly than GABA, it is conceivable that neuronal lactate metabolism was more prominent in glutamatergic neurons.

The present paper reports our own experience with MR perfusion imaging and gives an overview of contrast-enhanced pulmonary MR perfusion imaging, MR angiography, and ventilation MR imaging using hyperpolarized gases or oxygen as contrast agent. These methods are discussed within the context of their possible role in the diagnosis of pulmonary diseases, particularly embolism and emphysema.

The purpose of this study was to evaluate whether the detection of choline-containing compounds in in vivo (1)H magnetic resonance spectroscopy (MRS) of breast lesions is specific for carcinomas, whether a choline peak in in vivo (1)H MRS can be detected under physiological conditions of increased metabolism in breast parenchyma, and whether analysis of lipid signals can differentiate between various breast lesions and tissues. Forty patients and volunteers were examined with in vivo (1)H MR spectroscopy. Three spectra with identical localization but increasing echo times were obtained. Choline-containing compounds were detected in 9 of 11 carcinomas and in 2 of 11 benign lesions. A choline signal was also detected in five of seven volunteers who were breast-feeding at the time of examination, demonstrating that choline compounds can be detected by in vivo (1)H MRS in breast tissue under physiological conditions. Analysis of lipid signals did not contribute to differentiation between various breast lesions and tissues. J. Magn. Reson. Imaging 1999;10:159-164.

A simple two-compartment model was used to study the effects of water exchange on the signal produced by an inversion recovery prepared rapid gradient-echo sequence during the first passage of a low dose of an intravascular contrast agent. Water exchange at intermediate rates of exchange (1-10 Hz) between the vascular and extravascular spaces caused the form of the signal changes during the first pass to be dependent on both the fractional sizes of the vascular and extravascular compartments and on the exchange rate. Unless the effects of exchange are minimized by using a very short inversion time, parameters such as the peak height and area under the curve will be affected by regional and/or pathological variations in the exchange rate and the size of the vascular fraction. The mean transit time (MTT) is, however, less affected by water exchange. Experimental first-pass data produced by intravascular low-dose injections of iron oxide particles were studied in five pigs at 0.5 T. The MTT as derived from the first-pass curves, without deconvolution with the arterial input function, was well correlated with the myocardial blood flow (MBF) as measured using radioactive microspheres (r = 0.70, n = 52, P < 0.01). Other first-pass parameters such as the peak height or area under the curve exhibited either a poorer, or no, correlation with the MBF. The data suggest that the MTT of the first pass of an intravascular contrast agent may be a robust, quantitative method for assessing myocardial blood flow in patients.

The neuroprotective effect of post-ischemic treatment with the novel, highly water-soluble, glutamate AMPA receptor antagonist YM872 was evaluated by using MR imaging and histopathology of rats subjected to permanent MCA occlusion. Two treatment groups with continuous i.v. infusion of 20 mg kg−1 h−1 YM872 during either the first 4 h or first 24 h after MCA occlusion, called 4 h YM872 treatment group (n=9) and 24 h YM872 treatment group (n=8) respectively, were compared to a control group (n=8). The main end-point was T2 weighted MR imaging and histopathology 24 h after MCA occlusion. Also the time evolution of the ischemic tissue damage was studied by diffusion weighted MR imaging 4 1 2 and 24 h after MCA occlusion. The volume of ischemic tissue damage as assessed by diffusion weighted MR imaging 4 1 2 h after MCA occlusion was significantly smaller in both YM872 treatment groups (99±52 mm3 and 102±44 mm3 compared to 186±72 mm3 in the control group, ±S.D. and p=0.008). The infarct volume as assessed by T2 weighted MR imaging 24 h after MCA occlusion was significantly smaller only in the 24 h YM872 treatment group (262±57 mm3 compared to 366±49 mm3 in the control group, ±S.D. and p=0.01) while the infarct volume in the 4 h YM872 treatment group (357±88 mm3) was similar to the control group. YM872 treatment significantly reduced the infarct volume 24 h after MCA occlusion when the drug was administered as continuous infusion during the 24-h observation period.

