Mn-enhanced Magnetic Resonance Imaging Research Articles

Noninvasive Assessment of Kidney Injury by Combining Structure and Function Using Artificial Intelligence-Based Manganese-Enhanced Magnetic Resonance Imaging.

Contrast-enhanced magnetic resonance imaging (MRI) is seriously limited in kidney injury detection due to the nephrotoxicity of clinically used gadolinium-based contrast agents. Herein, we propose a noninvasive method for the assessment of kidney injury by combining structure and function information based on manganese (Mn)-enhanced MRI for the first time. As a proof of concept, the Mn-melanin nanoprobe with good biocompatibility and excellent T1 relaxivity is applied in MRI of a unilateral ureteral obstruction mice model. The abundant renal structure and function information is obtained through qualitative and quantitative analysis of MR images, and a brand new comprehensive assessment framework is proposed to precisely identify the degree of kidney injury successfully. Our study demonstrates that Mn-enhanced MRI is a promising approach for the highly sensitive and biosafe assessment of kidney injury in vivo.

Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats

Neuropathic pain induced by a nerve injury can lead to chronic pain. Recent studies have reported hyperactive neural activities in the nociceptive-related area of the brain as a result of chronic pain. Although cerebral activities associated with hyperalgesia and allodynia in chronic pain models are difficult to represent with functional imaging techniques, advances in manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) could facilitate the visualization of the activation of pain-specific neural responses in the cerebral cortex. In order to investigate the alleviation of pain nociception by mammalian target of rapamycin (mTOR) modulation, we observed cerebrocortical excitability changes and compared regional Mn2+ enhancement after mTOR inhibition. At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Therein, signal intensities of the insular cortex (IC), primary somatosensory cortex of the hind limb region, motor cortex 1/2, and anterior cingulate cortex regions were significantly reduced after application of mTOR inhibitors (Torin1 and XL388). Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats.

Neural Plastic Changes in the Subcortical Auditory Neural Pathway after Single-Sided Deafness in Adult Mice: A MEMRI Study.

Single-sided deafness (SSD) induces cortical neural plastic changes according to duration of deafness. However, it is still unclear how the auditory cortical changes accompany the subcortical neural changes. The present study aimed to find the neural plastic changes in the cortical and subcortical auditory system following adult-onset single-sided deafness (SSD) using Mn-enhanced magnetic resonance imaging (MEMRI). B57BL/6 mice (postnatal 8-week-old) were divided into three groups: the SSD-4-week group (postnatal 12-week-old, n = 11), the SSD-8-week group (postnatal 16-week-old, n = 11), and a normal-hearing control group (postnatal 8-week-old, n = 9). The left cochlea was ablated in the SSD groups. White Gaussian noise was delivered for 24 h before MEMRI acquisition. T1-weighted MRI data were analyzed from the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus (LL), inferior colliculus (IC), medial geniculate body (MG), and auditory cortex (AC). The differences in relative Mn2+-enhanced signal intensities (Mn2+SI) and laterality were analyzed between the groups. Four weeks after the SSD procedure, the ipsilateral side of the SSD showed significantly lower Mn2+SI in the CN than the control group. On the other hand, the contralateral side of the SSD demonstrated significantly lower Mn2+SI in the SOC, LL, and IC. These decreased Mn2+SI values were partially recovered at 8 weeks after the SSD procedure. The interaural Mn2+SI differences representing the interaural dominance were highest in CN and then became less prominently higher in the auditory neural system. The SSD-8-week group still showed interaural differences in the CN, LL, and IC. In contrast, the MG and AC did not show any significant intergroup or interaural differences in Mn2+SI. In conclusion, subcortical auditory neural activities were decreased after SSD, and the interaural differences were diluted in the higher auditory nervous system. These findings were attenuated with time. Subcortical auditory neural changes after SSD may contribute to the change in tinnitus severity and the outcomes of cochlear implantation in SSD patients.

Manganese-Enhanced Magnetic Resonance Imaging for Detection and Characterization of Colorectal Cancers.

