Matter Lesions In Multiple Sclerosis Research Articles

Transcript Profiles of Microglia/Macrophage Cells at the Borders of Chronic Active and Subpial Gray Matter Lesions in Multiple Sclerosis.

Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and the cortex in the brains of multiple sclerosis patients. Microglia/macrophages associated with chronic white matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis, whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression. We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNA sequencing on isolated cells followed by immunocytochemistry to determine the distribution of translational products of transcripts increased in WM line microglia. Cells in the WM line appear activated, with shorter processes and larger cell bodies, whereas those in the GM line appear more homeostatic, with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line microglia, whereas genes belonging to the canonical Wnt signaling pathway were increased in GM line microglia. We propose that the mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of the Fc epsilon receptor, spleen tyrosine kinase, and Bruton's tyrosine kinase, play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions. ANN NEUROL 2024;95:907-916.

Characterization of white matter lesions in multiple sclerosis using proton density and T1-relaxation measures

PurposeAlthough lesion dissemination in time is a defining characteristic of multiple sclerosis (MS), there is a limited understanding of lesion heterogeneity. Currently, conventional sequences such as fluid attenuated inversion recovery (FLAIR) and T1-weighted (T1W) data are used to assess MS lesions qualitatively. Estimating water content could provide a measure of local tissue rarefaction, or reduced tissue density, resulting from chronic inflammation. Our goal was to utilize the proton spin density (PD), derived from a rapid, multi-contrast STAGE (strategically acquired gradient echo) protocol to characterize white matter (WM) lesions seen on T2W, FLAIR and T1W data. Materials and methodsTwenty (20) subjects with relapsing-remitting MS were scanned at 3 T using T1W, T2-weighted, FLAIR and strategically acquired gradient echo (STAGE) sequences. PD and T1 maps were derived from the STAGE data. Disease severity scores, including Extended Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), were correlated with total, high PD and high T1 lesion volumes. A probability map of high PD regions and all lesions across all subjects was generated. Five perilesional normal appearing WM (NAWM) bands surrounding the lesions were generated to compare the median PD and T1 values in each band with the lesional values and the global WM. ResultsT1W intensity was negatively correlated with PD as expected (R = −0.87, p < 0.01, R2 = 0.756) and the FLAIR signal was suppressed for high PD volumes within the lesions, roughly for PD ≥ 0.85. The threshold for high PD and T1 regions was set to 0.909 and 1953.6 ms, respectively. High PD regions showed a high probability of occurrence near the boundary of the lateral ventricles. EDSS score and nine-hole peg test (dominant and non-dominant hand) were significantly correlated with the total lesion volume and the volumes of high PD and T1 regions (p < 0.05). There was a significant difference in PD/T1 values between the high PD/T1 regions within the lesions and the remaining lesional tissue (p < 0.001). In addition, the PD values of the first NAWM perilesional band directly adjacent to the lesional boundary displayed a significant difference (p < 0.05) compared to the global WM. ConclusionLesions with high PD and T1s had the highest probability of occurrence at the boundary of the lateral ventricles and likely represent chronic lesions with significant local tissue rarefaction. Moreover, the perilesional NAWM exhibited subtly increasing PD and T1 values from the NAWM up to the lesion boundary. Unlike on the T1 maps, the perilesional band adjacent to the lesion boundary possessed a significantly higher PD value than the global WM PD values. This shows that PD maps were sensitive to the subtle changes in NAWM surrounding the lesions.

