Diffusion-weighted magnetic resonance spectroscopy of brain metabolites offers unique access to compartment-specific microstructural information on neural tissue. Here, we investigated in detail the diffusion characteristics of the neuronal/axonal markers N-acetylaspartate + N-acetyl aspartyl glutamate (tNAA) in a small region of the human corpus callosum at 7 T. The diffusion-weighted spectroscopy data were analyzed by fitting to a model in which information about cross-callosal tract orientation within the spectroscopy volume, obtained from diffusion tensor imaging data, was incorporated. We estimated the microscopic misalignment of axons (σ φ  = 18.6° ± 3.0°) in excellent agreement with independent histological results (σ φ  = 18.1° ± 4.6°) obtained from microscopic analysis of axonal orientations in the body of the corpus callosum from post-mortem human brain slices. We also robustly quantified the diffusion coefficient of tNAA (0.51 ± 0.06 × 10(-3) mm(2)/s) in axonal cytoplasm, unbiased by the tract curvature. This work supports the notion that microscopic axonal misalignment is a dominant microstructural property in white matter tracts and has a strong impact on the evaluation of tissue microstructure using diffusion information, and should therefore be taken into consideration in the evaluation of white matter microstructure. Additionally, this study enabled robust and unbiased assessment of the cytosolic diffusion coefficient of tNAA, a potential biomarker for axonopathy and neuronal degeneration.

Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 μm(2)/ms, P = 0.018) and total choline (0.142 ± 0.031 μm(2)/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm(2)/ms, 0.124 ± 0.018 μm(2)/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P = 0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positiv...

The strong correlation with myelin water imaging and its low coefficient of variation suggest that ihMT has the potential to become a new structural imaging marker of myelin. The substantial orientational dependence of ihMT should be taken into account when evaluating and quantitatively interpreting ihMT results.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage.

Diffusion-weighted magnetic resonance spectroscopy (DWS) offers unique access to compartment-specific microstructural information on tissue, and potentially sensitive detection of compartment-specific changes in disease. The specificity of DWS is, however, offset by its relative low sensitivity, intrinsic to all MRS-based methods, and further exacerbated by the signal loss due to the diffusion weighting and long echo times. In this work we first provide an experimental example for the type of compartment-specific information that can be obtained with DWS from a small volume of interest (VOI) in brain white matter. We then propose and discuss a strategy for the analysis of DWS data, which includes the use of models of diffusion in compartments with simple geometries. We conclude with a broader discussion of the potential role of DWS in the characterization of tissue microstructure and the complementarity of DWS with less-specific but more sensitive microstructural tools such as diffusion tensor imaging.