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Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis.

ABSTRACT: Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions.

SUBMITTER: Lipp I

PROVIDER: S-EPMC6563497 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Irreversible white matter (WM) damage, including severe demyelination and axonal loss, is a main determinant of long-term disability in multiple sclerosis (MS). Non-invasive detection of changes in microstructural WM integrity in the disease is challenging since commonly used imaging metrics lack the necessary sensitivity, especially in the early phase of the disease. This study aims at assessing microstructural WM abnormalities in early-stage MS by using ultra-high gradient strength multi-shell diffusion MRI and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED), a metric sensitive to the volume fraction of axons. In 22 early MS subjects (disease duration ?5?years) and 15 age-matched healthy controls, restricted fraction estimates were obtained through the CHARMED model along with conventional Diffusion Tensor Imaging (DTI) metrics. All imaging parameters were compared cross-sectionally between the MS subjects and controls both in WM lesions and normal-appearing white matter (NAWM). We found a significant reduction in FR focally in WM lesions and widespread in the NAWM in MS patients relative to controls (corrected p?<?.05). Signal fraction changes in NAWM were not driven by perilesional tissue, nor were they influenced by proximity to the ventricles, challenging the hypothesis of an outside-in pathological process driven by CSF-mediated immune cytotoxic factors. No significant differences were found in conventional DTI parameters. In a cross-validated classification task, FR showed the largest effect size and outperformed all other diffusion imaging metrics in discerning lesions from contralateral NAWM. Taken together, our data provide evidence for the presence of widespread microstructural changes in the NAWM in early MS stages that are, at least in part, unrelated to focal demyelinating lesions. Interestingly, these pathological changes were not yet detectable by conventional diffusion imaging at this early disease stage, highlighting the sensitivity and value of multi-shell diffusion imaging for better characterizing axonal microstructure in MS.

Project description:IntroductionWhite matter damage in the visual pathway is common in multiple sclerosis (MS) and is associated with retinal thinning, although the underlying mechanism of association remains unclear. The goal of this work was to evaluate the presence and extent of white matter tract integrity (WMTI) alterations in the optic radiation (OR) in people with MS and to investigate the association between WMTI metrics and retinal thinning in the eyes of MS patients without a history of optic neuritis (ON) as measured by optical coherence tomography (OCT). We hypothesized that WMTI metrics would reflect axonal damage that occurs in the OR in MS, and that axonal alterations revealed by WMTI would be associated with retinal thinning.MethodsTwenty-nine MS patients without previous ON in at least one eye and twenty-nine age-matched healthy controls (HC) were scanned on a dedicated high-gradient 3-Tesla MRI scanner with 300 mT/m maximum gradient strength using a multi-shell diffusion MRI protocol (b = 800, 1500, 2400 s/mm2). The patients were divided into two subgroups according to history without ON (N = 18) or with ON in one eye (N = 11). Diffusion tensor imaging (DTI) metrics and WMTI metrics derived from diffusion kurtosis imaging were assessed in normal-appearing white matter (NAWM) of the OR and in focal lesions. Retinal thickness in the eyes of MS patients was measured by OCT. Student's t-test was used to assess group differences between MRI metrics. Linear regression was used to study the relationship between OCT metrics, including retinal nerve fiber layer (RNFL) and combined ganglion cell and inner plexiform layer thickness (GCL/IPL), visual acuity measures and DTI and WMTI metrics.ResultsOR NAWM in MS showed significantly decreased axonal water fraction (AWF) compared to HC (0.36 vs 0.39, p < 0.001), with similar trends observed in AWF of lesions compared to NAWM (0.27 vs 0.36, p < 0.001). Fractional anisotropy (FA) was lower in OR NAWM of MS patients compared to HC (0.49 vs 0.52, p < 0.001). In patients without ON, AWF was the only diffusion MRI metric that was significantly associated with average RNFL (r = 0.68, p = 0.005), adjusting for age, sex and disease duration and correcting for multiple comparisons. Of all the DTI and WMTI metrics, AWF was the strongest and most significant predictor of average RNFL thickness in MS patients without ON. There was no significant correlation between visual acuity scores and DTI or WMTI metrics after correction for multiple comparisons.ConclusionAxonal damage may be the substrate of previously observed DTI alterations in the OR, as supported by the significant reduction in AWF within both NAWM and lesions of the OR in MS. Our results support the concept that axonal damage is widespread throughout the visual pathway in MS and may be mediated through trans-synaptic degeneration.

