A Comparison of Iron Oxide Particles and Silica Particles for Tracking Organ Recellularization.

Reseeding of decellularized organ scaffolds with a patient's own cells has promise for eliminating graft versus host disease. This study investigated whether ultrasound imaging or magnetic resonance imaging (MRI) can track the reseeding of murine liver scaffolds with silica-labeled or iron-labeled liver hepatocytes. Mesoporous silica particles were created using the Stöber method, loaded with Alexa Flour 647 fluorophore, and conjugated with protamine sulfate, glutamine, and glycine. Fluorescent iron oxide particles were obtained from a commercial source. Liver cells from donor mice were loaded with the silica particles or iron oxide particles. Donor livers were decellularized and reperfused with silica-labeled or iron-labeled cells. The reseeded livers were longitudinally analyzed with ultrasound imaging and MRI. Liver biopsies were imaged with confocal microscopy and scanning electron microscopy. Ultrasound imaging had a detection limit of 0.28 mg/mL, while MRI had a lower detection limit of 0.08 mg/mL based on particle weight. The silica-loaded cells proliferated at a slower rate compared to iron-loaded cells. Ultrasound imaging, MRI, and confocal microscopy underestimated cell numbers relative to scanning electron microscopy. Ultrasound imaging had the greatest underestimation due to coarse resolution compared to the other imaging modalities. Despite this underestimation, both ultrasound imaging and MRI successfully tracked the longitudinal recellularization of liver scaffolds.

(1) H magnetic resonance spectroscopy of neurodegeneration in a mouse model of niemann-pick type C1 disease.

PURPOSE: To evaluate brain metabolite levels as in vivo indicators of disease progression in a widely studied mouse model of Niemann-Pick type C1 (NPC1) disease with quantitative (1) H magnetic resonance spectroscopy (MRS). MATERIALS AND METHODS: Single voxel MRS experiments were carried out in vivo in a mouse model of NPC1 disease and in control mice in two brain regions (central and posterior) at two timepoints (presymptomatic and endstage) to examine changes in metabolite levels in NPC1 disease. Concentrations of nine metabolites were quantified by fitting a simulated basis set of metabolite signals to the acquired spectra. RESULTS: The only differences found in brain metabolite levels between NPC1 disease model and control mice were increased myo-inositol and decreased taurine in the posterior region of the brain at the endstage of the disease. Metabolite changes reported in past clinical MRS studies of NPC disease were not found in the current study of the mouse model. CONCLUSIONS: The (1) H spectra obtained from NPC1 mice and control mice were very similar, even at endstages of the disease. Although differences in two metabolites associated with neurodegenerative diseases were found and could inform future studies of the disease model, it appears that MRS in this mouse model of NPC1 disease does not have the sensitivity desired for a biomarker.

In vivo assessment of neurodegeneration in Niemann-Pick type C mice by quantitative T2 mapping and diffusion tensor imaging.

PURPOSE: To quantitatively and noninvasively assess neurological disease progression in a mouse model of Niemann-Pick type C (NPC) disease by measuring white matter status with magnetic resonance imaging (MRI) techniques of T2 mapping and diffusion tensor imaging (DTI). MATERIALS AND METHODS: Quantitative T2 and DTI experiments were performed in vivo in NPC disease model and control mice at three timepoints to quantify differences and changes in white matter with measurements of T2 relaxation and DTI parameters. Histological staining for myelin content was also performed at two timepoints to compare with the MRI findings. RESULTS: The results of the T2 and DTI measurements show significant differences in white matter areas of the brain in the NPC disease model compared to control mice at several timepoints, and were seen to change over time in both groups. CONCLUSION: The findings of this study suggest that quantitative MRI measurements may be suitable in vivo biomarkers of disease status for future studies of NPC disease models. The changes in white matter measurements between timepoints in both control and NPC disease groups suggest that white matter structures continue to change and develop over time in the NPC model and can be tracked with MRI techniques.

Age-Related Regional Network Covariance of Magnetic Resonance Imaging Gray Matter in the Rat.

Healthy human aging has been associated with brain atrophy in prefrontal and selective temporal regions, but reductions in other brain areas have been observed. We previously found regional covariance patterns of gray matter with magnetic resonance imaging (MRI) in healthy humans and rhesus macaques, using multivariate network Scaled Subprofile Model (SSM) analysis and voxel-based morphometry (VBM), supporting aging effects including in prefrontal and temporal cortices. This approach has yet to be applied to neuroimaging in rodent models of aging. We investigated 7.0T MRI gray matter covariance in 10 young and 10 aged adult male Fischer 344 rats to identify, using SSM VBM, the age-related regional network gray matter covariance pattern in the rodent. SSM VBM identified a regional pattern that distinguished young from aged rats, characterized by reductions in prefrontal, temporal association/perirhinal, and cerebellar areas with relative increases in somatosensory, thalamic, midbrain, and hippocampal regions. Greater expression of the age-related MRI gray matter pattern was associated with poorer spatial learning in the age groups combined. Aging in the rat is characterized by a regional network pattern of gray matter reductions corresponding to aging effects previously observed in humans and non-human primates. SSM MRI network analyses can advance translational aging neuroscience research, extending from human to small animal models, with potential for evaluating mechanisms and interventions for cognitive aging.

