180 results on '"Zipp, Frauke"'
Search Results
2. Cytokines as emerging regulators of central nervous system synapses.
- Author
-
Zipp, Frauke, Bittner, Stefan, and Schafer, Dorothy P.
- Subjects
- *
CENTRAL nervous system , *SYNAPSES , *NEURAL circuitry , *CYTOKINES , *NEUROPLASTICITY - Abstract
Cytokines are key messengers by which immune cells communicate, and they drive many physiological processes, including immune and inflammatory responses. Early discoveries demonstrated that cytokines, such as the interleukin family members and TNF-α, regulate synaptic scaling and plasticity. Still, we continue to learn more about how these traditional immune system cytokines affect neuronal structure and function. Different cytokines shape synaptic function on multiple levels ranging from fine-tuning neurotransmission, to regulating synapse number, to impacting global neuronal networks and complex behavior. These recent findings have cultivated an exciting and growing field centered on the importance of immune system cytokines for regulating synapse and neural network structure and function. Here, we highlight the latest findings related to cytokines in the central nervous system and their regulation of synapse structure and function. Moreover, we explore how these mechanisms are becoming increasingly important to consider in diseases—especially those with a large neuroinflammatory component. Immunity contributes to brain function in both health and disease. Here, Zipp, Bittner, and Schafer review how immune cytokines shape synaptic function on multiple levels ranging from fine-tuning neurotransmission, to shaping synaptic function, to impacting global neuronal networks and behavior. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
3. Preventing disease progression in multiple sclerosis—insights from large real-world cohorts.
- Author
-
Engel, Sinah and Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis , *DISEASE progression , *CHRONIC diseases - Abstract
Multiple sclerosis is a chronic neuroinflammatory disease with a highly heterogeneous disease course. Preventing lasting disability requires early identification of persons at risk and novel approaches towards patient stratification for personalized treatment decisions. In this comment, we discuss the importance of large datasets of real-world cohorts in order to address this unmet need. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
4. A lymphocyte-glia connection sets the pace for smoldering inflammation.
- Author
-
Bittner, Stefan and Zipp, Frauke
- Subjects
- *
CENTRAL nervous system , *DISABILITIES , *MULTIPLE sclerosis , *NATALIZUMAB , *INFLAMMATION - Abstract
Successful therapeutic options directly targeting disability progression in patients with multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, are lacking. Now, a study published in Nature by Absinta and colleagues profiles a lymphocyte-glia connection at the edge of chronic active lesions that continuously drives neurodegenerative pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
5. Implementing the 2017 McDonald criteria for the diagnosis of multiple sclerosis.
- Author
-
Zipp, Frauke, Oh, Jiwon, Fragoso, Yara Dadalti, and Waubant, Emmanuelle
- Subjects
- *
MULTIPLE sclerosis , *CEREBROSPINAL fluid , *TECHNICAL specifications , *EARLY diagnosis , *INTERNET publishing - Abstract
The latest revision of the McDonald criteria for the diagnosis of multiple sclerosis (MS) was published online in 2017. New features of the criteria, which were designed to facilitate earlier diagnosis of MS, include the recognition of oligoclonal bands in the cerebrospinal fluid as a possible marker of dissemination of MS pathology in time, the introduction of symptomatic lesions as a parameter to demonstrate spatial or temporal pathology dissemination, and the use of cortical lesions to demonstrate dissemination in space. In this Viewpoint, a panel of world-renowned MS specialists share their personal experiences of the new criteria to date. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
6. T cell–neuron interaction in inflammatory and progressive multiple sclerosis biology.
- Author
-
Brummer, Tobias, Zipp, Frauke, and Bittner, Stefan
- Subjects
- *
MULTIPLE sclerosis , *NEUROGLIA , *BIOLOGY , *T cells , *CENTRAL nervous system , *B cells - Abstract
Multiple sclerosis (MS) is a chronic autoimmune condition of the central nervous system (CNS) characterized by acute inflammatory relapses, chronic neuro-axonal degeneration, and subsequent disability progression. T cells – in interaction with B cells and CNS-resident glial cells – are key initiators and drivers of neurodegeneration in MS. However, it is not entirely clear how encephalitogenic T cells orchestrate the local immune response within the brain and how they overtake disease stage-specific roles in MS pathogenesis. This review highlights recent advances in understanding direct and indirect T cell–neuron interactions in inflammatory and progressive MS. Finally, we discuss new diagnostic tools such as neurofilament light chain (NfL), which is on the cusp of becoming a key factor in clinical and therapeutic decision-making. • In multiple sclerosis (MS), T cells can interact with neurons via indirect or direct mechanisms. • Neuron–T cell interactions can have both noxious and beneficial effects. • Recent studies have identified new pathologically relevant T cell subsets in MS. • Serum NfL has become an important prognostic marker for neuro-axonal damage in MS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
