Acute Multiple Sclerosis Lesions Research Articles

Use of gadolinium-based contrast agents in multiple sclerosis: a review by the ESMRMB-GREC and ESNR Multiple Sclerosis Working Group.

Magnetic resonance imaging (MRI) is the most sensitive technique for detecting inflammatory demyelinating lesions in multiple sclerosis (MS) and plays a crucial role in diagnosis and monitoring treatment effectiveness, and for predicting the disease course. In clinical practice, detection of MS lesions is mainly based on T2-weighted and contrast-enhanced T1-weighted sequences. Contrast-enhancing lesions (CEL) on T1-weighted sequences are related to (sub)acute inflammation, while new or enlarging T2 lesions reflect the permanent footprint from a previous acute inflammatory demyelinating event. These two types of MRI features provide redundant information, at least in regular monitoring of the disease. Due to the concern of gadolinium deposition after repetitive injections of gadolinium-based contrast agents (GBCAs), scientific organizations and regulatory agencies in Europe and North America have proposed that these contrast agents should be administered only if clinically necessary. In this article, we provide data on the mode of action of GBCAs in MS, the indications of the use of these agents in clinical practice, their value in MS for diagnostic, prognostic, and monitoring purposes, and their use in specific populations (children, pregnant women, and breast-feeders). We discuss imaging strategies that achieve the highest sensitivity for detecting CELs in compliance with the safety regulations established by different regulatory agencies. Finally, we will briefly discuss some alternatives to the use of GBCA for detecting blood-brain barrier disruption in MS lesions. CLINICAL RELEVANCE STATEMENT: Although use of GBCA at diagnostic workup of suspected MS is highly valuable for diagnostic and prognostic purposes, their use in routine monitoring is not mandatory and must be reduced, as detection of disease activity can be based on the identification of new or enlarging lesions on T2-weighted images. KEY POINTS: • Both the EMA and the FDA state that the use of GBCA in medicine should be restricted to clinical scenarios in which the additional information offered by the contrast agent is required. • The use of GBCA is generally recommended in the diagnostic workup in subjects with suspected MS and is generally not necessary for routine monitoring in clinical practice. • Alternative MRI-based approaches for detecting acute focal inflammatory MS lesions are not yet ready to be used in clinical practice.

Radiomics-based Unsupervised Clustering of Acute Multiple Sclerosis Lesions (P10-3.015)

<h3>Objective:</h3> To leverage radiomics and machine learning to identify clusters of focal acute MS lesions exhibiting similar spatial and/or textural patterns on conventional cross-sectional (pre- and post-contrast) T1-weighted, T2-weighted, PD-weighted and FLAIR brain MRIs. <h3>Background:</h3> Multiple sclerosis (MS) lesions exhibit substantial heterogeneity in terms of underlying pathology, anatomic location, and longitudinal evolution. Conventional MRI is sensitive to some aspects of lesion heterogeneity. Unsupervised clustering approaches may identify subtypes of acute MS lesions with specific pathologic features and help improve disease characterization and prognostication. <h3>Design/Methods:</h3> Brain MRIs from the ADVANCE trial (1,512 patients with relapsing-remitting MS, NCT00906399) were retrospectively analysed. For each scan, focal acute (gadolinium-enhancing and/or new or substantially enlarging) T2 lesions (N=3058) were identified in the white matter (WM). Each lesion was represented via its center of mass in standard ICBM-152 space and radiomics-based textural properties. Similar lesions were grouped together via k-means clustering, applied separately across the spatial and each sequence-specific textural domain. Cluster count was optimized based on the silhouette score, Davies-Bouldin index and Variance Ratio Criterion. <h3>Results:</h3> Optimal clustering quality resulted in 8 prototypical WM sites of lesion emergence, 3 prototypical textural patterns on each of post-contrast T1-, PD-weighted and FLAIR MRI and 5 patterns on each of pre-contrast T1- and T2-weighted MRI. Statistically significant cross-sectional associations were found between the occurrence of these lesion subtypes and patient age, sex, years since disease onset and EDSS score, via logistic regression analysis (p &lt; 0.05). <h3>Conclusions:</h3> Specific spatial and textural patterns of acute MS lesions were identified using unsupervised clustering. Further work will evaluate the clinical relevance of identified acute MS lesion patterns towards predicting clinical and MRI endpoints of disease progression. The longitudinal dynamics of each lesion pattern will be investigated via measurements of future lesion repair or transition towards chronic active/inactive lesion states. <b>Disclosure:</b> Mr. Caba has received personal compensation for serving as an employee of Therapanacea. Mr. Caba has received personal compensation for serving as an employee of Biogen. Mr. Caba has received personal compensation in the range of $50,000-$99,999 for serving as a Research Engineer with Therapanacea. Mr. Caba has received personal compensation in the range of $100,000-$499,999 for serving as a Scientist II, ML/AI with Biogen. Dr. Gafson has stock in Biogen. Dr. Ioannidou has received personal compensation for serving as an employee of Therapanacea. Xiaotong Jiang has nothing to disclose. Elizabeth Fisher has received personal compensation for serving as an employee of Biogen. Elizabeth Fisher has stock in Biogen. Elizabeth Fisher has received intellectual property interests from a discovery or technology relating to health care. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Celgene. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Frequency Therapeutics. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Arnold has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche. Dr. Arnold has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shionogi. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Xfacto communications. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Arnold has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Arnold has stock in NeuroRx. Colm Elliott has received personal compensation for serving as an employee of NeuroRx Research. Nikos Paragios has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AstraZeneca. Nikos Paragios has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Ipsen. Nikos Paragios has received personal compensation in the range of $500-$4,999 for serving as an officer or member of the Board of Directors for ArteDrone. Nikos Paragios has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Nikos Paragios has received intellectual property interests from a discovery or technology relating to health care. Nikos Paragios has received personal compensation in the range of $100,000-$499,999 for serving as a CEO with TheraPanacea. Dr. Belachew has received personal compensation for serving as an employee of Biogen Inc. Dr. Belachew has received stock or an ownership interest from Biogen Inc.

