scholarly journals Linking immune-mediated damage to neurodegeneration in multiple sclerosis: could network-based MRI help?

2021 ◽  
Author(s):  
Sergiu Groppa ◽  
Gabriel Gonzalez-Escamilla ◽  
Arman Eshaghi ◽  
Sven G Meuth ◽  
Olga Ciccarelli
Keyword(s):  
Multiple Sclerosis ◽  
Grey Matter ◽  
Dynamic Models ◽  
Ex Vivo ◽  
Unmet Need ◽  
Neuronal Loss ◽  
Structural Mri ◽  
Conceptual Shift ◽  
Brain Reorganization

Abstract Inflammatory demyelination characterizes the initial stages of multiple sclerosis, while progressive axonal and neuronal loss are coexisting and significantly contribute to the long-term physical and cognitive impairment. There is an unmet need for a conceptual shift from a dualistic view of multiple sclerosis pathology, involving either inflammatory demyelination or neurodegeneration, to integrative dynamic models of brain reorganization, where, glia-neuron interactions, synaptic alterations, and grey matter pathology are longitudinally envisaged at the whole-brain level. Functional and structural MRI can delineate network hallmarks for relapses, remissions or disease progression, which can be linked to the pathophysiology behind inflammatory attacks, repair, and neurodegeneration. Here, we aim to unify recent findings of grey matter circuits dynamics in multiple sclerosis within the framework of molecular and pathophysiological hallmarks combined with disease-related network reorganization, while highlighting advances from animal models (in vivo and ex vivo) and human clinical data (imaging and histological). We propose that MRI-based brain networks characterization is essential for better delineating ongoing pathology and elaboration of particular mechanisms that may serve for accurate modelling and prediction of disease courses throughout disease stages.

Surface-in pathology in multiple sclerosis: a new view on pathogenesis?

Brain ◽  
2021 ◽  
Author(s):  
Matteo Pardini ◽  
J William L Brown ◽  
Roberta Magliozzi ◽  
Richard Reynolds ◽  
Declan T Chard
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Grey Matter ◽  
Magnetization Transfer ◽  
Neuronal Loss ◽  
Magnetization Transfer Ratio ◽  
Supporting Evidence ◽  
Transfer Ratio ◽  
Meningeal Inflammation

Abstract While multiple sclerosis can affect any part of the CNS, it does not do so evenly. In white matter it has long been recognized that lesions tend to occur around the ventricles, and grey matter lesions mainly accrue in the outermost (subpial) cortex. In cortical grey matter, neuronal loss is greater in the outermost layers. This cortical gradient has been replicated in vivo with magnetization transfer ratio and similar gradients in grey and white matter magnetization transfer ratio are seen around the ventricles, with the most severe abnormalities abutting the ventricular surface. The cause of these gradients remains uncertain, though soluble factors released from meningeal inflammation into the CSF has the most supporting evidence. In this Update, we review this ‘surface-in’ spatial distribution of multiple sclerosis abnormalities and consider the implications for understanding pathogenic mechanisms and treatments designed to slow or stop them.

scholarly journals Focal and diffuse cortical degenerative changes in a marmoset model of multiple sclerosis

2010 ◽  
Vol 16 (5) ◽  
pp. 537-548 ◽  
Author(s):  
IM Pomeroy ◽  
EK Jordan ◽  
JA Frank ◽  
PM Matthews ◽  
MM Esiri
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Grey Matter ◽  
Neuronal Loss ◽  
Axonal Damage ◽  
Inflammatory Factors ◽  
Focal Lesions ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Background: Degenerative features, such as neuronal, glial, synaptic and axonal loss, have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration, but the pathological and clinical significance of these lesions is uncertain as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of myelin oligodendrocyte glycoprotein-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods. Results: We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6—36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size. Conclusions: The marmoset experimental autoimmune encephalomyelitis model, therefore, shows both focal and generalized neurodegeneration. The generalized changes cannot be directly related to focal lesions, suggesting that they are either a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.

