Brain Of Multiple Sclerosis Patients Research Articles

ASK1 activation in glial cells in post-mortem multiple sclerosis tissue.

Multiple sclerosis (MS), the leading cause of disability in young adults, is an inflammatory disease of the central nervous system characterized by localized areas of demyelination. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that has been shown to be implicated in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Interestingly, ASK1 signaling regulates glial cell interactions and drives neuroinflammation in EAE mice. To further investigate its clinical significance, in the present study, we examined the activation of ASK1 in the post-mortem brain of MS patients. ASK1 activation was found in active lesions of the corpus callosum in both microglia/macrophages and astrocytes. Moreover, ASK1 activation in astrocytes was higher than that in microglia/macrophages, which was in line with our findings in EAE mice. Our results suggest an important role of ASK1 in glial cells, indicating that ASK1 might be a good therapeutic target for MS.

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.

Optimization of functional diagnostic test: the effect of kernel method as an estimator of ROC curve

Technical development over the last few decades has resulted in the emergence of complex data, in many cases functional data (FD). This type of data can emerge in many medical studies which are geared towards detecting diseases, predicting their course or evaluating the response to a therapy, to name a few. Thus, it is very useful to have statistical methods enabling us to evaluate diagnostic tests based on functional biomarkers. In fact, a diagnostic test that uses functional variables as biomarkers has been developed recently. Their authors proposed a functional version of ROC analysis, resulting in an empirical estimate of the functional ROC curve. In order to improve this methodology, the present paper proposes a procedure to obtain a smooth version of non-parametric estimator of the ROC curve. In addition, a comprehensive simulation study lets to investigate the discriminatory and predictive abilities of the resulting functional diagnostic test. Two examples with real medical data illustrate the approach developed: one deals with gene expression levels for tumoural/normal samples of prostate cancer; the other dataset is about white matter structures in the brain in multiple sclerosis patients.

Multiple sclerosis: new insights into molecular pathogenesis and novel platforms for disease treatment.

Multiple sclerosis (MS), a chronic inflammatory disorder, affects the central nervous system via myelin degradation. The cause of MS is not fully known, but during recent years, our knowledge has deepened significantly regarding the different aspects of MS, including etiology, molecular pathophysiology, diagnosis and therapeutic options. Myelin basic protein (MBP) is the main myelin protein that accounts for maintaining the stability of the myelin sheath. Recent evidence has revealed that MBP citrullination or deamination, which is catalyzed by Ca2+ dependent peptidyl arginine deiminase (PAD) enzyme leads to the reduction of positive charge, and subsequently proteolytic cleavage of MBP. The overexpression of PAD2 in the brains of MS patients plays an essential role in new epitope formation and progression of the autoimmune disorder. Some drugs have recently entered phase III clinical trials with promising efficacy and will probably obtain approval in the near future. As different therapeutic platforms develop, finding an optimal treatment for each individual patient will be more challenging. This review provides a comprehensive insight into MS with a focus on its pathogenesis and recent advances in diagnostic methods and its present and upcoming treatment modalities. MS therapy alters quickly as research findings and therapeutic options surrounding MS expand. McDonald's guidelines have created different criteria for MS diagnosis. In recent years, ever-growing interest in the development of PAD inhibitors has led to the generation of many reversible and irreversible PAD inhibitors against the disease with satisfactory therapeutic outcomes.

N-acetylglucosamine inhibits inflammation and neurodegeneration markers in multiple sclerosis: a mechanistic trial

BackgroundIn the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence.Objectives and methodsAn open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS).ResultsPrior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points.ConclusionsOral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc’s potential to control residual brain inflammation, myelin repair and neurodegeneration in MS.

Deep Learning Reconstruction of Lesion-Free Representations of the Brain in Multiple Sclerosis Patients (P11-3.006)

Deep Learning Reconstruction of Lesion-Free Representations of the Brain in Multiple Sclerosis Patients (P11-3.006)

An Association of Chitinase-3 Like-Protein-1 With Neuronal Deterioration in Multiple Sclerosis.

