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Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra-axonal constituent N-acetylaspartate.

ABSTRACT: Multiple sclerosis (MS) is a pathologically complex CNS disease: inflammation, demyelination, and neuroaxonal degeneration occur concurrently and may depend on one another. Current therapies are aimed at the immune-mediated, inflammatory destruction of myelin, whereas axonal degeneration is ongoing and not specifically targeted. Diffusion-weighted magnetic resonance spectroscopy can measure the diffusivity of metabolites in vivo, such as the axonal/neuronal constituent N-acetylaspartate, allowing compartment-specific assessment of disease-related changes. Previously, we found significantly lower N-acetylaspartate diffusivity in people with MS compared to healthy controls (Wood et al., 2012) suggesting that this technique can measure axonal degeneration and could be useful in developing neuroprotective agents. In this longitudinal study, we found that N-acetylaspartate diffusivity decreased by 8.3% (p < 0.05) over 6 months in participants who were experiencing clinical or MRI evidence of inflammatory activity (n = 13), whereas there was no significant change in N-acetylaspartate diffusivity in the context of clinical and radiological stability (n = 6). As N-acetylaspartate diffusivity measurements are thought to more specifically reflect the intra-axonal space, these data suggest that N-acetylaspartate diffusivity can report on axonal health on the background of multiple pathological processes in MS, both cross-sectionally and longitudinally.

SUBMITTER: Wood ET

PROVIDER: S-EPMC5496488 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra-axonal constituent <i>N</i>-acetylaspartate.

Wood Emily Turner ET Ercan Ece E Sati Pascal P Cortese Irene C M ICM Ronen Itamar I Reich Daniel S DS

NeuroImage. Clinical 20170622

Multiple sclerosis (MS) is a pathologically complex CNS disease: inflammation, demyelination, and neuroaxonal degeneration occur concurrently and may depend on one another. Current therapies are aimed at the immune-mediated, inflammatory destruction of myelin, whereas axonal degeneration is ongoing and not specifically targeted. Diffusion-weighted magnetic resonance spectroscopy can measure the diffusivity of metabolites in vivo, such as the axonal/neuronal constituent <i>N</i>-acetylaspartate, ...[more]

PMID: 28702353

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Project description:Purpose To evaluate the ability of high-gradient-diffusion magnetic resonance (MR) imaging by using gradient strengths of up to 300 mT/m to depict axonal disease in lesions and normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) and to compare high-gradient-diffusion MR findings in these patients with those in healthy control subjects. Materials and Methods In this HIPAA-compliant institutional review board-approved prospective study in which all subjects provided written informed consent, six patients with relapsing-remitting MS and six healthy control subjects underwent diffusion-weighted imaging with a range of diffusion weightings performed with a 3-T human MR imager by using gradient strengths of up to 300 mT/m. A model of intra-axonal, extra-axonal, and free water diffusion was fitted to obtain estimates of axon diameter and density. Differences in axon diameter and density between lesions and NAWM in patients with MS were assessed by using the nonparametric Wilcoxon matched-pairs signed rank test, and differences between NAWM in subjects with MS and white matter in healthy control subjects were assessed by using the Mann-Whitney U test. Results MS lesions showed increased mean axon diameter (10.3 vs 7.9 ?m in the genu, 10.4 vs 9.3 ?m in the body, and 10.6 vs 8.2 ?m in the splenium; P < .05) and decreased axon density ([0.48 vs 1.1] × 10(10)/m(2) in the genu, [0.40 vs 0.70] × 10(10)/m(2) in the body, and [0.35 vs 1.1] × 10(10)/m(2) in the splenium; P < .05) compared with adjacent NAWM. No significant difference in mean axon diameter or axon density was detected between NAWM in subjects with MS and white matter in healthy control subjects. Conclusion High-gradient-diffusion MR imaging using gradient strengths of up to 300 mT/m can be used to characterize axonal disease in patients with MS, with results that agree with known trends from neuropathologic data showing increased axon diameter and decreased axon density in MS lesions when compared with NAWM. (©) RSNA, 2016 Online supplemental material is available for this article.