A polynomial regression-based approach to estimate relaxation rate maps suitable for multiparametric segmentation of clinical brain MRI studies in multiple sclerosis

Background and ObjectiveRelaxation parameter maps (RPMs) calculated from spin-echo data have provided a basis for the segmentation of normal brain tissues and white matter lesions in multiple sclerosis (MS) MRI studies. However, Conventional Spin-Echo (CSE) sequences, once the core of clinical MRI studies, have been largely replaced by faster ones, which do not allow the calculation a-posteriori of RPMs from clinical studies. Aim of the study was to develop and validate a method to estimate RPMs (pseudo-RPMs) from routine clinical MRI protocols (including 3D-Gradient Echo T1w, FLAIR and fast-T2w sequences), suitable for fully automatic multiparametric segmentation of normal-appearing and pathological brain tissues in MS. MethodsThe proposed method processes spatially normalized clinical MRI studies through a multistep pipeline, to collect a set of data points of matched signal intensities (from MRI studies) and relaxation parameters (from a CSE-derived digital template and an MS lesion database), which are then fitted by a multiple and multivariate 4-th degree polynomial regression, providing pseudo-RPMs. The method was applied to a dataset of 59 clinical MRI studies providing pseudo-RPMs that were segmented through a method originally developed for the CSE-derived RPMs. Results of the segmentation in 12 studies were used to iteratively optimize method parameters. Accuracy of segmentation of normal-appearing brain tissues from the pseudo-RPMs was assessed by comparing their age-related changes, as measured in 47 clinical studies, against those measured acquired using CSE sequences in a comparable dataset of 47 patients. Lesion segmentation was validated against manual segmentation carried out by three neuroradiologists. ResultsAge-related changes of normal-appearing brain tissue volumes measured using the pseudo-RPMs substantially overlapped those measured using the RPMs obtained from CSE sequences, and segmentation of MS lesions showed a moderate-high spatial overlap with manual segmentation, comparable to that achieved by the widely used Lesion Segmentation Tool on FLAIR images, with a greater volumetric agreement. ConclusionsThe proposed approach allows calculation from clinical studies of pseudo-RPMs, which are equivalent to those obtainable from CSE sequences, avoiding the need for the acquisition of additional, dedicated sequences for segmentation purposes.

Detection of Cortical and Deep Gray Matter Lesions in Multiple Sclerosis Using DIR and FLAIR at 3T.

The comparative detection rates of deep gray matter (GM) multiple sclerosis (MS) lesions using double inversion recovery (DIR) and fluid-attenuated inversion-recovery (FLAIR) on 3T MR imaging remain unknown. We aimed to assess the detectability of cortical and deep GM MS lesions using DIR and FLAIR on 3T clinical exams and evaluate the relationship between deep GM lesions and brain atrophy. One hundred fifty consecutive MS patients underwent routine brain MRI that included 3D DIR and 2D T2 FLAIR on the same 3T scanner. Three neuroradiologists independently reviewed all exams for cortical and deep GM lesions. Statistical parametric mapping (SPM) and FMRIB software library (FSL)-FIRST pipelines were used to determine normalized whole brain and deep GM volumes. A total of 65 cortical and 98 deep lesions were detected on DIR versus 24 and 20, respectively, on FLAIR. Among all 150 patients, the number and percentage of patients with GM lesions on DIR and FLAIR were as follows: cortical 43 (28.7%) versus 24 (16.0%) (P < .001), thalamus 47 (31.3%) versus 20 (13.3%) (P<.001), putamen 10 (6.7%) versus 3 (2.0%) (P = .02), globus pallidus 9 (6.0%) versus 3 (1.3%) (P = .02), and caudate 5 (3.3%) versus 1 (0.7%) (P = .125). Presence of deep GM lesions weakly correlated with deep GM volume fractions. Deep GM MS lesions can be detected using routine clinical brain MRI including DIR and FLAIR at 3T. Future studies to optimize these sequences may improve the detection rates of cortical and deep GM lesions. The presence of GM lesions showed weak correlation with GM atrophy.

MicroRNAs in gray and white matter multiple sclerosis lesions: impact on pathophysiology.