Quantitative magnetic resonance imaging of brain atrophy in a mouse model of Niemann-Pick type C disease.

In vivo magnetic resonance imaging (MRI) was used to investigate regional and global brain atrophy in the neurodegenerative Niemann Pick Type C1 (NPC1) disease mouse model. Imaging experiments were conducted with the most commonly studied mouse model of NPC1 disease at early and late disease states. High-resolution in vivo images were acquired at early and late stages of the disease and analyzed with atlas-based registration to obtain measurements of twenty brain region volumes. A two-way ANOVA analysis indicated eighteen of these regions were different due to genotype and thirteen showed a significant interaction with age and genotype. The ability to measure in vivo neurodegeneration evidenced by brain atrophy adds to the ability to monitor disease progression and treatment response in the mouse model.

Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI.

PURPOSE: We optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis. PROCEDURES: A CEST-FISP MRI protocol was used to image a flank SKOV3 tumor model. Bloch fitting modified to include the direct estimation of pH was developed to generate parametric maps of tumor pHe in the SKOV3 tumor model, a patient with high-grade invasive ductal carcinoma, and a patient with metastatic ovarian cancer. The acidoCEST MRI results of the patient with metastatic ovarian cancer were compared with DCE MRI and histopathology. RESULTS: The pHe maps of a flank model showed pHe measurements between 6.4 and 7.4, which matched with the expected tumor pHe range from past acidoCEST MRI studies in flank tumors. In the patient with metastatic ovarian cancer, the average pHe value of three adjacent tumors was 6.58, and the most reliable pHe measurements were obtained from the right posterior tumor, which favorably compared with DCE MRI and histopathological results. The average pHe of the kidney showed an average pHe of 6.73 units. The patient with high-grade invasive ductal carcinoma failed to accumulate sufficient agent to generate pHe measurements. CONCLUSIONS: Optimized acidoCEST MRI generated pHe measurements in a flank tumor model and could be translated to the clinic to assess a patient with metastatic ovarian cancer.

Design and optimization of pulsed Chemical Exchange Saturation Transfer MRI using a multiobjective genetic algorithm.

Pulsed Chemical Exchange Saturation Transfer (CEST) MRI experimental parameters and RF saturation pulse shapes were optimized using a multiobjective genetic algorithm. The optimization was carried out for RF saturation duty cycles of 50% and 90%, and results were compared to continuous wave saturation and Gaussian waveform. In both simulation and phantom experiments, continuous wave saturation performed the best, followed by parameters and shapes optimized by the genetic algorithm and then followed by Gaussian waveform. We have successfully demonstrated that the genetic algorithm is able to optimize pulse CEST parameters and that the results are translatable to clinical scanners.

Effects of the iron oxide nanoparticle Molday ION Rhodamine B on the viability and regenerative function of neural stem cells: relevance to clinical translation.

An essential component of developing successful neural stem cell (NSC)-based therapies involves the establishment of methodologies to noninvasively monitor grafted NSCs within brain tissues in real time. In this context, ex vivo labeling with ultrasmall superparamagnetic iron oxide (USPIO) particles has been shown to enable efficient tracking of transplanted NSCs via magnetic resonance imaging (MRI). However, whether and how USPIO labeling affects the intrinsic biology of NSCs is not thoroughly understood, and remains an active area of investigation. Here, we perform a comprehensive examination of rat NSC survival and regenerative function upon labeling with the USPIO, Molday ION Rhodamine B (MIRB), which allows for dual magnetic resonance and optical imaging. After optimization of labeling efficiency, two specific doses of MIRB (20 and 50 µg/mL) were chosen and were followed for the rest of the study. We observed that both MIRB doses supported the robust detection of NSCs, over an extended period of time in vitro and in vivo after transplantation into the striata of host rats, using MRI and post hoc fluorescence imaging. Both in culture and after neural transplantation, the higher 50 µg/mL MIRB dose significantly reduced the survival, proliferation, and differentiation rate of the NSCs. Interestingly, although the lower 20 µg/mL MIRB labeling did not produce overtly negative effects, it increased the proliferation and glial differentiation of the NSCs. Additionally, application of this dose also changed the morphological characteristics of neurons and glia produced after NSC differentiation. Importantly, the transplantation of NSCs labeled with either of the two MIRB doses upregulated the immune response in recipient animals. In particular, in animals receiving the 50 µg/mL MIRB-labeled NSCs, this immune response consisted of an increased number of CD68(+)-activated microglia, which appeared to have phagocytosed MIRB particles and cells contributing to an exaggerated MRI signal dropout in the animals. Overall, these results indicate that although USPIO particles, such as MIRB, may have advantageous labeling and magnetic resonance-sensitive features for NSC tracking, a further examination of their effects might be necessary before they can be used in clinical scenarios of cell-based transplantation.