In vivo mapping of cellular resolution neuropathology in brain ischemia with diffusion MRI.

Noninvasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent advances in diffusion magnetic resonance imaging enabled in vivo examination of tissue microstructures well beyond the imaging resolution. Here, we proposed to use diffusion time-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess cellular morphology and transmembrane permeability in hypoxic-ischemic (HI) brain injury. Through numerical simulations and organoid imaging, we demonstrated the feasibility of capturing effective size and permeability changes using tDKI. In vivo MRI of HI-injured mouse brains detected a shift of the tDKI peak to longer diffusion times, suggesting swelling of the cellular processes. Furthermore, we observed a faster decrease of the tDKI tail, reflecting increased transmembrane permeability associated with up-regulated water exchange or necrosis. Such information, unavailable from a single diffusion time, can predict salvageable tissues. Preliminary applications of tDKI in patients with ischemic stroke suggested increased transmembrane permeability in stroke regions, illustrating tDKI's potential for detecting pathological changes in the clinics.

Unusual triflic acid-promoted oligomerization of arabinofuranosides during glycosylation.

We discovered an unusual triflic acid-promoted oligomerization of arabinofuranosides during glycosylation of the primary hydroxy group of α-(1 â†’ 5)-linked tetraarabinofuranoside bearing 4-(2-chloroethoxy)phenyl aglycone with α-(1 â†’ 5), ß-(1 â†’ 2)-linked tetraarabinofuranoside containing N-phenyltrifluoroacetimidoyl leaving group, which led to octa-, dodeca- and hexadecaarabinofuranosides. The possible mechanism of triflic acid-promoted oligomerization was proposed. The choice of promoter was found to be a critical factor for the discovered oligomerization of arabinofuranosides. The obtained octa-, dodeca- and hexadecaarabinofuranosides may serve as useful blocks in the synthesis of oligosaccharide fragments of polysaccharides of Mycobacterium tuberculosis.

Callosal Interhemispheric Communication in Mild Traumatic Brain Injury: A Mediation Analysis on WM Microstructure Effects.

BACKGROUND AND PURPOSE: Because the corpus callosum connects the left and right hemispheres and a variety of WM bundles across the brain in complex ways, damage to the neighboring WM microstructure may specifically disrupt interhemispheric communication through the corpus callosum following mild traumatic brain injury. Here we use a mediation framework to investigate how callosal interhemispheric communication is affected by WM microstructure in mild traumatic brain injury. MATERIALS AND METHODS: Multishell diffusion MR imaging was performed on 23 patients with mild traumatic brain injury within 1 month of injury and 17 healthy controls, deriving 11 diffusion metrics, including DTI, diffusional kurtosis imaging, and compartment-specific standard model parameters. Interhemispheric processing speed was assessed using the interhemispheric speed of processing task (IHSPT) by measuring the latency between word presentation to the 2 hemivisual fields and oral word articulation. Mediation analysis was performed to assess the indirect effect of neighboring WM microstructures on the relationship between the corpus callosum and IHSPT performance. In addition, we conducted a univariate correlation analysis to investigate the direct association between callosal microstructures and IHSPT performance as well as a multivariate regression analysis to jointly evaluate both callosal and neighboring WM microstructures in association with IHSPT scores for each group. RESULTS: Several significant mediators in the relationships between callosal microstructure and IHSPT performance were found in healthy controls. However, patients with mild traumatic brain injury appeared to lose such normal associations when microstructural changes occurred compared with healthy controls. CONCLUSIONS: This study investigates the effects of neighboring WM microstructure on callosal interhemispheric communication in healthy controls and patients with mild traumatic brain injury, highlighting that neighboring noncallosal WM microstructures are involved in callosal interhemispheric communication and information transfer. Further longitudinal studies may provide insight into the temporal dynamics of interhemispheric recovery following mild traumatic brain injury.

Assessment of Precision and Accuracy of Brain White Matter Microstructure using Combined Diffusion MRI and Relaxometry.