Multiple sclerosis (MS) is a chronic disease of the CNS, hallmarked by inflammation and demyelination. Early stages of the disease frequently show active lesions containing numerous foamy macrophages and inflammatory cells. Disease progression is highlighted by increasing numbers of mixed active/inactive or inactive lesions showing sparse inflammation and pronounced astrogliosis. Furthermore, gray matter lesions increase in number and extent during disease progression. MicroRNAs (miRNAs) comprise a group of several thousand (in humans more than 2000), small non-coding RNA molecules with a fundamental influence on about one-third of all protein-coding genes. Furthermore, miRNAs have been detected in body fluids, including spinal fluid, and they are assumed to participate in intercellular communications. Several studies have determined miRNA profiles from dissected white and gray matter lesions of autoptic MS patients. In this review, we summarize in detail the current knowledge of individual miRNAs in gray and white matter lesions of MS patients and present the concepts of MS tissue lesion development based on the altered miRNA profiles. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

The extracellular matrix (ECM) provides protection, rigidity, and structure toward cells. It consists, among others, of a wide variety of glycoproteins and proteoglycans, which act together to produce a complex and dynamic environment, most relevant in transmembrane events. In the brain, the ECM occupies a notable proportion of its volume and maintains the homeostasis of central nervous system (CNS). In addition, remodeling of the ECM, that is transient changes in ECM proteins regulated by matrix metalloproteinases (MMPs), is an important process that modulates cell behavior upon injury, thereby facilitating recovery. Failure of ECM remodeling plays an important role in the pathogenesis of multiple sclerosis (MS), a neurodegenerative demyelinating disease of the CNS with an inflammatory response against protective myelin sheaths that surround axons. Remyelination of denuded axons improves the neuropathological conditions of MS, but this regeneration process fails over time, leading to chronic disease progression. In this review, we uncover abnormal ECM remodeling in MS lesions by discussing ECM remodeling in experimental demyelination models, that is when remyelination is successful, and compare alterations in ECM components to the ECM composition and MMP expression in the parenchyma of demyelinated MS lesions, that is when remyelination fails. Inter- and intralesional differences in ECM remodeling in the distinct white matter MS lesions are discussed in terms of consequences for oligodendrocyte behavior and remyelination (failure). Hence, the review will aid to understand how abnormal ECM remodeling contributes to remyelination failure in MS lesions and assists in developing therapeutic strategies to promote remyelination.

Anakinra for the Treatment of Chronically Inflamed White Matter Lesions in Multiple Sclerosis

Anakinra for the Treatment of Chronically Inflamed White Matter Lesions in Multiple Sclerosis

Tissue Transglutaminase Appears in Monocytes and Macrophages but Not in Lymphocytes in White Matter Multiple Sclerosis Lesions.

Leukocyte infiltration is an important pathological hallmark of multiple sclerosis (MS) and is therefore targeted by current MS therapies. The enzyme tissue transglutaminase (TG2) contributes to monocyte/macrophage migration and is present in MS lesions and could be a potential therapeutic target. We examined the cellular identity of TG2-expressing cells by immunohistochemistry in white matter lesions of 13 MS patients; 9 active and chronic active lesions from 4 patients were analyzed in detail. In these active MS lesions, TG2 is predominantly expressed in leukocytes (CD45+) but not in cells of the lymphocyte lineage, that is, T cells (CD3+) and B cells (CD20+). In general, cells of the monocyte/macrophage lineage (CD11b+ or CD68+) are TG2+ but no further distinction could be made regarding pro- or anti-inflammatory macrophage subtypes. In conclusion, TG2 is abundantly present in cells of the monocyte/macrophage lineage in active white matter MS lesions. We consider that TG2 can play a role in MS as it is associated with macrophage infiltration into the CNS. As such, TG2 potentially presents a novel target for therapeutic intervention that can support available MS therapies targeting lymphocyte infiltration.

Automated segmentation of changes in FLAIR-hyperintense white matter lesions in multiple sclerosis on serial magnetic resonance imaging.