Here, we investigated the diagnostic performance of manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) in colorectal cancer (CRC). The ability of CRC cell lines SW620 and SW480 to uptake Mn was evaluated and compared with a normal colon cell using MEMRI. Subcutaneous xenografts in nude mice underwent MRI examination at tumor sizes of 5, 10, and 15 mm. Contrast enhancement was compared between gadolinium (Gd)- and Mn-enhanced MRI. SW620 and SW480 cell lines took up more Mn2+ than normal cells, resulting in 4.5 and 2 times greater T1 value shortening than normal cell using in vitro MEMRI (P < .001). Most xenografts (17/23) enhanced markedly on MEMRI. A heterogeneous enhancement pattern invariably noted whether Mn or Gd agents were administered, but tumors imaged using MEMRI showed a greater degree of enhancement with a larger extent of enhanced area than those imaged using Gd-enhanced MRI. The numbers of markedly Mn-enhanced cases were more in the 5-mm-size tumor group than in 10- or 15-mm-size tumor groups. Overall, MEMRI could enhance CRCs and it showed potential in detecting early small lesions and markedly enhancing tumors that had minimal Gd enhancement.

Longitudinal Assessments of Normal and Perilesional Tissues in Focal Brain Ischemia and Partial Optic Nerve Injury with Manganese-enhanced MRI

Although manganese (Mn) can enhance brain tissues for improving magnetic resonance imaging (MRI) assessments, the underlying neural mechanisms of Mn detection remain unclear. In this study, we used Mn-enhanced MRI to test the hypothesis that different Mn entry routes and spatiotemporal Mn distributions can reflect different mechanisms of neural circuitry and neurodegeneration in normal and injured brains. Upon systemic administration, exogenous Mn exhibited varying transport rates and continuous redistribution across healthy rodent brain nuclei over a 2-week timeframe, whereas in rodents following photothrombotic cortical injury, transient middle cerebral artery occlusion, or neonatal hypoxic-ischemic brain injury, Mn preferentially accumulated in perilesional tissues expressing gliosis or oxidative stress within days. Intravitreal Mn administration to healthy rodents not only allowed tracing of primary visual pathways, but also enhanced the hippocampus and medial amygdala within a day, whereas partial transection of the optic nerve led to MRI detection of degrading anterograde Mn transport at the primary injury site and the perilesional tissues secondarily over 6 weeks. Taken together, our results indicate the different Mn transport dynamics across widespread projections in normal and diseased brains. Particularly, perilesional brain tissues may attract abnormal Mn accumulation and gradually reduce anterograde Mn transport via specific Mn entry routes.

In Vivo Mn-Enhanced MRI for Early Tumor Detection and Growth Rate Analysis in a Mouse Medulloblastoma Model

Mouse models have increased our understanding of the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor that often forms in the cerebellum. A major goal of ongoing research is to better understand the early stages of tumorigenesis and to establish the genetic and environmental changes that underlie MB initiation and growth. However, studies of MB progression in mouse models are difficult due to the heterogeneity of tumor onset times and growth patterns and the lack of clinical symptoms at early stages. Magnetic resonance imaging (MRI) is critical for noninvasive, longitudinal, three-dimensional (3D) brain tumor imaging in the clinic but is limited in resolution and sensitivity for imaging early MBs in mice. In this study, high-resolution (100 μm in 2 hours) and high-throughput (150 μm in 15 minutes) manganese-enhanced MRI (MEMRI) protocols were optimized for early detection and monitoring of MBs in a Patched-1 (Ptch1) conditional knockout (CKO) model. The high tissue contrast obtained with MEMRI revealed detailed cerebellar morphology and enabled detection of MBs over a wide range of stages including pretumoral lesions as early as 2 to 3 weeks postnatal with volumes close to 0.1 mm3. Furthermore, longitudinal MEMRI allowed noninvasive monitoring of tumors and demonstrated that lesions within and between individuals have different tumorigenic potentials. 3D volumetric studies allowed quantitative analysis of MB tumor morphology and growth rates in individual Ptch1-CKO mice. These results show that MEMRI provides a powerful method for early in vivo detection and longitudinal imaging of MB progression in the mouse brain.

Manganese-enhanced magnetic resonance imaging for early detection and characterization of breast cancers.

