Mesoscopic Assessment of Microstructure in Glioblastomas and Metastases by Merging Advanced Diffusion Imaging with Immunohistopathology.

BACKGROUND AND PURPOSE: Glioblastomas and metastases are the most common malignant intra-axial brain tumors in adults and can be difficult to distinguish on conventional MR imaging due to similar imaging features. We used advanced diffusion techniques and structural histopathology to distinguish these tumor entities on the basis of microstructural axonal and fibrillar signatures in the contrast-enhancing tumor component. MATERIALS AND METHODS: Contrast-enhancing tumor components were analyzed in 22 glioblastomas and 21 brain metastases on 3T MR imaging using DTI-fractional anisotropy, neurite orientation dispersion and density imaging-orientation dispersion, and diffusion microstructural imaging-micro-fractional anisotropy. Available histopathologic specimens (10 glioblastomas and 9 metastases) were assessed for the presence of axonal structures and scored using 4-level scales for Bielschowsky staining (0: no axonal structures, 1: minimal axonal fragments preserved, 2: decreased axonal density, 3: no axonal loss) and glial fibrillary acid protein expression (0: no glial fibrillary acid protein positivity, 1: limited expression, 2: equivalent to surrounding parenchyma, 3: increased expression). RESULTS: When we compared glioblastomas and metastases, fractional anisotropy was significantly increased and orientation dispersion was decreased in glioblastomas (each P < .001), with a significant shift toward increased glial fibrillary acid protein and Bielschowsky scores. Positive associations of fractional anisotropy and negative associations of orientation dispersion with glial fibrillary acid protein and Bielschowsky scores were revealed, whereas no association between micro-fractional anisotropy with glial fibrillary acid protein and Bielschowsky scores was detected. Receiver operating characteristic curves revealed high predictive values of both fractional anisotropy (area under the curve = 0.8463) and orientation dispersion (area under the curve = 0.8398) regarding the presence of a glioblastoma. CONCLUSIONS: Diffusion imaging fractional anisotropy and orientation dispersion metrics correlated with histopathologic markers of directionality and may serve as imaging biomarkers in contrast-enhancing tumor components.

What does FEXI measure?

Filter-exchange imaging (FEXI) has already been utilized in several biomedical studies for evaluating the permeability of cell membranes. The method relies on suppressing the extracellular signal using strong diffusion weighting (the mobility filter causing a reduction in the overall diffusivity) and monitoring the subsequent diffusivity recovery. Using Monte Carlo simulations, we demonstrate that FEXI is sensitive not uniquely to the transcytolemmal exchange but also to the geometry of involved compartments: complex geometry offers locations where spins remain unaffected by the mobility filter; moving to other locations afterwards, such spins contribute to the diffusivity recovery without actually permeating any membrane. This exchange mechanism is a warning for those who aim to use FEXI in complex media such as brain gray matter and opens wide scope for investigation towards crystallizing the genuine membrane permeation and characterizing the compartment geometry.

The larmor frequency shift in magnetically heterogeneous media depends on their mesoscopic structure.

PURPOSE: Recent studies have addressed the determination of the NMR precession frequency in biological tissues containing magnetic susceptibility differences between cell types. The purpose of this study is to investigate the dependence of the precession frequency on medium microstructure using a simple physical model. THEORY: This dependence is governed by diffusion of NMR-visible molecules in magnetically heterogeneous microenvironments. In the limit of fast diffusion, the precession frequency is determined by the average susceptibility-induced magnetic field, whereas in the limit of slow diffusion it is determined by the average local phase factor of precessing spins. METHODS: The main method used is Monte Carlo simulation of isotropic suspensions of impermeable magnetized spheres. In addition, NMR spectroscopy was performed in aqueous suspensions of polystyrene microbeads. RESULTS: The precession frequency depends on the structural organization of magnetized objects in the medium. Monte Carlo simulations demonstrated a nonmonotonic transition between the regimes of fast and slow diffusion. NMR experiments confirmed the transition, but were unable to confirm its precise form. Results for a given pattern of structural organization obey a scaling law. CONCLUSION: The NMR precession frequency exhibits a complex dependence on medium structure. Our results suggest that the commonly assumed limit of fast water diffusion holds for biological tissues with small cells. Magn Reson Med 79:1101-1110, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Tissue-blood exchange of extravascular longitudinal magnetization with account of intracompartmental diffusion.

The joint effect of both extravascular water diffusion and transcapillary water exchange on the longitudinal magnetisation is evaluated theoretically for tissues with sparse capillary networks (e.g., the brain and myocardium). The spatio-temporal profile of the extravascular longitudinal magnetisation is calculated for the limiting case of a high blood concentration of paramagnetic tracer resulting in negligible intravascular magnetisation, hence in a net flux of magnetisation from the extravascular tissue to its contained blood. A related parameter, termed the effective extravascular depolarised volume, is derived that quantifies the ensuing attenuation of the NMR signal and affords a taxonomy of exchange regimes. It is found that the spatio-temporal pattern of magnetisation decay may deviate strongly from that predicted by chemical exchange models when the rate of transcapillary exchange is limited by slow diffusive transport in the extravascular tissue but reproduces known results in the case of fast extravascular diffusion.

Effective medium theory of a diffusion-weighted signal.

Living tissues and other heterogeneous media generally consist of structural units with different diffusion coefficients and NMR properties. These blocks, such as cells or clusters of cells, can be much smaller than the imaging voxel, and are often comparable with the diffusion length. We have developed a general approach to quantify the medium heterogeneity when it is much finer than the sample size or the imaging resolution. The approach is based on the treatment of the medium statistically in terms of the correlation functions of the local parameters. The diffusion-weighted signal is explicity found for the case in which the local diffusivity varies in space, in the lowest order in the diffusivity variance. We demonstrate how the correlation length and the variance of the local diffusivity contribute to the time-dependent diffusion coefficient and the time-dependent kurtosis. Our results are corroborated by Monte Carlo simulations of diffusion in a two-dimensional heterogeneous medium.