Longitudinal analysis of white matter lesion changes on serial MRI has become an important parameter to study diseases with white-matter lesions. Here, we build on earlier work on cross-sectional lesion segmentation; we present a fully automatic pipeline for serial analysis of FLAIR-hyperintense white matter lesions. Our algorithm requires three-dimensional gradient echo T1- and FLAIR- weighted images at 3 Tesla as well as available cross-sectional lesion segmentations of both time points. Preprocessing steps include lesion filling and intrasubject registration. For segmentation of lesion changes, initial lesion maps of different time points are fused; herein changes in intensity are analyzed at the voxel level. Significance of lesion change is estimated by comparison with the difference distribution of FLAIR intensities within normal appearing white matter. The method is validated on MRI data of two time points from 40 subjects with multiple sclerosis derived from two different scanners (20 subjects per scanner). Manual segmentation of lesion increases served as gold standard. Across all lesion increases, voxel-wise Dice coefficient (0.7) as well as lesion-wise detection rate (0.8) and false-discovery rate (0.2) indicate good overall performance. Analysis of scans from a repositioning experiment in a single patient with multiple sclerosis did not yield a single false positive lesion. We also introduce the lesion change plot as a descriptive tool for the lesion change of individual patients with regard to both number and volume. An open source implementation of the algorithm is available at http://www.statistical-modeling.de/lst.html.

Cuprizone-induced demyelination in the mouse hippocampus is alleviated by phytoestrogen genistein

One of the major female sex hormones, estrogen, can influence a variety of mental states. Individuals with multiple sclerosis (MS) often suffer from mental health issues, which are correlated with the pathology of gray matter. In this study, we aimed to elucidate the validity of phytoestrogen genistein (GEN) for treating the gray matter lesions in MS using the mouse model of cuprizone (CPZ)-induced demyelination. First, we confirmed that 5-week 0.2% CPZ intoxication induced demyelination in the hippocampus, and that myelination was successfully recovered by GEN. Loss of mature oligodendrocytes following CPZ intoxication was counteracted by GEN. Neither CPZ nor GEN affected the densities of oligodendrocyte precursor cells and astrocytes. CPZ-induced activation and proliferation of microglia were not inhibited by GEN. Upregulation of gene expression of the pro-inflammatory cytokine, interleukin-1β, in sorted microglia by CPZ was not inhibited by GEN either. However, the expression levels of genes related to phagocytosis, such as cluster of differentiation 68 and lysosomal-associated membrane protein 1, in sorted microglia were elevated by CPZ but lowered by GEN. Notably, physical contact of microglia with myelin was increased by CPZ but decreased by GEN. The expression levels of myelin-related genes, such as myelin basic protein and myelin oligodendrocyte glycoprotein, in the whole hippocampal tissue were decreased by CPZ but recovered by GEN. These results show that GEN may act on mature oligodendrocytes in the hippocampus by promoting their survival and myelin formation, and suggest the therapeutic potential of phytoestrogens for treating MS patients suffering from mental health issues.

Significance and In Vivo Detection of Iron-Laden Microglia in White Matter Multiple Sclerosis Lesions.

Microglia are resident immune cells that fulfill protective and homeostatic functions in the central nervous system (CNS) but may also promote neurotoxicity in the aged brain and in chronic disease. In multiple sclerosis (MS), an autoimmune demyelinating disease of the CNS, microglia and macrophages contribute to the development of white matter lesions through myelin phagocytosis, and possibly to disease progression through diffuse activation throughout myelinated white matter. In this review, we discuss an additional compartment of myeloid cell activation in MS, i.e., the rim and normal adjacent white matter of chronic active lesions. In chronic active lesions, microglia and macrophages may contain high amounts of iron, express markers of proinflammatory polarization, are activated for an extended period of time (years), and drive chronic tissue damage. Iron-positive myeloid cells can be visualized and quantified with quantitative susceptibility mapping (QSM), a magnetic resonance imaging technique. Thus, QSM has potential as an in vivo biomarker for chronic inflammatory activity in established white matter MS lesions. Reducing chronic inflammation associated with iron accumulation using existing or novel MS therapies may impact disease severity and progression.