scholarly journals Neuron-specific activation of necroptosis signaling in multiple sclerosis cortical grey matter

2021 ◽  
Vol 141 (4) ◽  
pp. 585-604 ◽  
Author(s):  
Carmen Picon ◽  
Anusha Jayaraman ◽  
Rachel James ◽  
Catriona Beck ◽  
Patricia Gallego ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Signaling Pathway ◽  
Cortical Neurons ◽  
Grey Matter ◽  
Molecular Mechanisms ◽  
Fold Increase ◽  
Cell Types ◽  
Meningeal Inflammation ◽  
Cortical Grey Matter

AbstractSustained exposure to pro-inflammatory cytokines in the leptomeninges is thought to play a major role in the pathogenetic mechanisms leading to cortical pathology in multiple sclerosis (MS). Although the molecular mechanisms underlying neurodegeneration in the grey matter remain unclear, several lines of evidence suggest a prominent role for tumour necrosis factor (TNF). Using cortical grey matter tissue blocks from post-mortem brains from 28 secondary progressive MS subjects and ten non-neurological controls, we describe an increase in expression of multiple steps in the TNF/TNF receptor 1 signaling pathway leading to necroptosis, including the key proteins TNFR1, FADD, RIPK1, RIPK3 and MLKL. Activation of this pathway was indicated by the phosphorylation of RIPK3 and MLKL and the formation of protein oligomers characteristic of necrosomes. In contrast, caspase-8 dependent apoptotic signaling was decreased. Upregulation of necroptotic signaling occurred predominantly in macroneurons in cortical layers II–III, with little expression in other cell types. The presence of activated necroptotic proteins in neurons was increased in MS cases with prominent meningeal inflammation, with a 30-fold increase in phosphoMLKL+ neurons in layers I–III. The density of phosphoMLKL+ neurons correlated inversely with age at death, age at progression and disease duration. In vivo induction of chronically elevated TNF and INFγ levels in the CSF in a rat model via lentiviral transduction in the meninges, triggered inflammation and neurodegeneration in the underlying cortical grey matter that was associated with increased neuronal expression of TNFR1 and activated necroptotic signaling proteins. Exposure of cultured primary rat cortical neurons to TNF induced necroptosis when apoptosis was inhibited. Our data suggest that neurons in the MS cortex are dying via TNF/TNFR1 stimulated necroptosis rather than apoptosis, possibly initiated in part by chronic meningeal inflammation. Neuronal necroptosis represents a pathogenetic mechanism that is amenable to therapeutic intervention at several points in the signaling pathway.

Investigation of outer cortical magnetisation transfer ratio abnormalities in multiple sclerosis clinical subgroups

2014 ◽  
Vol 20 (10) ◽  
pp. 1322-1330 ◽  
Author(s):  
Rebecca S Samson ◽  
Manuel J Cardoso ◽  
Nils Muhlert ◽  
Varun Sethi ◽  
Claudia AM Wheeler-Kingshott ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Three Dimensional ◽  
Neuronal Loss ◽  
Magnetisation Transfer ◽  
Magnetisation Transfer Ratio ◽  
Outer Cortex ◽  
Transfer Ratio ◽  
Relapsing Remitting ◽  
Healthy Control

Background: Pathological abnormalities including demyelination and neuronal loss are reported in the outer cortex in multiple sclerosis (MS). Objective: We investigated for in vivo evidence of outer cortical abnormalities by measuring the magnetisation transfer ratio (MTR) in MS patients of different subgroups. Methods: Forty-four relapsing–remitting (RR) (mean age 41.9 years, median Expanded Disability Status Scale (EDSS) 2.0), 25 secondary progressive (SP) (54.1 years, EDSS 6.5) and 19 primary progressive (PP) (53.1 years, EDSS 6.0) MS patients and 35 healthy control subjects (mean age 39.2 years) were studied. Three-dimensional (3D) 1×1×1mm3 T1-weighted images and MTR data were acquired. The cortex was segmented, then subdivided into outer and inner bands, and MTR values were calculated for each band. Results: In a pairwise analysis, mean outer cortical MTR was lower than mean inner cortical MTR in all MS groups and controls ( p<0.001). Compared with controls, outer cortical MTR was decreased in SPMS ( p<0.001) and RRMS ( p<0.01), but not PPMS. Outer cortical MTR was lower in SPMS than PPMS ( p<0.01) and RRMS ( p<0.01). Conclusions: Lower outer than inner cortical MTR in healthy controls may reflect differences in myelin content. The lowest outer cortical MTR was seen in SPMS and is consistent with more extensive outer cortical (including subpial) pathology, such as demyelination and neuronal loss, as observed in post-mortem studies of SPMS patients.

