MP-PCA denoising for diffusion MRS data: promises and pitfalls.

Diffusion-weighted (DW) magnetic resonance spectroscopy (MRS) suffers from a lower signal to noise ratio (SNR) compared to conventional MRS owing to the addition of diffusion attenuation. This technique can therefore strongly benefit from noise reduction strategies. In the present work, Marchenko-Pastur principal component analysis (MP-PCA) denoising is tested on Monte Carlo simulations and on in vivo DW-MRS data acquired at 9.4 T in rat brain and at 3 T in human brain. We provide a descriptive study of the effects observed following different MP-PCA denoising strategies (denoising the entire matrix versus using a sliding window), in terms of apparent SNR, rank selection, noise correlation within and across b-values and quantification of metabolite concentrations and fitted diffusion coefficients. MP-PCA denoising yielded an increased apparent SNR, a more accurate B0 drift correction between shots, and similar estimates of metabolite concentrations and diffusivities compared to the raw data. No spectral residuals on individual shots were observed but correlations in the noise level across shells were introduced, an effect which was mitigated using a sliding window, but which should be carefully considered.

Mapping complex cell morphology in the grey matter with double diffusion encoding MR: A simulation study.

This paper investigates the impact of cell body (namely soma) size and branching of cellular projections on diffusion MR imaging (dMRI) and spectroscopy (dMRS) signals for both standard single diffusion encoding (SDE) and more advanced double diffusion encoding (DDE) measurements using numerical simulations. The aim is to investigate the ability of dMRI/dMRS to characterize the complex morphology of brain cells focusing on these two distinctive features of brain grey matter. To this end, we employ a recently developed computational framework to create three dimensional meshes of neuron-like structures for Monte Carlo simulations, using diffusion coefficients typical of water and brain metabolites. Modelling the cellular structure as realistically connected spherical soma and cylindrical cellular projections, we cover a wide range of combinations of sphere radii and branching order of cellular projections, characteristic of various grey matter cells. We assess the impact of spherical soma size and branching order on the b-value dependence of the SDE signal as well as the time dependence of the mean diffusivity (MD) and mean kurtosis (MK). Moreover, we also assess the impact of spherical soma size and branching order on the angular modulation of DDE signal at different mixing times, together with the mixing time dependence of the apparent microscopic anisotropy (µA), a promising contrast derived from DDE measurements. The SDE results show that spherical soma size has a measurable impact on both the b-value dependence of the SDE signal and the MD and MK diffusion time dependence for both water and metabolites. On the other hand, we show that branching order has little impact on either, especially for water. In contrast, the DDE results show that spherical soma size has a measurable impact on the DDE signal's angular modulation at short mixing times and the branching order of cellular projections significantly impacts the mixing time dependence of the DDE signal's angular modulation as well as of the derived µA, for both water and metabolites. Our results confirm that SDE based techniques may be sensitive to spherical soma size, and most importantly, show for the first time that DDE measurements may be more sensitive to the dendritic tree complexity (as parametrized by the branching order of cellular projections), paving the way for new ways of characterizing grey matter morphology, non-invasively using dMRS and potentially dMRI.

Multiparametric MR Investigation of Proteoglycan Diffusivity, T2 Relaxation, and Concentration in an Ex Vivo Model of Intervertebral Disc Degeneration.

BACKGROUND: Proteoglycan (PG) is a major component of the intervertebral disc extracellular matrix (ECM) that acts to hydrate the disc nucleus. Early detection of PG degradation is valuable for both diagnosis and preclinical research of intervertebral disc degeneration (IVDD). PURPOSE: To compare different MR techniques for detecting early degradative changes of PG in IVDD. STUDY TYPE: Prospective. PHANTOM/SPECIMEN: Glycosaminoglycan (GAG) phantom/bovine discs with papain injection and human cadaveric discs. FIELD STRENGTH/SEQUENCES: 7T/diffusion-weighted MR spectroscopy (DW-MRS), T2 -weighted MRS (T2 W-MRS), and chemical exchange saturation transfer (CEST) imaging. ASSESSMENT: DW-MRS, T2 W-MRS, and CEST imaging were applied longitudinally to measure PG diffusivity, T2 value, overall content, and spatial distribution in the disc nucleus with enzyme-induced proteolytic ECM degradation (n = 8). Similar MR measurements were applied in GAG phantom and human cadaveric discs with different levels of degeneration (n = 6). STATISTICAL TESTS: T-tests were conducted to measure the differences of PG properties between pre- and post-enzyme injection. Linear regression and mixed-effects models were used to assess the associations among different PG properties as well as the degeneration grades in human cadaveric discs. RESULTS: In bovine discs, PG diffusivity increased most rapidly after the enzyme was injected into the disc nucleus (12 hours postinjection, t = 5.76, P = 0.0007). The PG T2 value did not change significantly (t < 1.54, P > 0.17 for all timepoints) during ECM degradation and was not associated with PG diffusivity (t = 0.06, P = 0.95). PG distribution change was more rapid than overall PG content and was strongly associated with PG diffusivity increase (t = -9.25, P < 1 × 10-8 ). In severely degenerated human cadaveric discs, the PG ADCs and T2 values were both associated with degeneration grades. DATA CONCLUSION: PG diffusivity is a direct biomarker for early ECM degradation, while PG distribution can be an indirect biomarker for early IVDD. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:1390-1400.