Single-timepoint low-dimensional characterization and classification of acute versus chronic multiple sclerosis lesions using machine learning

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease characterized by the appearance of focal lesions across the central nervous system. The discrimination of acute from chronic MS lesions may yield novel biomarkers of inflammatory disease activity which may support patient management in the clinical setting and provide endpoints in clinical trials. On a single timepoint and in the absence of a prior reference scan, existing methods for acute lesion detection rely on the segmentation of hyperintense foci on post-gadolinium T1-weighted magnetic resonance imaging (MRI), which may underestimate recent acute lesion activity. In this paper, we aim to improve the sensitivity of acute MS lesion detection in the single-timepoint setting, by developing a novel machine learning approach for the automatic detection of acute MS lesions, using single-timepoint conventional non-contrast T1- and T2-weighted brain MRI. The MRI input data are supplemented via the use of a convolutional neural network generating “lesion-free” reconstructions from original “lesion-present” scans using image inpainting. A multi-objective statistical ranking module evaluates the relevance of textural radiomic features from the core and periphery of lesion sites, compared within “lesion-free” versus “lesion-present” image pairs. Then, an ensemble classifier is optimized through a recursive loop seeking consensus both in the feature space (via a greedy feature-pruning approach) and in the classifier space (via model selection repeated after each pruning operation). This leads to the identification of a compact textural signature characterizing lesion phenotype. On the patch-level task of acute versus chronic MS lesion classification, our method achieves a balanced accuracy in the range of 74.3–74.6% on fully external validation cohorts.

Susceptibility source separation from gradient echo data using magnitude decay modeling.

The objective is to demonstrate feasibility of separating magnetic sources in quantitative susceptibility mapping (QSM) by incorporating magnitude decay rates in gradient echo (GRE) MRI. Magnetic susceptibility source separation was developed using and compared with a prior method using that required an additional sequence to measure the transverse relaxation rate R2 . Both susceptibility separation methods were compared in multiple sclerosis (MS) patients (n=17). Susceptibility values of negative sources estimated with -based source separation in a set of enhancing MS lesions (n=44) were correlated against longitudinal myelin water fraction (MWF) changes. In in vivo data, linear regression of the estimated and susceptibility values between the - and the -based separation methods performed across 182 segmented lesions revealed correlation coefficient r=.96 and slope close .99. Correlation analysis in enhancing lesions revealed a significant positive association between the increase at 1-year post-onset relative to 0 year and the MWF increase at 1 year relative to 0 year (β= -0.144, 95% confidence interval: [-0.199, -0.1], p=.0008) and good agreement between and methods (r=.79, slope=.95). Separation of magnetic sources based solely on GRE complex data is feasible by combining magnitude decay rate modeling and phase-based QSM and change may serve as a biomarker for myelin recovery or damage in acute MS lesions.