Very early cancer detection is the key to improving cure. Our objective was to investigate manganese (Mn)-enhanced magnetic resonance imaging (MRI) for very early detection and characterization of breast cancers. Eighteen NOD scid gamma mice were inoculated with MCF7, MDA, and LM2 breast cancer cells and imaged periodically on a 3 T scanner beginning on day 6. T1-weighted imaging and T1 measurements were performed before and 24 hours after administering MnCl2. At the last imaging session, Gd-DTPA was administered and tumors were excised for histology (hematoxylin-eosin and CD34 staining). All mice, except for two inoculated with MCF7 cells, developed tumors. Tumors enhanced uniformly on Mn and showed clear borders. Early small tumors (≤ 5 mm3) demonstrated the greatest enhancement with a relative R1 (1/T1) change of 1.57 ± 0.13. R1 increases correlated with tumor size (r = -.34, p = .04). Differences in R1 increases among the three tumor subtypes were most evident in early tumors. Histology confirmed uniform cancer cell distribution within tumor masses and vasculature in the periphery, which was consistent with rim-like enhancement on Gd-DTPA. Mn-enhanced MRI is a promising approach for detecting very small breast cancers in vivo and may be valuable for very early cancer detection.

Manganese‐52 positron emission tomography tracer characterization and initial results in phantoms and in vivo

Manganese(II) is employed as a contrast agent with magnetic resonance imaging (MRI) for study of neuronal activation in rats and mice. However, at the concentrations required for MRI, Mn may induce pharmacological or toxic effects. Positron emission tomography (PET) imaging of (52)MnCl2 at tracer doses has the potential to allow similar Mn studies as manganese-enhanced MRI while providing quantitative results and avoiding toxic effects. In this work, (52)MnCl2 is produced and characterized as a PET tracer in phantoms and in rats. (52)MnCl2 was produced by proton irradiation of natural Cr foil and separated by column chromatography. Images were acquired on a Siemens Focus 120 small animal PET scanner. Phantom images were acquired to assess uniformity, resolution, cascade background correction, and count rate linearity. Images of rats were also acquired after systemic and intracerebroventricular (ICV) administration of (52)MnCl2 to investigate Mn(II) distribution in vivo. Irradiation yield was 74.6 ± 8.5 kBq/μA min (52)Mn at end of bombardment with initial specific activity of at least 3.5 MBq/nmol. (52)Mn PET images show similar uniformity and resolution to (18)F. (18)F based detector efficiency normalization is adequate for (52)Mn imaging. Subtraction of a rescaled random events distribution from sinogram data is effective for cascade correction of (52)Mn PET data. After systemic injection, (52)Mn appears in structures throughout the body of rats, including bones, liver, intestines, and the pituitary gland, but does not appear detectably throughout the brain. After ICV injection, (52)Mn remains in the brain and spinal cord. (52)Mn is a promising tracer for small animal PET imaging, yielding image quality comparable to (18)F. Potential applications include studies similar to Mn-enhanced neuronal MRI, and in other organ systems including bones, spinal cord, and the digestive tract.

Ultrashort Echo Time for Improved Positive-Contrast Manganese-Enhanced MRI of Cancer

ObjectiveManganese (Mn) is a positive magnetic resonance imaging (MRI) contrast agent that has been used to obtain physiological, biochemical, and molecular biological information. There is great interest to broaden its applications, but a major challenge is to increase detection sensitivity. Another challenge is distinguishing regions of Mn-related signal enhancement from background tissue with inherently similar contrast. To overcome these limitations, this study investigates the use of ultrashort echo time (UTE) and subtraction UTE (SubUTE) imaging for more sensitive and specific determination of Mn accumulation.Materials and MethodsSimulations were performed to investigate the feasibility of UTE and SubUTE for Mn-enhanced MRI and to optimize imaging parameters. Phantoms containing aqueous Mn solutions were imaged on a MRI scanner to validate simulations predictions. Breast cancer cells that are very aggressive (MDA-MB-231 and a more aggressive variant LM2) and a less aggressive cell line (MCF7) were labeled with Mn and imaged on MRI. All imaging was performed on a 3 Tesla scanner and compared UTE and SubUTE against conventional T 1-weighted spoiled gradient echo (SPGR) imaging.ResultsSimulations and phantom imaging demonstrated that UTE and SubUTE provided sustained and linearly increasing positive contrast over a wide range of Mn concentrations, whereas conventional SPGR displayed signal plateau and eventual decrease. Higher flip angles are optimal for imaging higher Mn concentrations. Breast cancer cell imaging demonstrated that UTE and SubUTE provided high sensitivity, with SubUTE providing background suppression for improved specificity and eliminating the need for a pre-contrast baseline image. The SubUTE sequence allowed the best distinction of aggressive breast cancer cells.ConclusionsUTE and SubUTE allow more sensitive and specific positive-contrast detection of Mn enhancement. This imaging capability can potentially open many new doors for Mn-enhanced MRI in vascular, cellular, and molecular imaging.