Modeling diffusion of intracellular metabolites in the mouse brain up to very high diffusion-weighting: Diffusion in long fibers (almost) accounts for non-monoexponential attenuation.

PURPOSE: To investigate how intracellular metabolites diffusion measured in vivo up to very high q/b in the mouse brain can be explained in terms of simple geometries. METHODS: 10 mice were scanned using our new STE-LASER sequence, at 11.7 Tesla (T), up to qmax = 1 µm-1 at diffusion time td = 63.2 ms, corresponding to bmax = 60 ms/µm². We model cell fibers as randomly oriented cylinders, with radius a and intracellular diffusivity Dintracyl, and fit experimental data as a function of q to estimate Dintracyl and a. RESULTS: Randomly oriented cylinders account well for measured attenuation, giving fiber radii and Dintracyl in the expected ranges (0.5-1.5 µm and 0.30-0.45 µm2/ms, respectively). The only exception is N-acetyl-aspartate (NAA) (extracted a∼0), which we show to be compatible with a small fraction of the NAA pool being confined in highly restricted compartments (with short T2). CONCLUSION: The non-monoexponential signal attenuation of intracellular metabolites in the mouse brain can be described by diffusion in long and thin cylinders, yielding realistic Dintra and fiber diameters. However, this simple model may require small "corrections" for NAA, in the form of a small fraction of the NAA signal originating from a highly restricted compartment. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Detection of extracellular matrix degradation in intervertebral disc degeneration by diffusion magnetic resonance spectroscopy.

PURPOSE: To investigate whether diffusion magnetic resonance spectroscopy (MRS) can detect the extracellular matrix (ECM) degradation during intervertebral disc degeneration (IVDD) by the increased mobility of ECM macromolecules such as proteoglycans and collagens. METHODS: Fresh bovine intervertebral discs were injected with papain solution to induce ECM degradation. The apparent diffusion coefficients (ADCs), T2 values, and contents of ECM macromolecules and water resonances were measured longitudinally in the nucleus pulposus. RESULTS: The macromolecule ADCs increased drastically at day 1 after papain injection, and continued increasing for 5 days. In contrast, the proteoglycan content exhibited a small and slow decrease after injection while the macromolecule T2 values, water T2, ADC, and content showed slight increase or no change. The protein gel electrophoresis analysis confirmed the gradually increased ECM fragmentation in accordance with the observed macromolecule ADC increases. CONCLUSION: Diffusion MRS provides a new method to characterize the ECM degradation processes directly and sensitively. Macromolecule ADCs offer a potentially more sensitive and earlier marker for ECM degradation than the proteoglycan content and T2, and water MR properties during early IVDD. Such diffusion approach offers the possibility to directly monitor ECM integrity and degradation processes in vivo at molecular and microstructural levels in both preclinical and clinical settings.

Reproducibility and optimization of in vivo human diffusion-weighted MRS of the corpus callosum at 3 T and 7 T.