A Child with Intractable Vomiting: Brainstem Mass or Neuromyelitis Optica Spectrum Disorder

Background: Neuromyelitis Optica Spectrum Disorder (NMOSD) is an immune-mediated disorder which is characterized by relapsing episodes of optic neuritis and myelitis. Brain stem related symptoms such as Intractable vomiting are not usually considered as the initial presentation and misdiagnosis has been frequently observed. Almost 4% of NMOSD cases are pediatric. Early differentiation of NMOSD from other childhood disorders including acute disseminated encephalmyelitis (ADEM), multiple sclerosis (MS), infections and mass lesions is critical.

Longitudinal Sodium MRI of Multiple Sclerosis Lesions: Is there Added Value of Sodium Inversion Recovery MRI.

Sodium enhancement has been demonstrated in multiple sclerosis (MS) lesions. To investigate sodium MRI with and without an inversion recovery pulse in acute MS lesions in an MS relapse and during recovery. Prospective. Twenty-nine relapsing-remitting MS patients with an acute relapse were included. A 3D density-adapted radial sodium sequence at 3 T using a dual-tuned (23 Na/1 H) head coil. Full-brain images of the tissue sodium concentration (TSC1, n=29) and a sodium inversion recovery sequence (SIR1, n=20) at the beginning of the anti-inflammatory therapy and on medium-term follow-up visits (days 27-99, n=12 [TSC], n=5 [SIR]) were measured. Regions of interest (RoIs) with contrast enhancement (T1 CE+) and without change in T1-weighted imaging (FL + T1n) were normalized (nTSC and nSIR). To gain insight on the origin of the TSC enhancement at time point 1, it is investigated whether the nTSC enhancement of the lesions is accompanied by a change of the respective nSIR. Potential prognostic value of nSIR1 is examined referring to the nTSC progression. STATISTICAL TESTS: nTSC and nSIR were compared regarding the type of lesion and the time point using a one-way ANOVA. Pearson's correlation coefficient was calculated for nTSC over nSIR and for nTSC1-nTSC2 over nSIR1. A P-value <0.05 was considered statistically significant. At the first measurement, all lesion types showed increased nTSC, while nSIR was decreased in the FL + T1 n and the T1 CE+ lesions in comparison to the normal-appearing white matter. For acute lesions, the difference between nTSC at baseline and nTSC at time point 2 showed a significant correlation with the baseline nSIR. At time point 1, nTSC is increased, while nSIR is unchanged or decreased in the lesions. The mean sodium IR signal at baseline correlates with recovery or progression of an acute lesion. 2 TECHNICAL EFFICACY: Stage 4.

Machine Learning-Based Classification of Acute versus Chronic Multiple Sclerosis Lesions using Radiomic Features from Unenhanced Cross-Sectional Brain MRI (4121)

Machine Learning-Based Classification of Acute versus Chronic Multiple Sclerosis Lesions using Radiomic Features from Unenhanced Cross-Sectional Brain MRI (4121)

A multiscale subvoxel perfusion model to estimate diffusive capillary wall conductivity in multiple sclerosis lesions from perfusion MRI data

We propose a new mathematical model to learn capillary leakage coefficients from dynamic susceptibility contrast MRI data. To this end, we derive an embedded mixed-dimension flow and transport model for brain tissue perfusion on a subvoxel scale. This model is used to obtain the contrast agent concentration distribution in a single MRI voxel during a perfusion MRI sequence. We further present a magnetic resonance signal model for the considered sequence including a model for local susceptibility effects. This allows modeling MR signal-time curves that can be compared with clinical MRI data. The proposed model can be used as a forward model in the inverse modeling problem of inferring model parameters such as the diffusive capillary wall conductivity. Acute multiple sclerosis lesions are associated with a breach in the integrity of the blood-brain barrier. Applying the model to perfusion MR data of a patient with acute multiple sclerosis lesions, we conclude that diffusive capillary wall conductivity is a good indicator for characterizing activity of lesions, even if other patient-specific model parameters are not well-known.