Elevated levels of Chitinase-3-like protein-1 (CHI3L1) in cerebrospinal fluid have previously been linked to inflammatory activity and disease progression in multiple sclerosis (MS) patients. This study aimed to investigate the presence of CHI3L1 in the brains of MS patients and in the cuprizone model in mice (CPZ), a model of toxic/metabolic demyelination and remyelination in different brain areas. In MS gray matter (GM), CHI3L1 was detected primarily in astrocytes and in a subset of pyramidal neurons. In neurons, CHI3L1 immunopositivity was associated with lipofuscin-like substance accumulation, a sign of cellular aging that can lead to cell death. The density of CHI3L1-positive neurons was found to be significantly higher in normal-appearing MS GM tissue compared to that of control subjects (p = .014). In MS white matter (WM), CHI3L1 was detected in astrocytes located within lesion areas, as well as in perivascular normal-appearing areas and in phagocytic cells from the initial phases of lesion development. In the CPZ model, the density of CHI3L1-positive cells was strongly associated with microglial activation in the WM and choroid plexus inflammation. Compared to controls, CHI3L1 immunopositivity in WM was increased from an early phase of CPZ exposure. In the GM, CHI3L1 immunopositivity increased later in the CPZ exposure phase, particularly in the deep GM region. These results indicate that CHI3L1 is associated with neuronal deterioration, pre-lesion pathology, along with inflammation in MS.

The Effect of Aerobic Training With the Consumption of Probiotics on the Myelination of Nerve Fibers in Cuprizone-induced Demyelination Mouse Model of Multiple Sclerosis.

Extensive human and animal research shows that exercise has beneficial effects on multiple clinical outcomes for patients suffering from multiple sclerosis (MS). This research was conducted to examine the effect of aerobic exercise with probiotic consumption on the myelination of nerve fibers in a cuprizone-induced demyelination mouse model of MS. Rats exposed to cuprizone (CPZ) for 13 weeks were subjected to motor and balance tests in week 5. They (5 people in each group) were assigned to five groups of control (C), MS, MS with exercise (MS+Exe), MS with probiotic (MS+Pro), and MS with probiotic and exercise (MS+Pro+Exe) randomly. The exercise groups conducted aerobic exercises 5 days a week for 60 days. The rats received probiotics by gavage. Performance and balance tests were repeated when the eight-week protocol of exercise and probiotic consumption was finished. One day after these interventions, they were sacrificed to undergo biochemical and molecular biology assays. The results showed that Myelin basic protein (MBP) was increased in the MS+Pro+Exe, MS+Pro, and MS+Exe compared to the MS group (P<0.05).The nestin mRNA showed an increase in MS+Pro+Exe, MS+Exe, and MS+Pro groups compared to the MS group, but this increase was not significant in MS+Pro+Exe and MS+Exe groups compared to the control and MS groups (P>0.05). According to the results, lifestyle interventions can effectively alleviate demyelinating-inflammatory processes that happen in the brains of MS patients.

Multiple sclerosis iron rim lesions are linked to impaired cervical spinal cord integrity using the T1/T2-weighted ratio.

In multiple sclerosis (MS), iron rim lesions (IRLs) are characterized by pronounced tissue matrix damage. The T1/T2-weighted (T1/T2w) ratio represents a postprocessing MRI approach to investigate tissue integrity, but studies investigating spinal cord pathology are missing until now. The aim of this study was to characterize tissue integrity using the T1/T2w ratio in lesions and the normal-appearing white and gray matter (NAWM, NAGM) in the spinal cord and brain in MS patients with and without brain IRLs. Forty MS patients (20 patients with at least one brain IRL and 20 age- and sex-matched patients without IRLs) were included. Normalized cross-sectional area (nCSA) of the upper cervical cord was calculated in addition to T1/T2w values and standard brain and spinal cord MRI parameters. Patients with IRLs had higher disability scores, a smaller nCSA, and a higher cervical T2 lesion volume. T1/T2w values of brain IRLs were significantly lower compared to non-IRLs (p<.001). Furthermore, T1/T2w values of lesions were significantly lower compared to the NAGM and NAWM, both in the brain and the spinal cord (p<.05 for all comparisons). T1/T2w values of the NAGM and NAWM in the brain and spinal cord did not statistically differ between the IRL group and the non-IRL group. IRLs constitute an imaging marker of disease severity. T1/T2w ratio maps represent an interesting technique to capture diffuse tissue properties. Calculation of T1/T2w ratio maps of the spinal cord might provide additional insights into the pathophysiological processes of MS.