7. Dendritic cells as therapeutic targets in neuroinflammation.
- Author
-
Lüssi, Felix, Zipp, Frauke, and Witsch, Esther
- Subjects
- *
MULTIPLE sclerosis treatment , *DENDRITIC cells , *ANTI-inflammatory agents , *IMMUNOREGULATION , *DEMYELINATION , *DISEASE relapse - Abstract
Multiple sclerosis (MS) is the most common chronic inflammatory demyelinating disorder of the central nervous system characterized by infiltration of immune cells and progressive damage to myelin sheaths and neurons. There is still no cure for the disease, but drug regimens can reduce the frequency of relapses and slightly delay progression. Myeloid cells or antigen-presenting cells (APCs) such as dendritic cells (DC), macrophages, and resident microglia, are key players in both mediating immune responses and inducing immune tolerance. Mounting evidence indicates a contribution of these myeloid cells to the pathogenesis of multiple sclerosis and to the effects of treatment, the understanding of which might provide strategies for more potent novel therapeutic interventions. Here, we review recent insights into the role of APCs, with specific focus on DCs in the modulation of neuroinflammation in MS. [ABSTRACT FROM AUTHOR]
- Published
- 2016
- Full Text
- View/download PDF
8. AAN unveils new guidelines for MS disease-modifying therapy.
- Author
-
Bittner, Stefan and Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis treatment , *NEUROLOGY , *PHARMACOLOGY , *ALEMTUZUMAB , *AZATHIOPRINE - Abstract
Following on from a recent European Academy of Neurology guideline on pharmacological treatment of multiple sclerosis (MS), the American Academy of Neurology has issued an updated practice guideline on disease-modifying therapies (DMTs) for MS. The guideline provides 30 general recommendations for initiating, switching and stopping DMTs, and indicates future research directions. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
9. Studying the blood–brain barrier will provide new insights into neurodegeneration – Commentary.
- Author
-
Bittner, Stefan and Zipp, Frauke
- Subjects
- *
BLOOD-brain barrier , *NEURODEGENERATION , *BLOOD-brain barrier disorders , *CENTRAL nervous system , *IMMUNE system , *BIOMARKERS , *PHYSIOLOGY - Abstract
The article focuses on the need of studying the blood–brain barrier to get new insights into neurodegeneration. It states that vascular dysfunction in the brain may be a predisposition factor and pathways restoring impaired vascular function may provide means of fighting neurological diseases, and mentions that blood–brain barrier is involved in the crosstalk of the immune and nervous systems. It notes the scope of developing biomarkers like neurofilament light chain in the blood.
- Published
- 2018
- Full Text
- View/download PDF
10. Molecular mechanisms linking neuroinflammation and neurodegeneration in MS.
- Author
-
Ellwardt, Erik and Zipp, Frauke
- Subjects
- *
INFLAMMATION , *NEURODEGENERATION , *MULTIPLE sclerosis , *AUTOIMMUNE diseases , *CENTRAL nervous system diseases , *DISEASE progression , *IMMUNOREGULATION - Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) and one of the leading causes of neurological deficits and disability in young adults in western countries. Current medical treatment mainly influences disease progression via immunomodulatory or immunosuppressive actions. Indeed, MS research has been foremost focused on inflammation in the CNS, but more recent evidence suggests that chronic disability in MS is caused by neurodegeneration. Imaging studies show an early involvement of neurodegeneration as brain atrophy and gray matter lesions can be observed at disease onset. Thus, neuroprotective treatment strategies and the elucidation of the molecular mechanisms underlying neurodegeneration in MS have attracted the attention of the scientific community. Experimental autoimmune encephalomyelitis (EAE; the most commonly used animal model for MS), novel in-vivo imaging techniques such as two-photon microscopy and recently discovered molecular changes have offered new insights into the pathogenesis of neuroinflammation as well as neurodegeneration in MS. This review focuses on the interaction between components of the immune system and the neuronal compartment, as well as describing the most important molecular mechanisms that lead to axonal and neuronal degeneration in MS and EAE. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
11. Neurodegeneration in autoimmune CNS inflammation
- Author
-
Herz, Josephine, Zipp, Frauke, and Siffrin, Volker
- Subjects
- *
TREATMENT of neurodegeneration , *DEMYELINATION , *CENTRAL nervous system diseases , *ANIMAL models in research , *MYELIN sheath diseases , *AXONS , *CELL death , *WOUNDS & injuries , *THERAPEUTICS - Abstract
Abstract: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, in which the myelin sheath has been considered to be the primary target for many years. However, an increasing number of reports have focused on neurodegenerative aspects of the disease pathogenesis. Recent studies in post-mortem MS biopsies and in the animal model Experimental Autoimmune Encephalomyelitis (EAE) have shown that key features of neurodegeneration, i.e. axonal transection, neuronal cell atrophy and neuronal death already occur in early disease phases. Furthermore, it has become clear that irreversible disability correlates stronger with the neuronal affectation than with demyelination. However the cause of neuronal damage still remains elusive, since both demyelination-dependent and direct immune cell-mediated mechanisms have been suggested so far. Here, we summarize the current concepts and recently identified molecular mechanisms of inflammatory neurodegeneration in autoimmune CNS inflammation and highlight the role of different immune cells in the complex network of interactions leading to neuronal damage. [ABSTRACT FROM AUTHOR]
- Published
- 2010
- Full Text
- View/download PDF
12. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in central nervous system inflammation.