The landscape of myeloid and astrocyte phenotypes in acute multiple sclerosis lesions

Activated myeloid cells and astrocytes are the predominant cell types in active multiple sclerosis (MS) lesions. Both cell types can adopt diverse functional states that play critical roles in lesion formation and resolution. In order to identify phenotypic subsets of myeloid cells and astrocytes, we profiled two active MS lesions with thirteen glial activation markers using imaging mass cytometry (IMC), a method for multiplexed labeling of histological sections. In the acutely demyelinating lesion, we found multiple distinct myeloid and astrocyte phenotypes that populated separate lesion zones. In the post-demyelinating lesion, phenotypes were less distinct and more uniformly distributed. In both lesions cell-to-cell interactions were not random, but occurred between specific glial subpopulations and lymphocytes. Finally, we demonstrated that myeloid, but not astrocyte phenotypes were activated along a lesion rim-to-center gradient, and that marker expression in glial cells at the lesion rim was driven more by cell-extrinsic factors than in cells at the center. This proof-of-concept study demonstrates that highly multiplexed tissue imaging, combined with the appropriate computational tools, is a powerful approach to study heterogeneity, spatial distribution and cellular interactions in the context of MS lesions. Identifying glial phenotypes and their interactions at different lesion stages may provide novel therapeutic targets for inhibiting acute demyelination and low-grade, chronic inflammation.

Acute multiple sclerosis lesion pathology does not predict subsequent clinical course-a biopsy study.

Knowledge of the clinical outcome in tumefactive demyelination remains limited. This study aims to characterise the natural history of biopsy-proven, pathogen-free, cerebral demyelination in an adult Irish population. We identified all patients with biopsy-proven demyelination in a single neuropathology centre between 1999 and 2017. A baseline, and at least one follow-up MRI scan was available in each instance (mean of 3 scans per patient), together with both the presenting and most recent clinical details including disability level and disease-modifying drugs. In 21 patients, white matter biopsies showed the following: macrophages with myelin debris, myelin-axonal dissociation, reactive astrocytes and occasional lymphocytes. During a mean follow-up time of 8years (± 4.4), 17 patients developed MS, confirmed both clinically and on MRI, using the 2010 McDonald criteria: 11 relapsing remitting (RR) MS, four secondary progressive and two primary progressive MS. Four patients had a monophasic illness with lesion regression, without clinical or radiological evidence of any further disease activity on follow-up. The patients with progressive MS had significantly higher levels of physical disability than either the RRMS or monophasic patients. Uniform white matter subacute demyelination is associated with a diverse clinical course ranging from a monophasic illness to progressive MS, suggesting that extraneous factors distinct from the basic pathology significantly influence the clinical course in MS.

Temporal evolution of acute multiple sclerosis lesions on serial sodium (23Na) MRI

BackgroundSeveral studies have reported the characteristics of acute multiple sclerosis (MS) lesions on diffusion-weighted magnetic resonance imaging (DWI MRI). Current publications reported a transient reduction of the apparent diffusion coefficient (ADC) delineating an early phase of lesion evolution, before increased diffusion occurs in parallel to blood-brain-barrier (BBB) breakdown. Sodium MRI might provide another perspective on lesion development, but clinical applications have been limited to high field MR systems. The objective in this study was to investigate the temporal evolution of acute MS lesions using conventional (T2-fluid-attenuated inversion recovery (T2-FLAIR) images, post-contrast T1-weighted images), diffusion and sodium MRI. MethodsInitial and follow-up MRI (23Na and 1H MRI) were performed on a 3T scanner. Quantitative assessment of total sodium concentration (TSC) and ADC was performed. The study was designed for frequent follow-up MRI examinations during 4 weeks after the initial presentation. ResultsThirty-one acute MS lesions (7 lesions with reduced diffusion) in eleven MS patients were included. On initial MRI, TSC in contrast-enhancing lesions was increased when compared to the normal-appearing white matter (NAWM), while lesions with an initial reduced diffusion showed a TSC comparable to the NAWM. On follow-up MRI, in lesions with reduced diffusion subsequent increase of ADC and TSC values occurred along with signs of the development of vasogenic edema and contrast-enhancement. After four weeks, TSC values decreased along with regression of vasogenic edema and contrast-enhancement. ConclusionsIn lesions with a reduction of the ADC sodium levels are near normal and precede signs of BBB breakdown. These findings suggest a relatively preserved tissue structure in this early phase of lesion evolution.