Contrast-Enhanced 3D Spin Echo T1-Weighted Sequence Outperforms 3D Gradient Echo T1-Weighted Sequence for the Detection of Multiple Sclerosis Lesions on 3.0 T Brain MRI.

Using reliable contrast-enhanced T1 sequences is crucial to detect enhancing brain lesions for multiple sclerosis (MS) at the time of diagnosis and over follow-up. Contrast-enhanced 3D gradient-recalled echo (GRE) T1-weighted imaging (WI) and 3D turbo spin echo (TSE) T1-WI are both available for clinical practice and have never been compared within the context of this diagnosis. The aim of this study was to compare contrast-enhanced 3D GRE T1-WI and 3D TSE T1-WI for the detection of enhancing lesions in the brains of MS patients. This single-center prospective study enrolled patients with MS who underwent a 3.0 T brain MRI from August 2017 to April 2021 for follow-up. Contrast-enhanced 3D GRE T1-WI and 3D TSE T1-WI were acquired in randomized order. Two independent radiologists blinded to all data reported all contrast-enhanced lesions in each sequence. Their readings were compared with a reference standard established by a third expert neuroradiologist. Interobserver agreement, contrast ratio, and contrast-to-noise ratio were calculated for both sequences. A total of 158 MS patients were included (mean age, 40 ± 11 years; 95 women). Significantly more patients had at least 1 contrast-enhanced lesion on 3D TSE T1-WI than on 3D GRE T1-WI for both readers (61/158 [38.6%] vs 48/158 [30.4%] and 60/158 [38.6%] vs 47/158 [29.7%], P < 0.001). Significantly more contrast-enhanced lesions per patient were detected on 3D TSE T1-WI (mean 2.47 vs 1.56 and 2.56 vs 1.39, respectively, P < 0.001). Interobserver agreement was excellent for both sequences, κ = 0.96 (confidence interval [CI], 0.91-1.00) for 3D TSE T1-WI and 0.92 (CI, 0.86-0.99) for 3D GRE T1-WI. Contrast ratio and contrast-to-noise ratio were significantly higher on 3D TSE T1-WI (0.84 vs 0.53, P < 0.001, and 87.9 vs 57.8, P = 0.03, respectively). At 3.0 T, contrast-enhanced 3D TSE-T1-WI supports the detection of significantly more enhancing lesions than 3D GRE T1-WI and should therefore be used for MS patients requiring contrast-enhanced examination.

Comparison of Apparent Diffusion Coefficient Value Measurement and Contrast-Enhanced T1-Weighted Imaging in Detecting Active Demyelinating Lesions in Multiple Sclerosis

Objective: To find a difference in apparent diffusion coefficient (ADC) values of non-enhancing and enhancing lesions in patients with multiple sclerosis (MS) and to find a cutoff ADC value to predict the enhancement of the MS lesion. Materials and Methods: A retrospective review of magnetic resonance imaging (MRI) of the brain in MS patients between January 2015 and December 2019 was done. The MS plaques in the images were mapped in fluid attenuation inversion recovery (FLAIR) and post-contrast T1- weighted imaging sequences (T1WI). The lesions were categorized into enhancing and non-enhancing lesions based on the presence of enhancement on post-contrast T1WI. The ADC value of each lesion was measured using circular regions of interest (ROI) placed in the enhancing portion. The difference in mean ADC values between the two groups was assessed. Results: There were 22 patients with 194 MS lesions. The mean ADC values of the enhancing lesions at 0.891±0.164×10⁻³ mm²/s were significantly lower than those of the non-enhancing lesions at 1.303±0.280×10⁻³ mm²/s (p&lt;0.001). A cutoff ADC value of 1.117×10⁻³ mm²/s was used to distinguish between the enhancing and the non-enhancing lesions. The best results were obtained with a sensitivity of 93.9%, specificity of 71.4%, positive predictive value (PPV) of 40.3%, negative predictive value (NPV) of 98.3%, and accuracy of 75.3%. Conclusion: ADC value measurement can be used to predict the enhancement of the MS plaque, which may be helpful as a screening tool for active demyelinating plaque in MS patients. Keywords: Multiple sclerosis; Active demyelinating lesion; Active MS; Contrast-enhanced T1-weighted imaging; ADC value