scholarly journals Restoration of Visual Function and Cortical Connectivity After Ischemic Injury Through NeuroD1-Mediated Gene Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yu Tang ◽  
Qiuyu Wu ◽  
Mang Gao ◽  
Esther Ryu ◽  
Zifei Pei ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Neuronal Loss ◽  
Ischemic Injury ◽  
Direct Conversion ◽  
Neuronal Population ◽  
Visual Responses ◽  
Brain Functions ◽  
Cortical Circuit ◽  
Visual Cortical

Neural circuits underlying brain functions are vulnerable to damage, including ischemic injury, leading to neuronal loss and gliosis. Recent technology of direct conversion of endogenous astrocytes into neurons in situ can simultaneously replenish the neuronal population and reverse the glial scar. However, whether these newly reprogrammed neurons undergo normal development, integrate into the existing neuronal circuit, and acquire functional properties specific for this circuit is not known. We investigated the effect of NeuroD1-mediated in vivo direct reprogramming on visual cortical circuit integration and functional recovery in a mouse model of ischemic injury. After performing electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells in vivo and mapping the synaptic connections formed onto these cells ex vivo, we discovered that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual experience, the reprogrammed neurons demonstrated maturation of orientation selectivity and functional connectivity. Our results show that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit leading to vision recovery after ischemic injury.

scholarly journals Alterations in sensorimotor and mesiotemporal cortices and diffuse white matter changes in primary progressive multiple sclerosis detected by adiabatic relaxometry

2020 ◽  
Author(s):  
Pavel Filip ◽  
Michal Dufek ◽  
Silvia Mangia ◽  
Shalom Michaeli ◽  
Martin Bares ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Large Scale ◽  
Diffusion Tensor ◽  
Neuronal Loss ◽  
Progressive Multiple Sclerosis ◽  
Primary Progressive Multiple Sclerosis ◽  
Primary Progressive ◽  
T1 And T2

Abstract Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced MRI protocols searching for disease-specific microstructural changes. Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ maps in combination with diffusion weighted parameters were acquired in 13 PPMS patients and 13 age and sex-matched controls.Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, sensorimotor cortex and cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols completely dwarfed the outcomes of both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches –methods previously implicated in the MRI research of PPMS.Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical grey matter, cerebellar and white matter alterations in PPMS invisible to other in vivo biomarkers.

scholarly journals A platform utilizing Drosophila ovulation for nonhormonal contraceptive screening

2021 ◽  
Vol 118 (28) ◽  
pp. e2026403118
Author(s):  
Kewa Jiang ◽  
Jiyang Zhang ◽  
Yuping Huang ◽  
Yingzheng Wang ◽  
Shuo Xiao ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Unmet Need ◽  
Dependent Manner ◽  
Female Reproduction ◽  
Contraceptive Agents ◽  
Follicle Rupture ◽  
Approved Drugs ◽  
Fda Approved Drugs