Multiple Sclerosis: Destruction and Regeneration of Astrocytes in Acute Lesions.

There are reports that astrocyte perivascular endfeet are damaged in some cases of multiple sclerosis (MS). This study was designed to determine the origin and outcome of astrocyte damage in acute, resolving, and inactive plaques. Ten acute plaques from 10 early MS cases and 14 plaques of differing histological age from 9 subacute and chronic cases were examined immunohistochemically. Also examined were nonnecrotic early lesions in 3 patients with neuromyelitis optica (NMO). Plaques from 3 MS cases were examined electron microscopically. The edge zones in each of the 10 acute MS lesions revealed a complete loss of astrocyte cell bodies and their pericapillary, perineuronal, and perivascular foot processes. Dendrophagocytosis of degenerate astrocytes was observed. Astrocyte precursors, similar to those that replace destroyed astrocytes in nonnecrotic NMO lesions, were present in areas depleted of astrocytes. Resolving plaques were repopulated initially by stellate astrocytes that stained negatively for the water channel molecule aquaporin4 (AQP4). In older lesions, astrocytes were predominantly AQP4-positive. Loss and recovery of astrocytes in new MS lesions may be as important as myelin loss as a cause of conduction block responsible for symptoms in patients with relapsing and remitting and secondary progressive MS.

Rebound After Fingolimod and a Single Daclizumab Injection in a Patient Retrospectively Diagnosed With NMO Spectrum Disorder-MRI Apparent Diffusion Coefficient Maps in Differential Diagnosis of Demyelinating CNS Disorders.

Objective: Differential diagnosis of neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) or mimics can be challenging, especially in patients with atypical presentations and negative serostatus for aquaporin-4 antibodies (AQP4-Ab). This brief research report describes magnetic resonance imaging (MRI) findings focusing on quantitative apparent diffusion coefficient (ADC) histogram analysis as a potential tool to differentiate NMOSD from MS.Methods: Longitudinal MRI data obtained during routine clinical examinations were retrospectively analyzed in a patient with histologically determined cerebral NMOSD, a patient with an acute tumefactive MS lesion, and a patient with ischemic stroke. Histogram analyses of ADC maps were evaluated.Results: A patient diagnosed with MS experienced a severe rebound after fingolimod withdrawal and a single daclizumab injection. Cerebral NMOSD manifestation was confirmed by brain biopsy. However, the patient did not fulfill consensus criteria for NMOSD and was AQP4-Ab negative. Comparison of ADC histogram analyses of this patient with those from a patient with MS and one with ischemic stroke revealed differential ADC characteristics: namely a more pronounced and prolonged ADC leftward shift in inflammatory than in ischemic pathology, even more accentuated in NMOSD versus MS.Conclusion: ADC map histograms and ADC threshold values for different conditions may be useful for differentiation of large inflammatory brain lesions and further studies are merited.

Elevated expression of granulocyte-macrophage colony-stimulating factor receptor in multiple sclerosis lesions

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease that disproportionately affects young adults, leading to disability and high costs to society. Infiltration of T cells and monocytes into the central nervous system (CNS) is critical for disease initiation and progression. However, despite a great deal of effort the molecular mechanisms by which immune cells initiate and perpetuate CNS damage in MS have not yet been elucidated. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by pathogenic Th1 and Th17 cells is critical for the recruitment of monocytes into the CNS during the initial stage of disease. We and others have recently shown that, compared with healthy individuals, MS patients have greater numbers of CD4+ and CD8+ T cells that produce GM-CSF. Here, we describe the expression of GM-CSF and its receptor, GM-CSFR, in normal brain and MS lesions. Our data show that in acute and chronic MS lesions, microglia and astrocytes have upregulated expression of GM-CSFR; in addition, we show that GM-CSF-associated molecules are also upregulated in MS lesions. These findings further strengthen the argument that GM-CSF signaling contributes to MS pathogenesis.