STUDY DESIGN: A single-blinded, randomized treatment study with a follow-up period of 6 months. OBJECTIVE: To study the long-term consequences of whiplash neck sprain injuries in patients treated with two different regimes during the first 14 days after the car accident. Patients in the first group were encouraged to act as usual, i.e., continue to engage in their normal, pre-injury activities; that group was compared with another group of patients who were given time off from work and who were immobilized using a soft neck collar. The end point of the comparison was the evaluation of subjective symptoms 6 months after the accident. SUMMARY OF BACKGROUND DATA: Few randomized treatment studies have been performed to evaluate the clinical outcome for patients with neck sprain. METHOD: Patients who participated in the study were recruited from the Emergency Clinic at the University Hospital in Trondheim, Norway. The study group included 201 patients (47% of the study group) with neck sprain that resulted from a car accident. Neck and shoulder movements and subjective symptoms, which were assessed using several different measurements, were assessed during the follow-up period. RESULTS: There was a significant reduction of symptoms from the time of intake to 24 weeks after the treatment period in both groups. There was a significantly better outcome for the act-as-usual group in terms of subjective symptoms, including pain localization, pain during daily activities, neck stiffness, memory, and concentration, and in terms of visual analog scale measurements of neck pain and headache. CONCLUSIONS: The outcome was better for patients who were encouraged to continue engaging in their normal, pre-injury activities as usual than for patients who took sick leave from work and who were immobilized during the first 14 days after the neck sprain injury. Language: en

Pyruvate recycling is a well established pathway in the liver, but in the brain, the cellular localization of pyruvate recycling remains controversial and its physiological significance is unknown. In cultured cortical astrocytes, pyruvate formed from [U-13C]glutamate was shown to re-enter the TCA cycle after conversion to acetyl-CoA, as demonstrated by the labelling patterns in aspartate C-2 and C-3, lactate C-2, and glutamate C-4, which provides evidence for pyruvate recycling in astrocytes. This finding is in agreement with previous studies of astrocytic cultures, in which pyruvate recycling has been described from [U-13C]glutamine, in the presence of glutamate, and from [U-13C]aspartate. Pyruvate recycling in brain was studied in fasted rats receiving either an intraperitoneal or a subcutaneous injection of [1,2-13C]acetate followed by decapitation 30 min later. Extracts of cortical tissue were analysed with 13C-NMR spectroscopy and total amounts of amino acids quantified by HPLC. Plasma extracts were analysed with 1H- and 13C-NMR spectroscopy, and showed a significantly larger amount of [1,2-13C]acetate in the intraperitoneal group compared to the subcutaneous group. Furthermore, a small amount of label was detected in glucose in both groups. In the subcutaneously injected rats, [4-13C]glutamate and [2-13C]GABA were less enriched than plasma glucose, which might have been the precursor. In the intraperitoneally injected rats, however, pyruvate formation from [1,2-13C]acetate, and re-entry of this pyruvate into the TCA cycle was demonstrated by the presence of greater 13C enrichment in [4-13C]glutamate and [4-13C]glutamine compared to the subcutaneous group, probably resulting from the significantly higher [1,2-13C]acetate concentration in brain and plasma.

A susceptibility contrast agent which does not pass into the extra-cellular space was used to study the effect of changes in the relative cerebral blood volume (CBV) on the haemodynamic response to anoxia, for both normal and ischaemic brain tissue, in a rat model of acute focal ischaemia. In non-ischaemic tissue a strong CBV component was observed in the haemodynamic response, both during and after anoxia. During anoxia the change in the CBV of the non-ischaemic tissue was estimated to be 40% in the caudate putamen and 70% in the frontal-parietal cortex. For severely ischaemic tissue (ischaemic caudate putamen) there was no change in the CBV during anoxia while in areas of moderate ischaemia (ischaemic frontal parietal cortex) a change of 20% was observed. The effect of the contrast agent on spin-echo images was consistent with a small reduction in the microvascular blood volume of the ischaemic tissue.

PURPOSE: To evaluate the feasibility of magnetic resonance (MR) perfusion imaging in the human lung to help detect perfusion defects distal to suspected pulmonary embolism. MATERIALS AND METHODS: Seven patients suspected of having pulmonary embolism first underwent ventilation-perfusion lung scintigraphy followed by MR perfusion imaging with rapid acquisition of two sets of dynamic images in the coronal and transaxial planes. A bolus of 0.05 mmol per kilogram of body weight gadopentetate dimeglumine or gadodiamide was administered. Single images obtained in each section that showed peak signal intensity from the first passage of contrast material were evaluated visually. An analysis of change in signal intensity over time was performed both on a pixel-by-pixel basis and in selected regions of interest. RESULTS: In the seven patients, a total of 18 regions of lung tissue with perfusion defects were shown on the ventilation-perfusion scans. In 16 of these regions, MR perfusion images showed a reduced peak signal intensity during first passage of the contrast agent. Perfusion defects could be detected in both the coronal and the transaxial planes on MR perfusion images. CONCLUSION: MR perfusion imaging was feasible for detection of perfusion defects distal to a pulmonary embolism.