Diagnosis of gray matter lesions in multiple sclerosis using variant sequences of magnetic resonance imaging (T2, fluid-attenuated inversion recovery, and double inversion recovery)

Background and aim Gray matter atrophy is significantly correlated with both physical and cognitive disability in patients with multiple sclerosis (MS). Patients and methods The study was conducted on 40 patients with definite relapsing-remitting MS according to McDonald criteria. All patients were subjected to conventional MRI [T2 and fluid-attenuated inversion recovery (FLAIR) sequences] and double inversion recovery (DIR) sequence to assess their sensitivity for detecting gray matter lesions in patients with MS. Results Comparative studies between serial MRI sequences revealed highly significant increase in detected number of white matter lesions in FLAIR and DIR-MRI sequences (P=0.0007). Comparative studies also revealed a nonsignificant difference in detection rate in all 3 MRI sequences (P>0.05). Moreover, there were significant increases in detected number of gray matter lesions in DIR-MRI sequences (P=0.021) and a highly significant increase in detection rate in DIR-MRI sequences compared with T2 and FLAIR-MRI sequences (P Conclusion DIR is a valuable MRI sequence in imaging of MS because of the following: (a) it showed better delineation between the white matter, the gray matter, and the MS lesions owing to its high image contrast measurements; (b) it detected more MS lesions compared with T2WI and FLAIR sequences in all anatomic locations; (c) it revealed more periventricular and juxta-cortical MS lesions, which are characteristic of MS; and (d) it detected more intracortical lesions as well, which should be considered in all patients with MS.

Seven-Tesla Magnetization Transfer Imaging to Detect Multiple Sclerosis White Matter Lesions.

Fluid-attenuated inversion recovery (FLAIR) imaging at 3 Tesla (T) field strength is the most sensitive modality for detecting white matter lesions in multiple sclerosis. While 7T FLAIR is effective in detecting cortical lesions, it has not been fully optimized for visualization of white matter lesions and thus has not been used for delineating lesions in quantitative magnetic resonance imaging (MRI) studies of the normal appearing white matter in multiple sclerosis. Therefore, we aimed to evaluate the sensitivity of 7T magnetization-transfer-weighted (MTw ) images in the detection of white matter lesions compared with 3T-FLAIR. Fifteen patients with clinically isolated syndrome, 6 with multiple sclerosis, and 10 healthy participants were scanned with 7T 3-dimensional (D) MTw and 3T-2D-FLAIR sequences on the same day. White matter lesions visible on either sequence were delineated. Of 662 lesions identified on 3T-2D-FLAIR images, 652 were detected on 7T-3D-MTw images (sensitivity, 98%; 95% confidence interval, 97% to 99%). The Spearman correlation coefficient between lesion loads estimated by the two sequences was .910. The intrarater and interrater reliability for 7T-3D-MTw images was good with an intraclass correlation coefficient (ICC) of 98.4% and 81.8%, which is similar to that for 3T-2D-FLAIR images (ICC 96.1% and 96.7%). Seven-Tesla MTw sequences detected most of the white matter lesions identified by FLAIR at 3T. This suggests that 7T-MTw imaging is a robust alternative for detecting demyelinating lesions in addition to 3T-FLAIR. Future studies need to compare the roles of optimized 7T-FLAIR and of 7T-MTw imaging.

Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis.

Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient's disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

Patient-specific 3D FLAIR for enhanced visualization of brain white matter lesions in multiple sclerosis.

