multiple sclerosis

The role of real-word data in scientific evidence. Experiences from the Danish Multiple Sclerosis Registry

How the brain barriers ensure CNSimmune privilege”

Britta Engelhard’s research is devoted to understanding thefunction of the different brain barriers in regulating CNS immunesurveillance and how their impaired function contributes toneuroinflammatory diseases such as Multiple Sclerosis (MS) orAlzheimer’s disease (AD). Her laboratory combines expertise invascular biology, neuroimmunology and live cell imaging and hasdeveloped sophisticated in vitro and in vivo approaches to studyimmune cell interactions with the brain barriers in health andneuroinflammation.

Development of a small molecule to promote neuroprotection and repair in progressive multiple sclerosis

The role of CNS microglia in health and disease

Microglia are the resident CNS macrophages of the brain parenchyma. They have many and opposing roles in health and disease, ranging from inflammatory to anti-inflammatory and protective functions, depending on the developmental stage and the disease context. In Multiple Sclerosis, microglia are involved to important hallmarks of the disease, such as inflammation, demyelination, axonal damage and remyelination, however the exact mechanisms controlling their transformation towards a protective or devastating phenotype during the disease progression remains largely unknown until now. We wish to understand how brain microglia respond to demyelinating insults and how their behaviour changes in recovery. To do so we developed a novel histopathological analysis approach in 3D and a cell-based analysis tool that when applied in the cuprizone model of demyelination revealed region- and disease- dependent changes in microglial dynamics in the brain grey matter during demyelination and remyelination. We now use similar approaches with the aim to unravel sensitive changes in microglial dynamics during neuroinflammation in the EAE model. Furthermore, we employ constitutive knockout and tamoxifen-inducible gene-targeting approaches, immunological techniques, genetics and bioinformatics and currently seek to clarify the specific role of the brain resident microglial NF-κB molecular pathway versus other tissue macrophages in EAE.

Present and Future of the diagnostic work-up multiple sclerosis: the imaging perspective

Valentine’s Day for people with multiple sclerosis: promoting brain repair through remyelination

Current disease-modifying therapies in multiple sclerosis are all focused on suppressing the inflammatory phase of the disease. This has been extremely successful, and it is doubtful that significantly more efficacious anti-inflammatory treatments will be found. However, it remains the case that people with relapsing-remitting multiple sclerosis acquire disability on treatment, and enter the secondary progressive phase. I argue that we now need treatments that prevent neuronal degeneration. The most promising approach is to prevent axons degenerating by remyelination. Since the discovery that the adult brain contains stem cells which can remyelinate, the problem now is how to promote endogenous remyelination, and how to know when we have achieved this! We have successfully identified one drug which promotes remyelination but unfortunately it is too toxic for use in the clinic. So the hunt continues.

Pro-regenerative functions of microglia in demyelinating diseases

Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and remyelination, and their cross talk to other cells, in particular oligodendrocytes and the progenitor cells. In addition, we are exploring the link between lipid metabolism and inflammation, and its role in the regulation of regeneration. I will report about our recent progress in our understanding of how microglia promote regeneration in the CNS.

Autologous hematopoietic stem cell transplantation as a highly effective treatment for multiple sclerosis - clinical and mechanistic observations

Modulation of oligodendrocyte development and myelination by voltage-gated Ca++ channels

The oligodendrocyte generates CNS myelin, which is essential for normal nervous system function. Thus, investigating the regulatory and signaling mechanisms that control its differentiation and the production of myelin is relevant to our understanding of brain development and of adult pathologies such as multiple sclerosis. We have recently established that the activity of voltage-gated Ca++ channels is crucial for the adequate migration, proliferation and maturation of oligodendrocyte progenitor cells (OPCs). Furthermore, we have found that voltage-gated Ca++ channels that function in synaptic communication between neurons also mediate synaptic signaling between neurons and OPCs. Thus, we hypothesize that voltage-gated Ca++ channels are central components of OPC-neuronal synapses and are the principal ion channels mediating activity-dependent myelination.

