Characterization of normal-appearing white matter in multiple sclerosis using quantitative susceptibility mapping in conjunction with diffusion tensor imaging.
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ABSTRACT:
SUBMITTER: Yu FF
PROVIDER: S-EPMC6415662 | biostudies-literature | 2019 Jan
REPOSITORIES: biostudies-literature
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Characterization of normal-appearing white matter in multiple sclerosis using quantitative susceptibility mapping in conjunction with diffusion tensor imaging.
Yu Fang F FF Chiang Florence L FL Stephens Nicholas N Huang Susie Y SY Bilgic Berkin B Tantiwongkosi Bundhit B Romero Rebecca R
Neuroradiology 20181212 1
<h4>Purpose</h4>Quantitative susceptibility mapping (QSM) is influenced by iron as well as myelin, which makes interpretation of pathologic changes challenging. Concurrent acquisition of MR sequences that are sensitive to axonal/myelin integrity, such as diffusion tensor imaging (DTI), may provide context for interpreting quantitative susceptibility (QS) signal. The purpose of our study was to investigate alterations in normal-appearing white matter (NAWM) in multiple sclerosis (MS) using QSM in ...[more]
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Project description:Neuronal damage is the primary cause of long-term disability of multiple sclerosis (MS) patients. Assessment of axonal integrity from diffusion MRI parameters might enable better disease characterisation. 16 diffusion derived measurements from diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and fixel-based analysis (FBA) in lesions, peri-lesion and normal appearing white matter were investigated. Diffusion MRI scans of 11 MS patients were processed to generate DTI, DKI, and FBA images. Fractional anisotropy (FA) and fibre density (FD) were used to assess axonal integrity across brain regions. Subsequently, 359 lesions were identified, and lesion and peri-lesion segmentation was performed using structural T1w, T2w, T2w-FLAIR, and T1w post-contrast MRI. The segmentations were then used to extract 16 diffusion MRI parameters from lesion, peri-lesion, and contralateral normal appearing white matter (NAWM). The measurements for axonal integrity, DTI-FA, DKI-FA, FBA-FD, produced similar results. All diffusion MRI parameters were affected in lesions as compared to NAWM (p < 0.001), confirming loss of axonal integrity in lesions. In peri-lesions, most parameters, except FBA-FD, were also significantly different from NAWM, although the effect size was smaller than in lesions. The reduction in axonal integrity in peri-lesions, despite unaffected fibre density estimates, suggests an effect of Wallerian degeneration.
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Project description:The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains.Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels.Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity.The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.
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Project description:Our aim was to characterize the nature and extent of pathological changes in the normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS) using novel diffusion kurtosis imaging-derived white matter tract integrity (WMTI) metrics and to investigate the association between these WMTI metrics and clinical parameters. Thirty-two patients with relapsing-remitting MS and 19 age- and gender-matched healthy controls underwent MRI and neurological examination. Maps of mean diffusivity, fractional anisotropy and WMTI metrics (intra-axonal diffusivity, axonal water fraction, tortuosity and axial and radial extra-axonal diffusivity) were created. Tract-based spatial statistics analysis was performed to assess for differences in the NAWM between patients and controls. A region of interest analysis of the corpus callosum was also performed to assess for group differences and to evaluate correlations between WMTI metrics and measures of disease severity. Mean diffusivity and radial extra-axonal diffusivity were significantly increased while fractional anisotropy, axonal water fraction, intra-axonal diffusivity and tortuosity were decreased in MS patients compared with controls (p values ranging from <0.001 to <0.05). Axonal water fraction in the corpus callosum was significantly associated with the expanded disability status scale score (ρ = -0.39, p = 0.035). With the exception of the axial extra-axonal diffusivity, all metrics were correlated with the symbol digits modality test score (p values ranging from 0.001 to <0.05). WMTI metrics are thus sensitive to changes in the NAWM of MS patients and might provide a more pathologically specific, clinically meaningful and practical complement to standard diffusion tensor imaging-derived metrics.