Project description:Multiple sclerosis leads to diffuse damage of the central nervous system, affecting also the normal-appearing white matter. Demyelination and axonal degeneration reduce regional fractional anisotropy in normal-appearing white matter, which can be routinely mapped with diffusion tensor imaging. However, the standard fractional anisotropy metric is also sensitive to physiological variations in orientation dispersion of white matter fibres. This complicates the detection of disease-related damage in large parts of cerebral white matter where microstructure physiologically displays a high degree of fibre dispersion. To resolve this ambiguity, we employed a novel tensor-valued encoding method for diffusion MRI, which yields a microscopic fractional anisotropy metric that is unaffected by regional variations in orientation dispersion. In 26 patients with relapsing-remitting multiple sclerosis, 14 patients with primary-progressive multiple sclerosis and 27 age-matched healthy controls, we compared standard fractional anisotropy mapping with the novel microscopic fractional anisotropy mapping method, focusing on normal-appearing white matter. Mean microscopic fractional anisotropy and standard fractional anisotropy of normal-appearing white matter were significantly reduced in both patient groups relative to healthy controls, but microscopic fractional anisotropy yielded a better reflection of disease-related white-matter alterations. The reduction in mean microscopic fractional anisotropy showed a significant positive linear relationship with physical disability, as reflected by the expanded disability status scale. Mean reduction of microscopic fractional anisotropy in normal-appearing white matter also scaled positively with individual cognitive dysfunction, as measured with the symbol digit modality test. Mean microscopic fractional anisotropy reduction in normal-appearing white matter also showed a positive relationship with total white-matter lesion load as well as lesion load in specific tract systems. None of these relationships between normal-appearing white-matter microstructure and clinical, cognitive or structural measures emerged when using mean fractional anisotropy. Together, the results provide converging evidence that microscopic fractional anisotropy mapping substantially advances the assessment of cerebral white matter in multiple sclerosis by disentangling microstructure damage from variations in physiological fibre orientation dispersion at the stage of data acquisition. Since tensor-valued encoding can be implemented in routine diffusion MRI, microscopic fractional anisotropy mapping bears considerable potential for the future assessment of disease progression in normal-appearing white matter in both relapsing-remitting and progressive forms of multiple sclerosis as well as other white-matter-related brain diseases.

Project description:BackgroundPreterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI).MethodsWe studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2-33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38-45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance.ResultsIdentified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance.ConclusionThis study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

Project description:PurposeQuantitative assessment of white matter hyperintensities (WMH) on structural Magnetic Resonance Imaging (MRI) is challenging. It is important to harmonise results from different software tools considering not only the volume but also the signal intensity. Here we propose and evaluate a metric of white matter (WM) damage that addresses this need.MethodsWe obtained WMH and normal-appearing white matter (NAWM) volumes from brain structural MRI from community dwelling older individuals and stroke patients enrolled in three different studies, using two automatic methods followed by manual editing by two to four observers blind to each other. We calculated the average intensity values on brain structural fluid-attenuation inversion recovery (FLAIR) MRI for the NAWM and WMH. The white matter damage metric is calculated as the proportion of WMH in brain tissue weighted by the relative image contrast of the WMH-to-NAWM. The new metric was evaluated using tissue microstructure parameters and visual ratings of small vessel disease burden and WMH: Fazekas score for WMH burden and Prins scale for WMH change.ResultsThe correlation between the WM damage metric and the visual rating scores (Spearman ρ > =0.74, p < 0.0001) was slightly stronger than between the latter and WMH volumes (Spearman ρ > =0.72, p < 0.0001). The repeatability of the WM damage metric was better than WM volume (average median difference between measurements 3.26% (IQR 2.76%) and 5.88% (IQR 5.32%) respectively). The follow-up WM damage was highly related to total Prins score even when adjusted for baseline WM damage (ANCOVA, p < 0.0001), which was not always the case for WMH volume, as total Prins was highly associated with the change in the intense WMH volume (p = 0.0079, increase of 4.42 ml per unit change in total Prins, 95%CI [1.17 7.67]), but not with the change in less-intense, subtle WMH, which determined the volumetric change.ConclusionThe new metric is practical and simple to calculate. It is robust to variations in image processing methods and scanning protocols, and sensitive to subtle and severe white matter damage.

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Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis.

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