Regenerative Neuroimmunology - a stem cell perspective

There are currently no approved therapies to slow down the accumulation of neurological disability that occurs independently of relapses in multiple sclerosis (MS). International agencies are engaging to expedite the development of novel strategies capable of modifying disease progression, abrogating persistent CNS inflammation, and support degenerating axons in people with progressive MS. Understanding why regeneration fails in the progressive MS brain and developing new regenerative approaches is a key priority for the Pluchino Lab. In particular, we aim to elucidate how the immune system, in particular its cells called myeloid cells, affects brain structure and function under normal healthy conditions and in disease. Our objective is to find how myeloid cells communicate with the central nervous system and affect tissue healing and functional recovery by stimulating mechanisms of brain plasticity mechanisms such as the generation of new nerve cells and the reduction of scar formation. Applying combination of state-of-the-art omic technologies, and molecular approaches to study murine and human disease models of inflammation and neurodegeneration, we aim to develop experimental molecular medicines, including those with stem cells and gene therapy vectors, which slow down the accumulation of irreversible disabilities and improve functional recovery after progressive multiple sclerosis, stroke and traumatic injuries. By understanding the mechanisms of intercellular (neuro-immune) signalling, diseases of the brain and spinal cord may be treated more effectively, and significant neuroprotection may be achieved with new tailored molecular therapeutics.

Magnetic Resonance Measures of Brain Blood Vessels, Metabolic Activity, and Pathology in Multiple Sclerosis

The normally functioning blood-brain barrier (BBB) regulates the transfer of material between blood and brain. BBB dysfunction has long been recognized in multiple sclerosis (MS), and there is considerable interest in quantifying functional aspects of brain blood vessels and their role in disease progression. Parenchymal water content and its association with volume regulation is important for proper brain function, and is one of the key roles of the BBB. There is convincing evidence that the astrocyte is critical in establishing and maintaining a functional BBB and providing metabolic support to neurons. Increasing evidence suggests that functional interactions between endothelia, pericytes, astrocytes, and neurons, collectively known as the neurovascular unit, contribute to brain water regulation, capillary blood volume and flow, BBB permeability, and are responsive to metabolic demands. Increasing evidence suggests altered metabolism in MS brain which may contribute to reduced neuro-repair and increased neurodegeneration. Metabolically relevant biomarkers may provide sensitive readouts of brain tissue at risk of degeneration, and magnetic resonance offers substantial promise in this regard. Dynamic contrast enhanced MRI combined with appropriate pharmacokinetic modeling allows quantification of distinct features of BBB including permeabilities to contrast agent and water, with rate constants that differ by six orders of magnitude. Mapping of these rate constants provides unique biological aspects of brain vasculature relevant to MS.

The immunopathology of advanced multiple sclerosis

We recently analyzed a large cohort of multiple sclerosis (MS) autopsy cases of the Netherlands Brain Bank (NBB) and showed that 57% of the lesion in advanced MS is active (containing activated microglia/macrophages). These active lesions correlated with disease severity and differed between males and female MS patients.1 Already in normal appearing white matter microglia show early signs of demyelination.5 T cells are also frequently present in advanced stages of MS and have a tissue resident memory (Trm) phenotype, are more frequently CD8+ then CD4+, are located perivascular, enriched in active and mixed active/inactive MS lesions and correlated with lesion activity, lesion load and disease severity.2-4 Like Trm cells, B cells are located perivascular and were also enriched in active MS lesions but in lower numbers and a proportion of the MS patients had almost no detectable B cells in the regions analyzed. MS patients with limited presence of B cells had less severe MS, and less active and mixed active /inactive lesions. We conclude that advanced MS is characterize by a high innate and adaptive immune activity which is heterogeneous and relates to the clinical disease course.

Electrophysiology application for optic nerve and the central nervous system diseases

Electrophysiology of eye and visual pathway is useful tool in ophthalmology and neurology. It covers a few examinations to find out if defect of vision is peripheral or central. Visual evoked potentials (VEP) are most frequently used in neurology and neuroophthalmology. VEP are evoked by flash or pattern stimulations. The combination of these both examinations gives more information about the visual pathway. It is very important to remember that VEP originate in the retina and reflect its function as well. In many cases not only VEP but also electroretinography (ERG) is essential for diagnosis. The seminar presents basic electrophysiological procedures used for diagnosis and follow-up of optic neuropathies and some of central nervous system diseases which affect vision (mostly multiple sclerosis, CNS tumors, stroke, traumas, intracranial hypertension).