To improve the conspicuity of white matter lesions (WMLs) in multiple sclerosis (MS) using patient-specific optimization of single-slab 3D fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Sixteen MS patients were enrolled in a prospective 3.0T MRI study. FLAIR inversion time and echo time were automatically optimized for each patient during the same scan session based on measurements of the relative proton density and relaxation times of the brain tissues. The optimization criterion was to maximize the contrast between gray matter (GM) and white matter (WM), while suppressing cerebrospinal fluid. This criterion also helps increase the contrast between WMLs and WM. The performance of the patient-specific 3D FLAIR protocol relative to the fixed-parameter protocol was assessed both qualitatively and quantitatively. Patient-specific optimization achieved a statistically significant 41% increase in the GM-WM contrast ratio (P < 0.05) and 32% increase in the WML-WM contrast ratio (P < 0.01) compared with fixed-parameter FLAIR. The increase in WML-WM contrast ratio correlated strongly with echo time (P < 10-11 ). Two experienced neuroradiologists indicated substantially higher lesion conspicuity on the patient-specific FLAIR images over conventional FLAIR in 3-4 cases (intrarater correlation coefficient ICC = 0.72). In no case was the image quality of patient-specific FLAIR considered inferior to conventional FLAIR by any of the raters (ICC = 0.32). Changes in proton density and relaxation times render fixed-parameter FLAIR suboptimal in terms of lesion contrast. Patient-specific optimization of 3D FLAIR increases lesion conspicuity without scan time penalty, and has potential to enhance the detection of subtle and small lesions in MS. 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:557-564.

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). White matter lesions in MS are surrounded by areas of non-demyelinated normal appearing white matter (NAWM) with complex pathology, including blood brain barrier dysfunction, axonal damage and glial activation. Astrocytes, the most abundant cell type within the CNS, may respond and/or contribute to lesion pathogenesis. We aimed to characterise the transcriptomic profile of astrocytes in NAWM to determine whether specific glial changes exist in the NAWM which contribute to lesion development or prevent disease progression.Astrocytes were isolated from control and NAWM by laser capture microdissection (LCM), using glial fibrillary acidic protein (GFAP) as a marker, and the astrocyte transcriptome determined using microarray analysis. 452 genes were significantly differentially expressed (208 up-regulated and 244 down-regulated, FC≥1.5 and p-value≤0.05). Within the NAWM, astrocytes were associated with significant upregulation of genes involved in the control of iron homeostasis (including metallothionein-1 and -2, ferritin light chain and transferrin), oxidative stress responses, the immune response and neurotrophic support. These findings suggest a neuroprotective role of astrocytes in the NAWM in MS.

In Vivo 7T MR Quantitative Susceptibility Mapping Reveals Opposite Susceptibility Contrast between Cortical and White Matter Lesions in Multiple Sclerosis.

Magnetic susceptibility measured with quantitative susceptibility mapping has been proposed as a biomarker for demyelination and inflammation in patients with MS, but investigations have mostly been on white matter lesions. A detailed characterization of cortical lesions has not been performed. The purpose of this study was to evaluate magnetic susceptibility in both cortical and WM lesions in MS by using quantitative susceptibility mapping. Fourteen patients with MS were scanned on a 7T MR imaging scanner with T1-, T2-, and T2*-weighted sequences. The T2*-weighted sequence was used to perform quantitative susceptibility mapping and generate tissue susceptibility maps. The susceptibility contrast of a lesion was quantified as the relative susceptibility between the lesion and its adjacent normal-appearing parenchyma. The susceptibility difference between cortical and WM lesions was assessed by using a t test. The mean relative susceptibility was significantly negative for cortical lesions (P < 10-7) but positive for WM lesions (P < 10-22). A similar pattern was also observed in the cortical (P = .054) and WM portions (P = .043) of mixed lesions. The negative susceptibility in cortical lesions suggests that iron loss dominates the susceptibility contrast in cortical lesions. The opposite susceptibility contrast between cortical and WM lesions may reflect both their structural (degree of myelination) and pathologic (degree of inflammation) differences, in which the latter may lead to a faster release of iron in cortical lesions.

PREVAIL: Predicting Recovery through Estimation and Visualization of Active and Incident Lesions.