Dynamic manganese‐enhanced magnetic resonance imaging can detect chronic cryoinjury‐induced infarction in pig hearts in vivo

The purpose was to investigate whether MnCl(2) can serve as an MRI contrast agent to detect chronic cryoinjury infarction in pigs in vivo and whether MnCl(2) causes significant hemodynamic disturbances. Hearts were subjected to a topical 2 min cryothermia to establish myocardial infarction (MI). Thereafter GdDTPA-enhanced MRI was performed at 0, 1, 2 and 3 weeks using a 3 T scanner. Four weeks post-cryoinjury the pigs underwent in vivo Mn-enhanced magnetic resonance imaging (MEMRI). MnCl(2) (70 μmol/kg, 14 min) was infused i.v. intermittently (n = 4) or continuously (n = 5) and T(1)-weighted images were acquired every 2 min simultaneously recording heart rate and arterial blood pressure. Either infusion scheme led to an immediate increment in MR signal intensity (SI) within the left ventricular (LV) blood pool and LV normal and cryoinjured myocardium, which reached a maximum at the end of infusion. No significant difference was observed between the normal and cryoinjured myocardium. After infusion termination, SI decreased faster within the LV blood pool and the MI, as compared with the normal myocardium in either group, resulting in significant contrast between the MI and normal tissue (intermittent: 18 ± 7 vs 49 ± 13%, p = 0.002; continuous: 19 ± 8 vs 36 ± 9%, p = 0.004). Infarction sizes were similar in Mn(2+)- and GdDTPA-enhanced images at 4 and 3 weeks post injury, respectively. Thus, in vivo MEMRI differentiated infarcted from normal myocardium in pig hearts subjected to 4-week cryoinjury. Compared with intermittent infusion, continuous infusion minimized hemodynamic fluctuations.

In Vivo Tracking of Transplanted Mononuclear Cells Using Manganese-Enhanced Magnetic Resonance Imaging (MEMRI)

BackgroundTransplantation of mononuclear cells (MNCs) has previously been tested as a method to induce therapeutic angiogenesis to treat limb ischemia in clinical trials. Non-invasive high resolution imaging is required to track the cells and evaluate clinical relevance after cell transplantation. The hypothesis that MRI can provide in vivo detection and long-term observation of MNCs labeled with manganese contrast-agent was investigated in ischemic rat legs.Methods and FindingsThe Mn-labeled MNCs were evaluated using 7-tesla high-field magnetic resonance imaging (MRI). Intramuscular transplanted Mn-labeled MNCs were visualized with MRI for at least 7 and up to 21 days after transplantation in the ischemic leg. The distribution of Mn-labeled MNCs was similar to that of 111In-labeled MNCs measured with single-photon emission computed tomography (SPECT) and DiI-dyed MNCs with fluorescence microscopy. In addition, at 1–2 days after transplantation the volume of the site injected with intact Mn-labeled MNCs was significantly larger than that injected with dead MNCs, although the dead Mn-labeled MNCs were also found for approximately 2 weeks in the ischemic legs. The area covered by CD31-positive cells (as a marker of capillary endothelial cells) in the intact Mn-MNCs implanted site at 43 days was significantly larger than that at a site implanted with dead Mn-MNCs.ConclusionsThe present Mn-enhanced MRI method enabled visualization of the transplanted area with a 150–175 µm in-plane spatial resolution and allowed the migration of labeled-MNCs to be observed for long periods in the same subject. After further optimization, MRI-based Mn-enhanced cell-tracking could be a useful technique for evaluation of cell therapy both in research and clinical applications.

