Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De∥), extra-axonal radial diffusivity (De⊥), axonal water fraction (AWF), and tortuosity (α) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy (1H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, α, and fractional anisotropy; negative correlations between NAA and De,⊥ and the overall radial diffusivity (D⊥). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De∥ and Cho, and a positive trend between De∥ and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De∥ with mI and Cho, both predominantly present extra-axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra-axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De⊥, AWF, and α).

Although MRI assessment of white matter lesions is essential for the clinical management of multiple sclerosis, the processes leading to the formation of lesions and underlying their subsequent MRI appearance are incompletely understood. We used proton MR spectroscopy to study the evolution of N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-inositol (mI) in pre-lesional tissue, persistent and transient new lesions, as well as in chronic lesions, and related the results to quantitative MRI measures of T1-hypointensity and T2-volume. Within 10 patients with relapsing-remitting course, there were 180 regions-of-interest consisting of up to seven semi-annual follow-ups of normal-appearing white matter (NAWM, n=10), pre-lesional tissue giving rise to acute lesions which resolved (n=3) or persisted (n=3), and of moderately (n=9) and severely hypointense (n=6) chronic lesions. Compared to NAWM, pre-lesional tissue had higher Cr and Cho, while compared to lesions, pre-lesional tissue had higher NAA. Resolving acute lesions showed similar NAA levels pre- and post-formation, suggesting no long-term axonal damage. In chronic lesions, there was an increase in mI, suggesting accumulating astrogliosis. Lesion volume was a better predictor of axonal health than T1-hypointensity, with lesions larger than 1.5 cm3 uniformly exhibiting very low (<4.5 millimolar) NAA concentrations. A positive correlation between longitudinal changes in Cho and in lesion volume in moderately hypointense lesions implied that lesion size is mediated by chronic inflammation. These and other results are integrated in a discussion on the steady state metabolism of lesion evolution in multiple sclerosis, viewed in the context of conventional MRI measures.

Background 3D brain proton MR spectroscopic imaging (1H MRSI) facilitates simultaneous metabolic profiling of multiple loci, at higher, sub‐1 cm3, spatial resolution than single‐voxel 1H MRS with the ability to separate tissue‐type partial volume contribution(s). Purpose To determine if: 1) white matter (WM) damage in mild traumatic brain injury (mTBI) is homogeneously diffuse, or if specific regions are more affected; 2) partial‐volume‐corrected, structure‐specific 1H MRSI voxel averaging is sensitive to regional WM metabolic abnormalities. Study Type Retrospective cross‐sectional cohort study. Population Twenty‐seven subjects: 15 symptomatic mTBI patients, 12 matched controls. Field Strength/Sequence 3T using 3D 1H MRSI over a 360‐cm3 volume of interest (VOI) centered over the corpus callosum, partitioned into 480 voxels, each 0.75 cm3. Assessment N‐acetyl‐aspartate (NAA), creatine, choline, and myo‐inositol concentrations estimated in predominantly WM regions: body, genu, and splenium of the corpus callosum, corona radiata, frontal, and occipital WM. Statistical Tests Analysis of covariance (ANCOVA) to compare patients with controls in terms of regional concentrations. The effect sizes (Cohen's d) of the mean differences were compared across regions and with previously published global data obtained with linear regression of the WM over the entire VOI in the same dataset. Results Despite patients' global VOI WM NAA being significantly lower than the controls', no regional differences were observed for any metabolite. Regional NAA comparisons, however, were all unidirectional (patients' NAA concentrations < controls') within a narrow range: 0.3 ≤ Cohen's d ≤ 0.6. Data Conclusion Since the patient group was symptomatic and exhibiting global WM NAA deficits, these findings suggest: 1) diffuse axonal mTBI damage; that is 2) below the 1H MRSI detection threshold in small regions. Therefore, larger, ie, more sensitive, single‐voxel 1H MRS, placed anywhere in WM regions, may be well suited for mTBI 1H MRS studies, given that these results are confirmed in other cohorts. Level of Evidence: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;50:1424–1432.