ObjectiveThe goal of this study was to develop a model that integrates imaging and clinical information observed at lesion incidence for predicting the recovery of white matter lesions in multiple sclerosis (MS) patients.MethodsDemographic, clinical, and magnetic resonance imaging (MRI) data were obtained from 60 subjects with MS as part of a natural history study at the National Institute of Neurological Disorders and Stroke. A total of 401 lesions met the inclusion criteria and were used in the study. Imaging features were extracted from the intensity-normalized T1-weighted (T1w) and T2-weighted sequences as well as magnetization transfer ratio (MTR) sequence acquired at lesion incidence. T1w and MTR signatures were also extracted from images acquired one-year post-incidence. Imaging features were integrated with clinical and demographic data observed at lesion incidence to create statistical prediction models for long-term damage within the lesion.ValidationThe performance of the T1w and MTR predictions was assessed in two ways: first, the predictive accuracy was measured quantitatively using leave-one-lesion-out cross-validated (CV) mean-squared predictive error. Then, to assess the prediction performance from the perspective of expert clinicians, three board-certified MS clinicians were asked to individually score how similar the CV model-predicted one-year appearance was to the true one-year appearance for a random sample of 100 lesions.ResultsThe cross-validated root-mean-square predictive error was 0.95 for normalized T1w and 0.064 for MTR, compared to the estimated measurement errors of 0.48 and 0.078 respectively. The three expert raters agreed that T1w and MTR predictions closely resembled the true one-year follow-up appearance of the lesions in both degree and pattern of recovery within lesions.ConclusionThis study demonstrates that by using only information from a single visit at incidence, we can predict how a new lesion will recover using relatively simple statistical techniques. The potential to visualize the likely course of recovery has implications for clinical decision-making, as well as trial enrichment.

Hyaluronan synthesis is necessary for autoreactive T-cell trafficking, activation, and Th1 polarization.

The extracellular matrix polysaccharide hyaluronan (HA) accumulates at sites of autoimmune inflammation, including white matter lesions in multiple sclerosis (MS), but its functional importance in pathogenesis is unclear. We have evaluated the impact of 4-methylumbelliferone (4-MU), an oral inhibitor of HA synthesis, on disease progression in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Treatment with 4-MU decreases the incidence of EAE, delays its onset, and reduces the severity of established disease. 4-MU inhibits the activation of autoreactive T cells and prevents their polarization toward a Th1 phenotype. Instead, 4-MU promotes polarization toward a Th2 phenotpye and induction of Foxp3(+) regulatory T cells. Further, 4-MU hastens trafficking of T cells through secondary lymphoid organs, impairs the infiltration of T cells into the CNS parenchyma, and limits astrogliosis. Together, these data suggest that HA synthesis is necessary for disease progression in EAE and that treatment with 4-MU may be a potential therapeutic strategy in CNS autoimmunity. Considering that 4-MU is already a therapeutic, called hymecromone, that is approved to treat biliary spasm in humans, we propose that it could be repurposed to treat MS.

Reduced perfusion in white matter lesions in multiple sclerosis

To investigate dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) in white matter lesions (WML) in patients with multiple sclerosis (MS), using automatically generated binary masks of brain tissue. WML in MS have in some studies demonstrated perfusion abnormalities compared to normal appearing white matter (NAWM), however perfusion changes in WML in MS have in general not been well documented. DSC PWI was performed at 1.5 Tesla in 69 newly diagnosed MS patients. Parametric perfusion maps representing cerebral blood volume (CBV), cerebral blood flow (CBF) and mean transit time (MTT) were obtained. Binary masks of WML, white matter (WM) and grey matter (GM) were automatically generated and co-registered to the perfusion maps. The WML mask was manually edited and modified to correct for errors in the automatic lesion detection. Perfusion parameters were derived both from WML and NAWM using the manually modified WML mask, and using the original non-modified WML mask (with and without GM exclusion mask). Differences in perfusion measures between WML and NAWM were analyzed. CBF was significantly lower (p<0.001) and MTT significantly higher (p<0.001) in WML compared to NAWM. CBV did not show significant difference between WML and NAWM. The non-modified WML mask gave similar results as manually modified WML mask if the GM exclusion mask was used in the analysis. DSC PWI revealed lower CBF and higher MTT, consistent with reduced perfusion, in WML compared to NAWM in patients with early MS. Automatically generated binary masks are a promising tool in perfusion analysis of WML.