[Show abstract][Hide abstract] ABSTRACT: Liver glycogen represents an important physiological form of energy storage. It plays a key role in the regulation of blood glucose concentrations and dysregulations in hepatic glycogen metabolism are linked to many diseases including diabetes and insulin resistance. In this work we develop, optimize, and validate a non-invasive protocol to measure glycogen levels in isolated perfused mouse livers using Chemical Exchange Saturation Transfer (CEST) NMR spectroscopy. Model glycogen solutions were used to determine optimal saturation pulse parameters which were then applied to intact perfused mouse livers of varying glycogen content. Glycogen measurements from serially acquired CEST Z-spectra of livers were compared with measurements from interleaved natural abundance 13C NMR spectra. Experimental data revealed that CEST-based glycogen measurements were highly correlated with 13C NMR glycogen spectra. Monte Carlo simulations were then used to investigate the inherent (i.e. signal to noise based) errors in the quantification of glycogen with each technique. This revealed that CEST was intrinsically more precise than 13C NMR, although in practice may be prone to other errors induced by variations in experimental conditions. We also observed that the CEST signal from glycogen in liver was significantly less than that observed from identical amounts in solution. Our results demonstrate that CEST provides an accurate, precise, and readily accessible method to non-invasively measure liver glycogen levels and their changes. Furthermore this technique can be used to map glycogen distributions via conventional proton magnetic resonance imaging - a capability universally available on clinical and pre-clinical MRI scanners vs. 13C detection, which is limited to a small fraction of clinical-scale MRI scanners.
[Show abstract][Hide abstract] ABSTRACT: Recent demonstrations of correlated low-frequency MRI signal variations between subregions of the spinal cord at rest in humans, similar to those found in the brain, suggest that such resting-state functional connectivity constitutes a common feature of the intrinsic organization of the entire central nervous system. We report our detection of functional connectivity within the spinal cords of anesthetized squirrel monkeys at rest and show that the strength of connectivity within these networks is altered by the effects of injuries. By quantifying the low-frequency MRI signal correlations between different horns within spinal cord gray matter, we found distinct functional connectivity relationships between the different sensory and motor horns, a pattern that was similar to activation patterns evoked by nociceptive heat or tactile stimulation of digits. All horns within a single spinal segment were functionally connected, with the strongest connectivity occurring between ipsilateral dorsal and ventral horns. Each horn was strongly connected to the same horn on neighboring segments, but this connectivity reduced drastically along the spinal cord. Unilateral injury to the spinal cord significantly weakened the strength of the intrasegment horn-to-horn connectivity only on the injury side and in slices below the lesion. These findings suggest resting-state functional connectivity may be a useful biomarker of functional integrity in injured and recovering spinal cords.
Proceedings of the National Academy of Sciences 04/2015; 112(19). DOI:10.1073/pnas.1424106112 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop and evaluate a new method for detecting calcium deposits using their characteristic magnetic susceptibility effects on magnetic resonance (MR) images at high fields and demonstrate its potential in practice for detecting breast microcalcifications.
Characteristic dipole signatures of calcium deposits were detected in magnetic resonance phase images by computing the cross-correlation between the acquired data and a library of templates containing simulated phase patterns of spherical deposits. The influence of signal-to-noise ratio and various other MR parameters on the results were assessed using simulations and validated experimentally. The method was tested experimentally for detection of calcium fragments within gel phantoms and calcium-like inhomogeneities within chicken tissue at 7 T with optimized MR acquisition parameters. The method was also evaluated for detection of simulated microcalcifications, modeled from biopsy samples of malignant breast cancer, inserted in silico into breast magnetic resonance imaging (MRIs) of healthy subjects at 7 T. For both assessments of calcium fragments in phantoms and biopsy-based simulated microcalcifications in breast MRIs, receiver operator characteristic curve analyses were performed to determine the cross-correlation index cutoff, for achieving optimal sensitivity and specificity, and the area under the curve (AUC), for measuring the method's performance.
