Accurate quantification of chemical exchange saturation transfer (CEST) effects, including dipole-dipole mediated relayed nuclear Overhauser enhancements (rNOE) saturation transfer, is important for applications and studies of molecular concentration and transfer rate (and thereby pH or temperature). Although several quantification methods, such as Lorentzian difference (LD) analysis, multiple-pool Lorentzian fits, and the three-point method, have been extensively used in several preclinical and clinical applications, the accuracy of these methods has not been evaluated. Here we simulated multiple-pool Z-spectra containing the pools that contribute to the main CEST and rNOE saturation transfer signals in brain, and numerically fit them using the different methods, and then compared their derived CEST metrics with the known solute concentrations and exchange rates. Our results show that the LD analysis overestimates contributions from amide proton transfer (APT) and intermediate exchanging amine protons; the three-point method significantly underestimates both APT and rNOE saturation transfer at −3.5 ppm (NOE(−3.5)). In contrast, the multiple-pool Lorentzian fit is more accurate than the other two methods, but only at lower irradiation powers (< 1 μT at 9.4 T) within the range of our simulations. At higher irradiation powers, this method is also inaccurate because of the presence of a fast exchanging CEST signal that has a non-Lorentzian lineshape. Quantitative parameters derived from in vivo images of rodent brain tumor obtained using an irradiation power of 1 μT were also compared. Our results demonstrate that all three quantification methods show similar contrasts between tumor and contralateral normal tissue for both APT and the NOE(−3.5). However, the quantified values of the three methods are significantly different. Our work provides insight into the fitting accuracy obtainable in a complex tissue model and provides guidelines for evaluating other newly developed quantification methods.

Mapping mean axon diameter and intra-axonal volume fraction may have significant clinical potential because nerve conduction velocity is directly dependent on axon diameter, and several neurodegenerative diseases affect axons of specific sizes and alter axon counts. Diffusion-weighted MRI methods based on the pulsed gradient spin echo (PGSE) sequence have been reported to be able to assess axon diameter and volume fraction non-invasively. However, due to the relatively long diffusion times used, e.g. > 20 ms, the sensitivity to small axons (diameter < 2 µm) is low, and the derived mean axon diameter has been reported to be overestimated. In the current study, oscillating gradient spin echo (OGSE) diffusion sequences with variable frequency gradients were used to assess rat spinal white matter tracts with relatively short effective diffusion times (1 – 5 ms). In contrast to previous PGSE-based methods, the extra-axonal diffusion cannot be modeled as hindered (Gaussian) diffusion when short diffusion times are used. Appropriate frequency-dependent rates are therefore incorporated into our analysis and validated by histology-based computer simulation of water diffusion. OGSE data were analyzed to derive mean axon diameters and intra-axonal volume fractions of rat spinal white matter tracts (mean axon diameter ~ 1.27 – 5.54 µm). The estimated values were in good agreement with histology, including the small axon diameters (< 2.5 µm). This study establishes a framework for quantification of nerve morphology using the OGSE method with high sensitivity to small axons.

Purpose A new approach has been developed to quantify cell sizes and intracellular volume fractions using temporal diffusion spectroscopy with diffusion-weighted acquisitions. Theory and Methods Temporal diffusion spectra may be used to characterize tissue microstructure by measuring the effects of restrictions over a range of diffusion times. Oscillating gradients have been used previously to probe variations on cellular and subcellular scales, but their ability to accurately measure cell sizes larger than 10 μm is limited. By combining measurements made using oscillating gradient spin echo (OGSE) and a conventional pulsed gradient spin echo (PGSE) acquisition with a single, relatively long diffusion time, we can accurately quantify cell sizes and intracellular volume fractions. Results Based on a two compartment model (incorporating intra- and extracellular spaces), accurate estimates of cell sizes and intracellular volume fractions were obtained in vitro for (i) different cell types with sizes ranging from 10 to 20 μm, (ii) different cell densities, and (iii) before and after anti-cancer treatment. Conclusion Hybrid OGSE-PGSE acquisitions sample a larger region of temporal diffusion spectra and can accurately quantify cell sizes over a wide range. Moreover, the maximum gradient strength used was lower than 15 G/cm, suggesting that this approach is translatable to practical MR imaging.

Purpose This study investigates amide proton transfer (APT) and nuclear overhauser enhancement (NOE) in phantoms and 9L tumors in rat brains at 9.4 Tesla, using a recently developed method that can isolate different contributions to exchange. Methods Chemical exchange rotation transfer (CERT) was used to quantify APT and NOEs through subtraction of signals acquired at two irradiation flip angles, but with the same average irradiation power. Results CERT separates and quantifies specific APT and NOE signals without contamination from other proton pools, and thus overcomes a key shortcoming of conventional CEST asymmetry approaches. CERT thus has increased specificity, though at the cost of decreased signal strength. In vivo experiments show that the APT effect acquired with CERT in 9L rat tumors (3.1%) is relatively greater than that in normal tissue (2.5%), which is consistent with previous CEST asymmetry analysis. The NOE effect centered at −1.6 ppm shows substantial image contrast within the tumor and between the tumor and the surrounding tissue, while the NOE effect centered at −3.5 ppm shows little contrast. Conclusion CERT provides an image contrast that is more specific to chemical exchange than conventional APT by means of asymmetric CEST Z-spectra analysis.

A novel glucose-responsive controlled release of insulin system is constructed through coating enzyme multilayers on mesoporous silica particles (MSPs). The MSPs serve as the drug reservoir, and the enzyme multilayers cross-linked with glutaraldehyde act as a valve to control the release of insulin in response to the external glucose level.