Iterative algorithm for spatial and intensity normalization of MEMRI images. Application to tract-tracing of rat olfactory pathways

Manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) is an emerging technique for visualizing neuronal pathways and mapping brain activity modulation in animal models. Spatial and intensity normalizations of MEMRI images acquired from different subjects are crucial steps as they can influence the results of groupwise analysis. However, no commonly accepted procedure has yet emerged. Here, a normalization method is proposed that performs both spatial and intensity normalizations in a single iterative process without the arbitrary choice of a reference image. Spatial and intensity normalizations benefit from this iterative process. On one hand, spatial normalization increases the accuracy of region of interest (ROI) positioning for intensity normalization. On the other hand, improving the intensity normalization of the different MEMRI images leads to a better-averaged target on which the images are spatially registered. After automatic fast brain segmentation and optimization of the normalization process, this algorithm revealed the presence of Mn up to the posterior entorhinal cortex in a tract-tracing experiment on rat olfactory pathways. Quantitative comparison of registration algorithms showed that a rigid model with anisotropic scaling is the best deformation model for intersubject registration of three-dimensional MEMRI images. Furthermore, intensity normalization errors may occur if the ROI chosen for intensity normalization intersects regions where Mn concentration differs between experimental groups. Our study suggests that cross-comparing Mn-injected animals against a Mn-free group may provide a control to avoid bias introduced by intensity normalization quality. It is essential to optimize spatial and intensity normalization as the detectability of local between-group variations in Mn concentration is directly tied to normalization quality.

Morphological and functional midbrain phenotypes in Fibroblast Growth Factor 17 mutant mice detected by Mn-enhanced MRI

With increasing efforts to develop and utilize mouse models of a variety of neuro-developmental diseases, there is an urgent need for sensitive neuroimaging methods that enable in vivo analysis of subtle alterations in brain anatomy and function in mice. Previous studies have shown that the brains of Fibroblast Growth Factor 17 null mutants (Fgf17−/−) have anatomical abnormalities in the inferior colliculus (IC)—the auditory midbrain—and minor foliation defects in the cerebellum. In addition, changes in the expression domains of several cortical patterning genes were detected, without overt changes in forebrain morphology. Recently, it has also been reported that Fgf17−/− mutants have abnormal vocalization and social behaviors, phenotypes that could reflect molecular changes in the cortex and/or altered auditory processing / perception in these mice. We used manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) to analyze the anatomical phenotype of Fgf17−/− mutants in more detail than achieved previously, detecting changes in IC, cerebellum, olfactory bulb, hypothalamus and frontal cortex. We also used MEMRI to characterize sound-evoked activity patterns, demonstrating a significant reduction of the active IC volume in Fgf17−/− mice. Furthermore, tone-specific (16- and 40-kHz) activity patterns in the IC of Fgf17−/− mice were observed to be largely overlapping, in contrast to the normal pattern, separated along the dorsal-ventral axis. These results demonstrate that Fgf17 plays important roles in both the anatomical and functional development of the auditory midbrain, and show the utility of MEMRI for in vivo analyses of mutant mice with subtle brain defects.

Characterization of cryoinjury-induced infarction with manganese-and gadolinium-enhanced MRI and optical spectroscopy in pig hearts

To investigate progression of cryoinjury in pigs using contrast-enhanced magnetic resonance imaging (MRI) as well as optical spectroscopy and imaging. Cryoinjury was produced in 16 pigs in vivo and investigated using Gd-and Mn-enhanced MRI, optical imaging/spectroscopy and histology in acute and chronic setting up to 4 weeks after the injury. (1) Acute cryoinjury resulted in formation of a lesion with a severely reduced rate of sub-epicardial indocyanine green (intravascular optical flow tracer) passage. In vivo late Gd-enhanced MRI showed a approximately 10 mm deep hypointense area that was surrounded by a hyperintense rim while ex vivo Mn-enhanced MRI (MEMRI) detected a homogenous hypointense zone. Histological and spectroscopic examination revealed embolic erythrocytes blockages within the cryolesion with a thin necrotic rim neighboring the normal myocardium. (2) Chronic 4-week cryoinjury was characterized by uniform Gd-enhancement, whereas MEMRI revealed reduced Mn(2+)enhancement. Histological examination showed replacement of the cryoinjured myocardium by scar tissue. Acute cryoinjury resulted in formation of a no-reflow core embolized by erythrocytes and surrounded by a rim of necrotic tissue. Upon injury progression, the no-reflow zone shrunk and was completely replaced with scar tissue by 4 weeks after injury.