Joint modeling of diffusion and relaxation has seen growing interest due to its potential to provide complementary information about tissue microstructure. For brain white matter, we designed an optimal diffusion-relaxometry MRI protocol that samples multiple b-values, B-tensor shapes, and echo times (TE). This variable-TE protocol (27 min) has as subsets a fixed-TE protocol (15 min) and a 2-shell dMRI protocol (7 min), both characterizing diffusion only. We assessed the sensitivity, specificity and reproducibility of these protocols with synthetic experiments and in six healthy volunteers. Compared with the fixed-TE protocol, the variable-TE protocol enables estimation of free water fractions while also capturing compartmental T2 relaxation times. Jointly measuring diffusion and relaxation offers increased sensitivity and specificity to microstructure parameters in brain white matter with voxelwise coefficients of variation below 10%.

Signatures of microstructure in gradient-echo and spin-echo signals.

PURPOSE: To determine whether the spatial scale and magnetic susceptibility of microstructure can be evaluated robustly from the decay of gradient-echo and spin-echo signals. THEORY AND METHODS: Gradient-echo and spin-echo images were acquired from suspensions of spherical polystyrene microbeads of 10, 20, and 40 µm nominal diameter. The sizes of the beads and their magnetic susceptibility relative to the medium were estimated from the signal decay curves, using a lookup table generated from Monte Carlo simulations and an analytic model based on the Gaussian phase approximation. RESULTS: Fitting Monte Carlo predictions to spin-echo data yielded acceptable estimates of microstructural parameters for the 20 and 40 µm microbeads. Using gradient-echo data, the Monte Carlo lookup table provided satisfactory parameter estimates for the 20 µm beads but unstable results for the diameter of the largest beads. Neither spin-echo nor gradient-echo data allowed accurate parameter estimation for the smallest beads. The analytic model performed poorly over all bead sizes. CONCLUSIONS: Microstructural sources of magnetic susceptibility produce distinctive non-exponential signatures in the decay of gradient-echo and spin-echo signals. However, inverting the problem to extract microstructural parameters from the signals is nontrivial and, in certain regimes, ill-conditioned. For microstructure with small characteristic length scales, parameter estimation is hampered by the difficulty of acquiring accurate data at very short echo times. For microstructure with large characteristic lengths, the gradient-echo signal approaches the static-dephasing regime, where it becomes insensitive to size. Applicability of the analytic model was further limited by failure of the Gaussian phase approximation for all but the smallest beads.

The effects of axonal beading and undulation on axonal diameter estimation from diffusion MRI: Insights from simulations in human axons segmented from three-dimensional electron microscopy.

The increasing availability of high-performance gradient systems in human MRI scanners has generated great interest in diffusion microstructural imaging applications such as axonal diameter mapping. Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings b , where the deviation from the expected 1 / b scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three-dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next-generation Connectome 2.0 human MRI scanner ( ≲ 500 mT/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse-grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.

Volume electron microscopy in injured rat brain validates white matter microstructure metrics from diffusion MRI.

Biophysical modeling of diffusion MRI (dMRI) offers the exciting potential of bridging the gap between the macroscopic MRI resolution and microscopic cellular features, effectively turning the MRI scanner into a noninvasive in vivo microscope. In brain white matter, the Standard Model (SM) interprets the dMRI signal in terms of axon dispersion, intra- and extra-axonal water fractions and diffusivities. However, for SM to be fully applicable and correctly interpreted, it needs to be carefully evaluated using histology. Here, we perform a comprehensive histological validation of the SM parameters, by characterizing WM microstructure in sham and injured rat brains using volume (3d) electron microscopy (EM) and ex vivo dMRI. Sensitivity is evaluated by how close each SM metric is to its histological counterpart, and specificity by how independent it is from other, non-corresponding histological features. This comparison reveals that SM is sensitive and specific to microscopic properties, clearing the way for the clinical adoption of in vivo dMRI derived SM parameters as biomarkers for neurological disorders.