Evidence of increased sequestration of pro-resolving lipid mediators within brain esterified lipid pools of multiple sclerosis patients

BackgroundUnresolved inflammation in multiple sclerosis (MS) is associated with progressive demyelination and symptom worsening. In the brain, both inflammation and resolution pathways are mediated by free lipid mediators (i.e., oxylipins) that can be derived from the enzymatic hydrolysis of esterified oxylipins . It is not known whether disturbances in the turnover of free lipid mediators from esterified pools exist in postmortem brain of MS patients. We hypothesized that resolution pathways are impaired in MS patients because of disturbances in the turnover of free pro-resolving lipid mediators from esterified lipids. The objective was to characterize free and esterified oxylipins in postmortem prefrontal cortex of MS and unaffected control participants. MethodsOxylipins in free, neutral lipid and phospholipid pools were extracted from prefrontal cortex of 10 MS participants and 5 unaffected controls, separated by solid phase extraction columns, and quantified by ultra-high-pressure liquid chromatography-tandem mass spectrometry. Significant differences between the control and MS groups were determined by an unpaired t-test with Benjamini and Hochberg False Discovery Rate correction (10%) applied to oxylipins within each lipid pool. ResultsThe concentration of 7 esterified pro-resolving fatty acid epoxides within neutral lipids were significantly higher by 126%–285% in postmortem prefrontal cortex of MS compared to control participants. The concentration of esterified linoleic acid-derived 9(10)-epoxy-octadecenoic acid, a pro-inflammatory epoxide, was higher by 206% in MS compared to controls. No significant changes were observed in free or phospholipid-bound oxylipins. ConclusionIn MS, several pro-resolving lipid mediators are trapped within prefrontal cortex neutral lipids, potentially limiting their supply and availability in the free bioactive form. This may explain why inflammation resolution is impaired in MS patients.

Microglia Regulate Blood-Brain Barrier Integrity via MiR-126a-5p/MMP9 Axis during Inflammatory Demyelination.

Blood–brain barrier (BBB) impairment is an early prevalent feature of multiple sclerosis (MS), and remains vital for MS progression. Microglial activation precedes BBB disruption and cellular infiltrates in the brain of MS patients. However, little is known about the function of microglia in BBB impairment. Here, microglia acts as an important modulator of BBB integrity in inflammatory demyelination. Microglial depletion profoundly ameliorates BBB impairment in experimental autoimmune encephalomyelitis (EAE). Specifically, miR‐126a‐5p in microglia is positively correlated with BBB integrity in four types of MS plaques. Mechanistically, microglial deletion of miR‐126a‐5p exacerbates BBB leakage and EAE severity. The protective effect of miR‐126a‐5p is mimicked and restored by specific inhibition of MMP9 in microglia. Importantly, Auranofin, an FDA‐approved drug, is identified to protect BBB integrity and mitigate EAE progression via a microglial miR‐126a‐5p dependent mechanism. Taken together, microglia can be manipulated to protect BBB integrity and ameliorate inflammatory demyelination. Targeting microglia to regulate BBB permeability merits consideration in therapeutic interventions in MS.

Age-dependent gray matter demyelination is associated with leptomeningeal neutrophil accumulation.