CBIO-06. POTENTIAL ROLE OF RNU6 ISOLATED FROM CIRCULATING EXOSOMES AS A DIAGNOSTIC BIOMARKER FOR GLIOBLASTOMA

Glioblastomas (GBM) are highly malignant brain tumors with a poor prognosis despite intensive research and clinical effort. Circulating biomarkers for the disease would be desirable in order to allow for non-invasive tumor detection and follow-up. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. Previously, we observed that exosomes isolated from serum of GBM patients had an increased expression of RNU6 (a small non-coding RNA) compared to control samples, and hence could serve as a non-invasive diagnostic biomarker for GBM. In this study, we set to investigate whether this small non-coding RNA could serve as a differential diagnostic biomarker to distinguish GBM from other brain lesions resembling GBM in neuroimaging. We analyzed the expression of RNU6 in circulating exosomes of patients with six types of brain lesions that can mimic GBM on magnetic resonance imaging (i.e. subacute stroke, acute-subacute haemorrhage, acute demyelinating lesions, abscesses, brain metastases and primary CNS lymphomas). First, we isolated the exosomes from the serum of a subset of patients (20–30 patients) with these pathological conditions using an adsorption method (Exoquick). The same was done in a similar group of healthy controls and GBM patients. Then RNU6 levels were analyzed by digital droplet PCR (ddPCR). Corroborating our previous results, we found that the expression of RNU6 was significantly higher in GBM patients than in healthy controls. In addition, RNU6 levels were significantly higher in exosomes from GBM patients than in exosomes from patients with stroke, haemorrhage or acute multiple sclerosis lesions. We are currently analyzing the data regarding the expression of RNU6 in CNS metastasis and lymphomas. Our preliminary data suggest that RNU6 could serve as a differential diagnostic biomarker for GBM patients.

Myelin phagocytosis by astrocytes after myelin damage promotes lesion pathology.

Astrocytes are key players in the pathology of multiple sclerosis and can assume beneficial and detrimental roles during lesion development. The triggers and timing of the different astroglial responses in acute lesions remain unclear. Astrocytes in acute multiple sclerosis lesions have been shown previously to contain myelin debris, although its significance has not been examined. We hypothesized that myelin phagocytosis by astrocytes is an early event during lesion formation and leads to astroglial immune responses. We examined multiple sclerosis lesions and other central nervous system pathologies with prominent myelin injury, namely, progressive multifocal leukoencephalopathy, metachromatic leukodystrophy and subacute infarct. In all conditions, we found that myelin debris was present in most astrocytes at sites of acute myelin breakdown, indicating that astroglial myelin phagocytosis is an early and prominent feature. Functionally, myelin debris was taken up by astrocytes through receptor-mediated endocytosis and resulted in astroglial NF-κB activation and secretion of chemokines. These in vitro results in rats were validated in human disease where myelin-positive hypertrophic astrocytes showed increased nuclear localization of NF-κB and elevated chemokine expression compared to myelin-negative, reactive astrocytes. Thus, our data suggest that myelin uptake is an early response of astrocytes in diseases with prominent myelin injury that results in recruitment of immune cells. This first line response of astrocytes to myelin injury may exert beneficial or detrimental effects on the lesion pathology, depending on the inflammatory context. Modulating this response might be of therapeutic relevance in multiple sclerosis and other demyelinating conditions.

Regulation of effector function of CNS autoreactive CD4 T cells through inhibitory receptors and IL-7Rα.

BackgroundMultiple sclerosis (MS) is a chronic CNS autoimmune disease characterized by inflammation, demyelination, and neuronal degeneration, where myelin-specific CD4 T cells play critical roles in the formation of acute MS lesions and disease progression. The suppression of IL-7Rα expression and the upregulation of inhibitory receptors (PD-1, etc.) are essential parts of the cell-intrinsic immunosuppressive program regulating T effector functions to prevent autoimmunity. However, little is known on the factors regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T effector/memory cells during the development of CNS autoimmunity.MethodsWe analyzed the roles of the transcription factor T-bet in regulating the expression of IL-7Rα and inhibitory receptors in myelin-specific CD4 T cells. Furthermore, we compared the effects of different inflammatory cytokines that are crucial for Th1 and Th17 development in regulating the IL-7Rα/PD-1 balance.ResultsWe discovered that T-bet suppresses the expression of inhibitory receptors (PD-1 and LAG-3) and promotes IL-7Rα expression in myelin-specific CD4 T cells in vitro and in vivo. As a result, T-bet skews IL-7Rα/PD-1 balance towards IL-7Rα and promotes enhanced effector function. Furthermore, IL-12 enhances IL-7Rα expression in a T-bet independent manner in myelin-specific Th1 cells. Meanwhile, IL-6, the cytokine inducing highly encephalitogenic Th17 differentiation, suppresses PD-1 while upregulating IL-7Rα, skewing IL-7Rα/PD-1 balance towards IL-7Rα, and promoting enhanced effector function. Moreover, blocking IL-7 signaling in myelin-specific CD4 T cells by αIL-7Rα significantly delays experimental autoimmune encephalomyelitis (EAE) onset and reduces disease severity.ConclusionsT-bet is a major transcription factor regulating IL-7Rα/PD-1 balance in myelin-specific CD4 T cells during EAE development, and there is a positive correlation between several major determinants promoting T cell encephalitogenicity (T-bet, IL-6, IL-12) and an IL-7Rα/PD-1 balance skewed towards IL-7Rα. Furthermore, IL-7 signaling inhibits PD-1 expression in myelin-specific CD4 T cells and blocking IL-7 signaling suppresses T cell encephalitogenicity. Therefore, interference with inhibitory pathways and IL-7Rα expression may suppress the encephalitogenic potential of myelin-specific CD4 T cells and have therapeutic benefits for MS patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0768-3) contains supplementary material, which is available to authorized users.