The method detected calcium fragments with sizes of 0.14-0.79 mm, 1 mm calcium-like deposits, and simulated microcalcifications with sizes of 0.4-1.0 mm in images with voxel sizes between (0.2 mm)(3) and (0.6 mm)(3). In images acquired at 7 T with voxel sizes of (0.2 mm)(3)-(0.4 mm)(3), calcium fragments (size 0.3-0.4 mm) were detected with a sensitivity, specificity, and AUC of 78%-90%, 51%-68%, and 0.77%-0.88%, respectively. In images acquired with a human 7 T scanner, acquisition times below 12 min, and voxel sizes of (0.4 mm)(3)-(0.6 mm)(3), simulated microcalcifications with sizes of 0.6-1.0 mm were detected with a sensitivity, specificity, and AUC of 75%-87%, 54%-87%, and 0.76%-0.90%, respectively. However, different microcalcification shapes were indistinguishable.
The new method is promising for detecting relatively large microcalcifications (i.e., 0.6-0.9 mm) within the breast at 7 T in reasonable times. Detection of smaller deposits at high field may be possible with higher spatial resolution, but such images require relatively long scan times. Although mammography can detect and distinguish the shape of smaller microcalcifications with superior sensitivity and specificity, this alternative method does not expose tissue to ionizing radiation, is not affected by breast density, and can be combined with other MRI methods (e.g., dynamic contrast-enhanced MRI and diffusion weighted MRI), to potentially improve diagnostic performance.
Medical Physics 03/2015; 42(3):1436. DOI:10.1118/1.4908009 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
In previous work, we demonstrated the presence of hydroxyapetite (type II microcalcification), HAP, in triple negative MDA-MB-231 breast cancer cells. We used (18)F-NaF to detect these types of cancers in mouse models as the free fluorine, (18)F(-), binds to HAP similar to bone uptake. In this work, we investigate other bone targeting agents and techniques including (99m)Tc-MDP SPECT and Osteosense 750EX FMT imaging as alternatives for breast cancer diagnosis via targeting HAP within the tumor microenvironment.
Thirteen mice were injected subcutaneously in the right flank with 10(6) MDA-MB-231 cells. When the tumor size reached ~0.6 cm(3), mice (n=9) were injected with ~37 MBq of (99m)Tc-MDP intravenously and then imaged one hour later in a NanoSPECT/CT or injected intravenously with 4 nmol/g of Osetosense 750EX and imaged 24 hours later in an FMT (n=4). The imaging probe concentration in the tumor was compared to that of muscle. Following SPECT imaging, the tumors were harvested, sectioned into 10 μm slices, and underwent autoradiography or von Kossa staining to correlate (99m)Tc-MDP binding with HAP distribution within the tumor. The SPECT images were normalized to the injected dose and regions-of-interest (ROIs) were drawn around bone, tumor, and muscle to obtain the radiotracer concentration in these regions in units of percent injected dose per unit volume. ROIs were drawn around bone and tumor in the FMT images as no FMT signal was observed in normal muscle.
Uptake of (99m)Tc-MDP was observed in the bone and tumor with little or no uptake in the muscle with concentrations of 11.34±1.46 (mean±SD), 2.22±0.95, and 0.05±0.04%ID/cc, respectively. Uptake of Osteosense 750EX was also observed in the bone and tumor with concentrations of 0.35±0.07 (mean±SD) and 0.04±0.01picomoles, respectively. No FMT signal was observed in the normal muscle. There was no significant difference in the bone-to-tumor ratio between the two modalities (5.1±2.3 for SPECT and 8.8±2.2 for FMT) indicating that there is little difference in tumor uptake between these two agents.
This study provides evidence of the accessibility of HAP within the breast tumor microenvironment as an in vivo imaging target for bone-seeking agents. SPECT imaging using (99m)Tc-MDP can be rapidly translated to the clinic. FMT imaging using Osteosense 750EX is not currently approved for clinical use and is limited to animal research.
Nuclear Medicine and Biology 12/2014; 42(3). DOI:10.1016/j.nucmedbio.2014.11.010 · 2.41 Impact Factor