People living with multiple sclerosis (MS) experience episodic CNS white matter lesions instigated by autoreactive T cells. With age, patients with MS show evidence of gray matter demyelination and experience devastating nonremitting symptomology. What drives progression is unclear and studying this has been hampered by the lack of suitable animal models. Here, we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induced a nonremitting clinical phenotype that was associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young, SJL/J mice. Although the quantity and quality of T cells did not differ in the brains of old versus young EAE mice, an increase in neutrophils and a decrease in B cells were observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and gray matter pathology are dictated by age and associated with other immune cells, such as neutrophils.

Brain Structural and Functional Alterations in Multiple Sclerosis-Related Fatigue: A Systematic Review.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS); it influences patients’ quality of life. The etiology of fatigue is complex, and its pathogenesis is still unclear and debated. The objective of this review was to describe potential brain structural and functional dysfunctions underlying fatigue symptoms in patients with MS. To reach this purpose, a systematic review was conducted of published studies comparing functional brain activation and structural brain in MS patients with and without fatigue. Electronic databases were searched until 24 February 2021. The structural and functional outcomes were extracted from eligible studies and tabulated. Fifty studies were included: 32 reported structural brain differences between patients with and without fatigue; 14 studies described functional alterations in patients with fatigue compared to patients without it; and four studies showed structural and functional brain alterations in patients. The results revealed structural and functional abnormalities that could correlate to the symptom of fatigue in patients with MS. Several studies reported the differences between patients with fatigue and patients without fatigue in terms of conventional magnetic resonance imaging (MRI) outcomes and brain atrophy, specifically in the thalamus. Functional studies showed abnormal activation in the thalamus and in some regions of the sensorimotor network in patients with fatigue compared to patients without it. Patients with fatigue present more structural and functional alterations compared to patients without fatigue. Specifically, abnormal activation and atrophy of the thalamus and some regions of the sensorimotor network seem linked to fatigue.

Age-related susceptibility to grey matter demyelination and neurodegeneration is associated with meningeal neutrophil accumulation in an animal model of MS

Abstract People living with multiple sclerosis (MS) experience episodic central nervous system (CNS) white matter lesions instigated by autoreactive T cells. With age, MS patients show evidence of grey matter demyelination and experience devastating non-remitting symptomology. What drives progression is unclear and has been hampered by the lack of suitable animal models. Here we show that passive experimental autoimmune encephalomyelitis (EAE) induced by an adoptive transfer of young Th17 cells induces a non-remitting clinical phenotype that is associated with persistent leptomeningeal inflammation and cortical pathology in old, but not young SJL/J mice. While the quantity and quality of T cells did not differ in the brains of old vs young EAE mice, an increase in neutrophils and a decrease in B cells was observed in the brains of old mice. Neutrophils were also found in the leptomeninges of a subset of progressive MS patient brains that showed evidence of leptomeningeal inflammation and subpial cortical demyelination. Taken together, our data show that while Th17 cells initiate CNS inflammation, subsequent clinical symptoms and grey matter pathology are dictated by age and associated with other immune cells such as neutrophils.

CD4+c-Met+Itg\u03b14+ T cell subset promotes murine neuroinflammation

Objectivec-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).Methodsc-Met expression by CD4+ T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4+c-Met+ T cells was assessed in EAE.ResultsCD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4+Vα3.2+c-Met+ T cells induces increased disease severity compared to CD4+Vα3.2+c-Met− T cells. Finally, CD4+c-Met+ T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.

Effective Connectivity within the Papez Circuit in the Multiple Sclerosis Patients: A Comparative Study Using Resting-State fMRI.