Diffusion-weighted MRS (DWS) of brain metabolites enables the study of cell-specific alterations in tissue microstructure by probing the diffusion of intracellular metabolites. In particular, the diffusion properties of neuronal N-acetylaspartate (NAA), typically co-measured with N-acetylaspartyl glutamate (NAAG) (NAA + NAAG = tNAA), have been shown to be sensitive to intraneuronal/axonal damage in pathologies such as stroke and multiple sclerosis. Lacking, so far, are empirical assessments of the reproducibility of DWS measures across time and subjects, as well as a systematic investigation of the optimal acquisition parameters for DWS experiments, both of which are sorely needed for clinical applications of the method. In this study, we acquired comprehensive single-volume DWS datasets of the human corpus callosum at 3 T and 7 T. We investigated the inter- and intra-subject variability of empirical and modeled diffusion properties of tNAA [D(avg) (tNAA) and D(model) (tNAA), respectively]. Subsequently, we used a jackknife-like resampling approach to explore the variance of these properties in partial data subsets reflecting different total scan durations. The coefficients of variation (C(V)) and repeatability coefficients (C(R)) for D(avg) (tNAA) and D(model) (tNAA) were calculated for both 3 T and 7 T, with overall lower variability in the 7 T results. Although this work is limited to the estimation of the diffusion properties in the corpus callosum, we show that a careful choice of diffusion-weighting conditions at both field strengths allows the accurate measurement of tNAA diffusion properties in clinically relevant experimental time. Based on the resampling results, we suggest optimized acquisition schemes of 13-min duration at 3T and 10-min duration at 7 T, whilst retaining low variability (C(V) ≈ 8%) for the tNAA diffusion measures. Power calculations for the estimation of D(model )(tNAA) and D(avg) (tNAA) based on the suggested schemes show that less than 21 subjects per group are sufficient for the detection of a 10% effect between two groups in case-control studies.

Practical considerations of diffusion-weighted MRS with ultra-strong diffusion gradients.

Introduction: Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) offers improved cellular specificity to microstructure-compared to water-based methods alone-but spatial resolution and SNR is severely reduced and slow-diffusing metabolites necessitate higher b-values to accurately characterize their diffusion properties. Ultra-strong gradients allow access to higher b-values per-unit time, higher SNR for a given b-value, and shorter diffusion times, but introduce additional challenges such as eddy-current artefacts, gradient non-uniformity, and mechanical vibrations. Methods: In this work, we present initial DW-MRS data acquired on a 3T Siemens Connectom scanner equipped with ultra-strong (300 mT/m) gradients. We explore the practical issues associated with this manner of acquisition, the steps that may be taken to mitigate their impact on the data, and the potential benefits of ultra-strong gradients for DW-MRS. An in-house DW-PRESS sequence and data processing pipeline were developed to mitigate the impact of these confounds. The interaction of TE, b-value, and maximum gradient amplitude was investigated using simulations and pilot data, whereby maximum gradient amplitude was restricted. Furthermore, two DW-MRS voxels in grey and white matter were acquired using ultra-strong gradients and high b-values. Results: Simulations suggest T2-based SNR gains that are experimentally confirmed. Ultra-strong gradient acquisitions exhibit similar artefact profiles to those of lower gradient amplitude, suggesting adequate performance of artefact mitigation strategies. Gradient field non-uniformity influenced ADC estimates by up to 4% when left uncorrected. ADC and Kurtosis estimates for tNAA, tCho, and tCr align with previously published literature. Discussion: In conclusion, we successfully implemented acquisition and data processing strategies for ultra-strong gradient DW-MRS and results indicate that confounding effects of the strong gradient system can be ameliorated, while achieving shorter diffusion times and improved metabolite SNR.

Differentiating between axonal damage and demyelination in healthy aging by combining diffusion-tensor imaging and diffusion-weighted spectroscopy in the human corpus callosum at 7 T.

Diffusion-tensor imaging and single voxel diffusion-weighted magnetic resonance spectroscopy were used at 7T to explore in vivo age-related microstructural changes in the corpus callosum. Sixteen healthy elderly (age range 60-71 years) and 13 healthy younger controls (age range 23-32 years) were included in the study. In healthy elderly, we found lower water fractional anisotropy and higher water mean diffusivity and radial diffusivity in the corpus callosum, indicating the onset of demyelination processes with healthy aging. These changes were not associated with a concomitant significant difference in the cytosolic diffusivity of the intra-axonal metabolite N-acetylaspartate (p = 0.12), the latter representing a pure measure of intra-axonal integrity. It was concluded that the possible intra-axonal changes associated with normal aging processes are below the detection level of diffusion-weighted magnetic resonance spectroscopy in our experiment (e.g., smaller than 10%) in the age range investigated. Lower axial diffusivity of total creatine was observed in the elderly group (p = 0.058), possibly linked to a dysfunction in the energy metabolism associated with a deficit in myelin synthesis.