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Project description:In this study, we perform a region of interest diffusion tensor imaging and advanced diffusion complexity analysis of normal appearing white matter to determine the impact of vascular health on these diffusivity metrics in midlife adults. 77 participants (26 black, 35 female) at year 30 visit in the Coronary Artery Risk Development in Young Adults longitudinal study were scanned with an advanced diffusion-weighted imaging and fluid-attenuated inversion recovery protocol. Fractional anisotropy and non-linear diffusion complexity measures were estimated. Cumulative measures across 30 years (9 study visits) of systolic blood pressure, body mass index, glucose, smoking and cholesterol were calculated as the area under the curve from baseline up to year 30 examination. Partial correlation analyses assessed the association between cumulative vascular health measures and normal appearing white matter diffusion metrics in these participants. Midlife normal appearing white matter diffusion properties were significantly associated (P < 0.05) with cumulative exposure to vascular risk factors from young adulthood over the 30-year time period. Higher cumulative systolic blood pressure exposure was associated with increased complexity and decreased fractional anisotropy. Higher cumulative body mass index exposure was associated with decreased fractional anisotropy. Additionally, in the normal appearing white matter of black participants (P < 0.05), who exhibited a higher cumulative vascular risk exposure, fractional anisotropy was lower and complexity was higher in comparison to normal appearing white matter in white participants. Higher burden of vascular risk factor exposure from young adulthood to midlife is associated with changes in the diffusion properties of normal appearing white matter in midlife. These changes which may reflect axonal disruption, increased inflammation and/or increased glial proliferation, were primarily observed in both anterior and posterior normal appearing white matter regions of the corpus callosum. These results suggest that microstructural changes in normal appearing white matter are sensitive to vascular health during young adulthood and are possibly therapeutic targets in interventions focused on preserving white matter health across life.
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Project description:Background and purposeLoss of integrity in nonlesional white matter occurs as a fundamental feature of multiple sclerosis in adults. The purpose of our study was to evaluate DTI-derived measures of white matter microstructure in children with MS compared with age- and sex-matched controls by using tract-based spatial statistics.Materials and methodsFourteen consecutive pediatric patients with MS (11 female/3 male; mean age, 15.1 ± 1.6 years; age range, 12-17 years) and age- and sex-matched healthy subjects (11 female/3 male; mean age, 14.8 ± 1.7 years) were included in the study. After we obtained DTI sequences, data processing was performed by using tract-based spatial statistics.ResultsCompared with healthy age- and sex-matched controls, children with multiple sclerosis showed a global decrease in mean fractional anisotropy (P ≤ .001), with a concomitant increase in mean (P < .001), radial (P < .05), and axial diffusivity (P < .001). The most pronounced fractional anisotropy value decrease in patients with MS was found in the splenium of the corpus callosum (P < .001). An additional decrease in fractional anisotropy was identified in the right temporal and right and left parietal regions (P < .001). Fractional anisotropy of the white matter skeleton was related to disease duration and may, therefore, serve as a diagnostic marker.ConclusionsThe microstructure of white matter is altered early in the disease course in childhood multiple sclerosis.
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Project description:Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images ('nanotomy') of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury.
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Project description:Background and purposeBrain white matter is frequently affected in mitochondrial diseases; optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy are the most frequent mitochondrial monosymptomatic optic neuropathies. In this observational study, brain white matter microstructure was characterized by DTI in patients with optic atrophy gene 1-autosomal dominant optic atrophy and Leber hereditary optic neuropathy, in relation to clinical and genetic features.Materials and methodsNineteen patients with optic atrophy gene 1-autosomal dominant optic atrophy and 17 with Leber hereditary optic neuropathy older than 18 years of age, all genetically diagnosed, and 19 healthy volunteers underwent DTI by using a 1.5T MR imaging scanner and neurologic and ophthalmologic assessments. Brain white matter DTI metrics were calculated for all participants, and, in patients, their correlations with genetics and clinical findings were calculated.ResultsCompared with controls, patients with optic atrophy gene 1-autosomal dominant optic atrophy had an increased mean diffusivity in 29.2% of voxels analyzed within major white matter tracts distributed throughout the brain, while fractional anisotropy was reduced in 30.3% of voxels. For patients with Leber hereditary optic neuropathy, the proportion of altered voxels was only 0.5% and 5.5%, respectively, of which half was found within the optic radiation and 3.5%, in the smaller acoustic radiation. In almost all regions, fractional anisotropy diminished with age in patients with optic atrophy gene 1-autosomal dominant optic atrophy and correlated with average retinal nerve fiber layer thickness in several areas. Mean diffusivity increased in those with a missense mutation. Patients with Leber hereditary optic neuropathy taking idebenone had slightly milder changes.ConclusionsPatients with Leber hereditary optic neuropathy had preferential involvement of the optic and acoustic radiations, consistent with trans-synaptic degeneration, whereas patients with optic atrophy gene 1-autosomal dominant optic atrophy presented with widespread involvement suggestive of a multisystemic, possibly a congenital/developmental, disorder. White matter changes in Leber hereditary optic neuropathy and optic atrophy gene 1-autosomal dominant optic atrophy may be exploitable as biomarkers.
| S-EPMC7965282 | biostudies-literature