Background: Multiple sclerosis (MS) disease causes structural and functional damage to brain. Structural imaging of the MS-induced damage cannot adequately describe the functional impairment of the brain in MS patients. Therefore, it seems that advanced functional imaging analysis such as functional magnetic resonance imaging (fMRI) data is needed for better management of this disease.Objective: The aim of present study was to evaluate the effective connectivity within the Papez circuit in MS patients using resting-state fMRI.Material and Methods: In this cross-sectional analytical study, 22 healthy individuals and 24 patients with MS underwent resting-state fMRI. After pre-processing of the obtained data, the time series of Cingulate gyrus (CG), Para hippocampus gyrus (PHG), anterior thalamic nuclei (ATN), Mammillary body (MB), and Hippocampus (HPC) were extracted as the main Papez circuit components. The obtained time series were statistically analyzed as an input of the dynamic causal model in order to evaluate the effective connectivity in the Papez circuit.Results: The power of effective connectivity between each pair of tested nodes in Papez circuit was significantly lower in MS patients than healthy subjects. Also, the effective connectivity level of MS patients in direction of HPC→ATN was higher in men than women. In addition, effective self-connection in CG→CG and MB→MB regions in healthy subjects were higher in women than them in men.Conclusion: The present study reveals significant difference in effective connectivity of the Papez nodes in MS patients than control group, which can be exploited to diagnosis and predict or evaluate the treatment response of these patients.

DNA methylation changes in glial cells of the normal-appearing white matter in Multiple Sclerosis patients

ABSTRACT Multiple Sclerosis (MS), the leading cause of non-traumatic neurological disability in young adults, is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS). Due to the poor accessibility to the target organ, CNS-confined processes underpinning the later progressive form of MS remain elusive thereby limiting treatment options. We aimed to examine DNA methylation, a stable epigenetic mark of genome activity, in glial cells to capture relevant molecular changes underlying MS neuropathology. We profiled DNA methylation in nuclei of non-neuronal cells, isolated from 38 post-mortem normal-appearing white matter (NAWM) specimens of MS patients (n = 8) in comparison to white matter of control individuals (n = 14), using Infinium MethylationEPIC BeadChip. We identified 1,226 significant (genome-wide adjusted P-value < 0.05) differentially methylated positions (DMPs) between MS patients and controls. Functional annotation of the altered DMP-genes uncovered alterations of processes related to cellular motility, cytoskeleton dynamics, metabolic processes, synaptic support, neuroinflammation and signaling, such as Wnt and TGF-β pathways. A fraction of the affected genes displayed transcriptional differences in the brain of MS patients, as reported by publically available transcriptomic data. Cell type-restricted annotation of DMP-genes attributed alterations of cytoskeleton rearrangement and extracellular matrix remodelling to all glial cell types, while some processes, including ion transport, Wnt/TGF-β signaling and immune processes were more specifically linked to oligodendrocytes, astrocytes and microglial cells, respectively. Our findings strongly suggest that NAWM glial cells are highly altered, even in the absence of lesional insult, collectively exhibiting a multicellular reaction in response to diffuse inflammation.

Advanced glycation end-products as potential triggering factors of self-reactivity against myelin antigens in Multiple Sclerosis

Multiple Sclerosis (MS) is a demyelinating autoimmune disease in which autoreactive T lymphocytes infiltrate the central nervous system (CNS) and react against antigens derived from proteins of the myelin sheath. The reason why T lymphocytes recognize certain myelin antigens as exogenous, activating the autoimmune response, remains unknown and represents the key to understand the pathogenesis of MS. Neurons are characterized by an elevated glycolytic metabolism. Methylglyoxal (MG) is a highly reactive α-oxoaldehyde spontaneously formed as a by-product of glycolysis, and it reacts with proteins, nucleotides and phospholipids forming stable adducts called advanced glycation end-products (AGEs). Several studies demonstrate that MG-derived AGEs accumulate in the plasma and brain of MS patients. Furthermore, there are evidences that post-myelinated oligodendrocytes, the myelin-forming glial cells, increase their glycolytic metabolism to maintain their survival and functions, likely explaining the progressive accumulation of MG in MS lesions. The hypothesis proposed here is that the MG-derived AGEs, accumulated on the proteins composing the myelin sheath, are responsible for the altered antigen presentation process, mimicking exogenous antigens and triggering the autoimmune response. If this hypothesis will be experimentally confirmed a new pathogenic mechanism of MS will be identified.