A significant unmet need for new contraceptive options for both women and men remains due to side-effect profiles, medical concerns, and the inconvenience of many currently available contraceptive products. Unfortunately, the development of novel nonsteroidal female contraceptive medicine has been stalled in the last couple of decades due to the lack of effective screening platforms. Drosophila utilizes conserved signaling pathways for follicle rupture, a final step in ovulation that is essential for female reproduction. Therefore, we explored the potential to use Drosophila as a model to screen compounds that could inhibit follicle rupture and be nonsteroidal contraceptive candidates. Using our ex vivo follicle rupture assay, we screened 1,172 Food and Drug Administration (FDA)–approved drugs and identified six drugs that could inhibit Drosophila follicle rupture in a dose-dependent manner. In addition, we characterized the molecular actions of these drugs in the inhibition of adrenergic signaling and follicle rupture. Furthermore, we validated that three of the four drugs consistently inhibited mouse follicle rupture in vitro and that two of them did not affect progesterone production. Finally, we showed that chlorpromazine, one of the candidate drugs, can significantly inhibit mouse follicle rupture in vivo. Our work suggests that Drosophila ovulation is a valuable platform for identifying lead compounds for nonsteroidal contraceptive development and highlights the potential of these FDA-approved drugs as novel nonsteroidal contraceptive agents.

A GMCSF/Interleukin-15 Fusokine Leads to the Generation of a Novel Type of CD2/MHCII Immune Regulatory Cell with Potent Immune Suppressive Properties as Demonstrated in the EAE Mouse Model of Multiple Sclerosis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2295-2295
Author(s):  
Moutih Rafei ◽  
Jeremy Hsieh ◽  
Meng Yang Li ◽  
Simone Zehntner ◽  
Kathy Forner ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Autoimmune Disease ◽  
Ex Vivo ◽  
Regulatory Cell ◽  
Autoreactive T Cell ◽  
Experimental Allergic Encephalitis ◽  
Over Time

Abstract Multiple sclerosis (MS) is an autoimmune disease characterised by the infiltration of autoreactive T-cell causing damages to the central nervous system. So far, interferon-β and glatiramer acetate are the only two immunomodulatory coumpounds that have been approved as non-curative disease managing strategies. Therefore, there is an urgent need for the development of novel efficient therapies that can be both safe and potent in inhibiting MS progression and promote reversal of disease state. We have recently published a report describing a novel synthetic GMCSF and IL15 Fusion Transgene (GIFT15) and have described its paradoxical and potent immune suppressive properties in vivo [Rafei et al., Blood (March 2007)]. Its mechanism of action relies on STAT3 hyperactivation arising from aberrant signalling taking place downstream of the IL15 receptor. We have now further studied the effect of GIFT15 on mouse spleen cells in vitro and here demonstrate that it leads to the conversion of murine T-cells to a novel suppressive regulatory cell type. Indeed, GIFT15-treated splenocytes (hereafter GIFT15 regs) shed their TCR and loose expression of CD3, CD4 and CD8, retain CD2 expression and acquire expression of MHC II. Distinct to classic T-regulatory cells, GIFT15 regs do not express CD25 or FOXP3. GIFT15 regs were able to suppress an in vitro two-way MLR by a contact-dependent mechanism as well as by the contemporaneous production of interleukin (IL)-10. Furthermore, GIFT15 regs were able to block antigen-specific activation of CD4-T-cells in response to autologous macrophage stimulation. As a proof-of-principle in vivo study, GIFT15 regs were injected intravenously in mice with pre-established experimental allergic encephalitis (EAE) and disease score was monitored over time. Interestingly, mice recovered significantly faster than controls following administration GIFT15 regs and a blockade in EAE progression was also noticed over time. In conclusion, our data suggests that GIFT15 can be used as a method to ex vivo generate suppressor cells of a new type which are distinct from classic Tregs or Tr1 cells. We propose that GIFT15 regs derived from autologous lymphocytes may be exploited for the treatment of autoimmune disease such as MS and may also be of use for other autoimmune ailments as well.

scholarly journals LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Weiwei Tang ◽  
Kumaraguruparan Ramasamy ◽  
Sureshkumar M. A. Pillai ◽  
Bindu Santhamma ◽  
Swapna Konda ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Cell Viability ◽  
Cancer Progression ◽  
Ex Vivo ◽  
Unmet Need ◽  
In Vivo Studies ◽  
Stem Cell Markers ◽  
Oncogenic Signaling ◽  
Ec Cells

AbstractEndometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC50 in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

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