Project description:Axonal loss in the CNS is a key driver of progressive neurological impairments in people with multiple sclerosis. Currently, there are no established methods for tracking axonal loss clinically. This study aimed to determine the sensitivity of longitudinal diffusion MRI-derived fibre-specific measures of axonal loss in people with multiple sclerosis. Fibre measures were derived from diffusion MRI acquired as part of a standard radiological MRI protocol and were compared (i) to establish measures of neuro-axonal degeneration: brain parenchymal fraction and retinal nerve fibre layer thickness and (ii) between different disease stages: clinically isolated syndrome and early/late relapsing-remitting multiple sclerosis. Retrospectively identified data from 59 people with multiple sclerosis (18 clinically isolated syndrome, 22 early and 19 late relapsing-remitting) who underwent diffusion MRI as part of their routine clinical monitoring were collated and analysed. Twenty-six patients had 1-year and 14 patients had a 2-year follow-up. Brain parenchymal fraction was calculated from 3D MRI scans, and fibre-specific measures were calculated from diffusion MRI using multi-tissue constrained spherical deconvolution. At each study visit, patients underwent optical coherence tomography to determine retinal nerve fibre layer thickness, and standard neurological assessment expanded the disability status scale. We found a significant annual fibre-specific neuro-axonal degeneration (mean ± SD = -3.49 ± 3.32%, P < 0.001) that was ∼7 times larger than the annual change of brain parenchymal fraction (-0.53 ± 0.95%, P < 0.001), and more than four times larger than annual retinal nerve fibre layer thinning (-0.75 ± 2.50% P = 0.036). Only fibre-specific measures showed a significant difference in annual degeneration between the disease stages (P = 0.029). Reduced brain parenchymal fraction, retinal nerve fibre layer thickness and fibre-specific measures were moderately related to higher expanded disability status scale (rho = -0.368, rho = -0.408 and rho = -0.365, respectively). Fibre-specific measures can be measured from data collected within a standard radiological multiple sclerosis study and are substantially more sensitive to longitudinal change compared with brain atrophy and retinal nerve fibre layer thinning.

Project description:Background The time course of cellular damage after acute ischemic stroke (IS) is currently not well known, and specific noninvasive markers of microstructural alterations linked to inflammation are lacking, which hinders the monitoring of anti-inflammatory treatment. Purpose To evaluate the temporal pattern of neuronal and glial microstructural changes after stroke using in vivo single-voxel diffusion-weighted MR spectroscopy. Materials and Methods In this prospective longitudinal study, participants with IS and healthy volunteers (HVs) underwent MRI at 3.0 T. In participants with IS, apparent diffusion coefficients (ADCs) and concentrations of total N-acetyl-aspartate (tNAA), total creatine (tCr), and total choline (tCho) were measured in volumes of interest (VOIs), including the lesion VOI (VOIles) and the contralateral VOI (VOIcl) at 2 weeks, 1 month, and 3 months after IS. HVs were examined once, with VOIs located in the same brain regions as participants with IS. Within- and between-group differences and longitudinal changes were examined using linear mixed-effects models. Results Twenty participants with IS (mean age, 61 years ± 13 [SD]; 12 women) and 20 HVs (mean age, 59 years ± 13; 12 women) were evaluated. No differences in ADCs or concentrations were observed in VOIcl between HVs and participants with IS. In participants with IS, the ADC of tCr was higher in VOIles than in VOIcl at 1 month (+14.4%, P = .004) and 3 months after IS (+19.0%, P < .001), while the ADC of tCho was higher only at 1 month (+16.7%, P = .001). No difference in the ADC of tNAA was observed between the two VOIs at any time point. tNAA and tCr concentrations were lower in VOIles than in VOIcl and were stable over time (approximately -50% and -30%, respectively; P < .001). Conclusion High diffusivity of choline-containing compounds and total creatine (tCr) in the ischemic lesion 1 month after ischemic stroke (IS) indicates glial morphologic changes, suggesting that active inflammation is still ongoing at this time point. High tCr diffusivity up to 3 months after IS likely reflects the presence of astrogliosis at the chronic stage of cerebral ischemia. Clinical trial registration no. NCT02833961 © RSNA, 2022 Online supplemental material is available for this article.

Project description: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 (?) 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 ((1)H-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, ?, 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 ?).

Dataset Information

Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra-axonal constituent N-acetylaspartate.

Publications

Longitudinal MR spectroscopy of neurodegeneration in multiple sclerosis with diffusion of the intra-axonal constituent <i>N</i>-acetylaspartate.

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