Sodium MRI in Multiple Sclerosis is Compatible with Intracellular Sodium Accumulation and Inflammation-Induced Hyper-Cellularity of Acute Brain Lesions.

The cascade of inflammatory pathogenetic mechanisms in multiple sclerosis (MS) has no specific conventional MRI correlates. Clinicians therefore stipulate improved imaging specificity to define the pathological substrates of MS in vivo including mapping of intracellular sodium accumulation. Based upon preclinical findings and results of previous sodium MRI studies in MS patients we hypothesized that the fluid-attenuated sodium signal differs between acute and chronic lesions. We acquired brain sodium and proton MRI data of N = 29 MS patients; lesion type was defined by the presence or absence of contrast enhancement. N = 302 MS brain lesions were detected, and generalized linear mixed models were applied to predict lesion type based on sodium signals; thereby controlling for varying numbers of lesions among patients and confounding variables such as age and medication. Hierarchical model comparisons revealed that both sodium signals average tissue (χ2(1) = 27.89, p < 0.001) and fluid-attenuated (χ2(1) = 5.76, p = 0.016) improved lesion type classification. Sodium MRI signals were significantly elevated in acute compared to chronic lesions compatible with intracellular sodium accumulation in acute MS lesions. If confirmed in further studies, sodium MRI could serve as biomarker for diagnostic assessment of MS, and as readout parameter in clinical trials promoting attenuation of chronic inflammation.

Neuropilin-1 modulates interferon-γ-stimulated signaling in brain microvascular endothelial cells.

Inflammatory response of blood-brain barrier (BBB) endothelial cells plays an important role in pathogenesis of many central nervous system inflammatory diseases, including multiple sclerosis; however, the molecular mechanism mediating BBB endothelial cell inflammatory response remains unclear. In this study, we first observed that knockdown of neuropilin-1 (NRP1), a co-receptor of several structurally diverse ligands, suppressed interferon-γ (IFNγ)-induced C-X-C motif chemokine 10 expression and activation of STAT1 in brain microvascular endothelial cells in a Rac1-dependent manner. Moreover, endothelial-specific NRP1-knockout mice, VECadherin-Cre-ERT2/NRP1flox/flox mice, showed attenuated disease progression during experimental autoimmune encephalomyelitis, a mouse neuroinflammatory disease model. Detailed analysis utilizing histological staining, quantitative PCR, flow cytometry and magnetic resonance imaging demonstrated that deletion of endothelial NRP1 suppressed neuron demyelination, altered lymphocyte infiltration, preserved BBB function and decreased activation of the STAT1-CXCL10 pathway. Furthermore, increased expression of NRP1 was observed in endothelial cells of acute multiple sclerosis lesions. Our data identify a new molecular mechanism of brain microvascular endothelial inflammatory response through NRP1-IFNγ crosstalk that could be a potential target for intervention of endothelial cell dysfunction in neuroinflammatory diseases.

Heterogeneity of acute multiple sclerosis lesions on sodium (23Na) MRI

Background: Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS. Objectives: We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with 23Na MRI. Methods: 23Na MRI and 1H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM). Results: TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM). Conclusions: TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood–brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.