Interleukin-9 protects from microglia- and TNF-mediated synaptotoxicity in experimental multiple sclerosis

FENS Forum 2024

Transcriptional changes in the prefrontal cortex are associated with cognitive impairment in an experimental mouse model of multiple sclerosis

FENS Forum 2024

Unveiling fusion between bone marrow-derived cells and Purkinje cells: Patch-Seq analysis in a mouse model of multiple sclerosis

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Visual impairments in a mouse model of multiple sclerosis: A transcriptomic analysis

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Aptamers to remyelinate multiple sclerosis: effects of ApTOLL© treatment in preclinical models and detection of mechanisms in human samples

Assessment of IL-38 levels in Multiple Sclerosis

Chemogenetic locus coeruleus activation alleviates experimental multiple sclerosis

Comparison of motion correction strategies for task-fMRI studies in Multiple Sclerosis

Contribution of ambient glutamate and glutamate transporters to retinal ganglion cell vulnerability in experimental multiple sclerosis

Deciphering the impact of myeloid-derived suppressor cell function on disease progression and neural tissue damage in Multiple Sclerosis

The emerging role of microRNAs in experimental and clinical multiple sclerosis: implications for inflammation-driven synaptic dysfunctions and disease course

Extracellular circulating miRNAs as potential biomarkers in multiple sclerosis and epilepsy

Identification of functional biomarkers of demyelination in two animal models of Multiple Sclerosis with functional Ultrasound Imaging

Impact of vagal nerve stimulation on the progression of demyelinated lesions in a murine model of multiple sclerosis

Inhibition of Chondroitin Sulfate Proteoglycans (CSPGs) to Promote Regeneration in the CNS in Multiple Sclerosis

Olfactory dysfunction and pronounced gliosis in the olfactory bulb precede motor impairment in the rat model of multiple sclerosis

Peripheral Myeloid Derived Suppressor Cells are good biomarkers of response and efficacy for Fingolimod treatment in multiple sclerosis

Plasma concentration of IFNα2, MCP-3, IL-6 and IL-8 is differentially decreased in non-active primary progressive multiple sclerosis

The prevalence and topography of demyelination and inflammatory activity in the multiple sclerosis spinal cord

Proteomic Alteration and Morphological Changes of Sibling NG2 Glial Cells in Response to Two Experimental Models of Multiple Sclerosis

Purkinje cell fusion dynamics in a mouse model of multiple sclerosis

Role of adenosine A2B receptors in myelination processes: new challenge in treating multiple sclerosis

Role of Netrin-1 in experimental model of multiple sclerosis

The S100B protein as a therapeutic target for multiple sclerosis processes

Vagus nerve stimulation reduces disease in rodent model of multiple sclerosis

Validation of nanoparticle-peptide targeting biomarker in the blood-brain barrier under neuroinflammation related to multiple sclerosis

Validation of IHC markers antibody panel in rat Experimental Autoimmune Encephalomyelitis (EAE) model of multiple sclerosis

Application of single-cell CRISPRi/a screen to characterize multiple sclerosis-associated single nucleotide polymorphisms in oligodendrocytes

FENS Forum 2024

B cell reconstitution and the alteration of immune cell landscape in ocrelizumab-treated patients with multiple sclerosis

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Use of high-tech eye gaze augmentative and alternative communication system to enhance communication and quality of life in multiple sclerosis: A single case study

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The immediate effect of lumbar transcutaneous spinal cord stimulation in patients with multiple sclerosis: Preliminary results of a sham-controlled study

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Inflammasomes, M2 cells, long non-coding RNAs and nanoparticles: The four wheels of multiple sclerosis?

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Melatonin reduces neuroinflammation and ameliorates gut dysbiosis in the preclinical mouse model of progressive multiple sclerosis

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Metabolomic profiling unveils novel insights into multiple sclerosis pathogenesis

FENS Forum 2024

miR-145 depletion promotes myelin regeneration in a novel mouse model of multiple sclerosis

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Modulation of mouse hippocampal lipidomic signature by FTY720, a sphingosine-1-phosphate analogue used for treating relapsing-remitting multiple sclerosis

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N-aglycosylated extracellular loop of the potassium channel KCNJ10 as contributor to autoimmunity in multiple sclerosis

FENS Forum 2024

Novel potential biomarkers for multiple sclerosis: Evaluating the expression levels of miR-141, miR-9, MEG3, IFNG-AS1 and their relationship to different LINC00513 polymorphisms

FENS Forum 2024

Olfactory dysfunction as a common denominator in multiple sclerosis and Parkinson’s disease – Evidence from animal models

FENS Forum 2024

Re-emergence of T lymphocytes-mediated synaptopathy in progressive multiple sclerosis

FENS Forum 2024