- Author
-
Hoffmann, Olaf, Zipp, Frauke, and Weber, Joerg R.
- Subjects
- *
CENTRAL nervous system , *NEUROLOGY , *CELL death , *APOPTOSIS , *MULTIPLE sclerosis - Abstract
In a wide variety of acute and chronic central nervous system (CNS) disorders, inflammatory processes contribute to the damage of brain cells and progression of the disease. Along with other regulatory cytokines, tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is involved in the pathology of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE), bacterial meningitis (BM), HIV encephalitis (HIVE), stroke and Alzheimer's disease (AD). In these conditions, TRAIL is released within the brain mainly by activated microglia and leukocytes infiltrating from the blood stream. TRAIL promotes apoptosis of parenchymal cells in MS/EAE, HIVE, AD and stroke through interaction with TRAIL death receptors expressed on these cells. Frequently, cells in the diseased brain display increased susceptibility to apoptosis induction by TRAIL due to upregulation of death receptors and downregulation of decoy receptors. On the other hand, TRAIL inhibits the proliferation of encephalitogenic T cells in EAE, and it is involved in the clearance of infected brain macrophages in HIVE and of activated neutrophils in BM by interaction with their death receptors. Especially in BM, the ability of TRAIL to limit an acute granulocyte-driven inflammation carries significant neuroprotective potential. Given the diversity of beneficial and harmful effects in the immune and nervous system, TRAIL is a double-edged sword in diseases involving CNS inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
13. Therapeutic targeting of chemokine signaling in Multiple Sclerosis
- Author
-
Hamann, Isabell, Zipp, Frauke, and Infante-Duarte, Carmen
- Subjects
- *
MULTIPLE sclerosis treatment , *CHEMOKINES , *IMMUNITY , *CELLS - Abstract
Abstract: Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that is initiated and maintained by continuous migration of inflammatory immune cells from the periphery into the target organ. However, in autoimmunity, migration of immune cells is not only involved in the pathogenesis but also in the down-modulation of the autoimmune attack, which is probably mediated by the infiltration of certain regulatory immune cell populations inside the affected organs. The migratory activity of both proinflammatory and regulatory leucocytes is controlled by chemokines and their receptors. Thus, targeting the directed migration of immune cells and regulating leukocyte trafficking across the blood-brain barrier (BBB) by means of modulation of chemokine signaling receptors might open up new therapeutic avenues not only for MS but also for other autoimmune diseases. In this review we summarize the chemotactic signaling pathways known to be involved in neuroinflammation to date and the viability of these pathways as targets for therapeutic strategies. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
14. Impact of HMG-CoA reductase inhibition on brain pathology
- Author
-
Zipp, Frauke, Waiczies, Sonia, Aktas, Orhan, Neuhaus, Oliver, Hemmer, Bernhard, Schraven, Burkhard, Nitsch, Robert, and Hartung, Hans-Peter
- Subjects
- *
ENZYME inhibitors , *COENZYMES , *BLOOD cholesterol , *GUANOSINE triphosphatase , *MEMBRANE lipids , *BRAIN research - Abstract
Over the past two decades, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMGCRIs), originally designed to lower cholesterol blood levels, have been found to affect GTPase signaling during normal intracellular tasks. This finding has prompted use of these drugs in pathological situations, where such signaling processes need to be manipulated. Here, we review recent progress on the outcome of modulating GTPase signaling after inhibition of protein prenylation by HMGCRIs. We also discuss current controversies over the direct implications of these cholesterol-lowering agents on cholesterol-rich membrane lipid rafts and associated signaling. By reviewing these two different cellular events and the evidence from clinical studies, an overall assessment can be made of the concept of interfering with the HMG-CoA reductase pathway in different brain pathologies. We thereby provide a rational link between the benefit of applying HMGCRIs in brain pathologies, such as multiple sclerosis, Alzheimer''s disease and stroke, and the impact on signaling in specific cell types crucial to disease pathogenesis. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
15. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases
- Author
-
Zipp, Frauke and Aktas, Orhan
- Subjects
- *
BRAIN diseases , *ENCEPHALITIS , *NEURODEGENERATION , *IMMUNE system , *PREVENTIVE medicine - Abstract
Classical knowledge distinguishes between inflammatory and non-inflammatory diseases of the brain. Either the immune system acts on the CNS and initiates a damage cascade, as in autoimmune (e.g. multiple sclerosis) and infectious conditions, or the primary insult is not inflammation but ischemia or degeneration, as in stroke and Alzheimer''s disease, respectively. However, as we review here, recent advances have blurred this distinction. On the one hand, the classical inflammatory diseases of the brain also exhibit profound and early neurodegenerative features – remarkably, it has been known for more than a century that neuronal damage is a key feature of multiple sclerosis pathology, yet this was neglected until very recently. On the other hand, immune mechanisms might set the pace of progressive CNS damage in primary neurodegeneration. Despite differing initial events, increasing evidence indicates that even in clinically heterogeneous diseases, there might be common immunological pathways that result in neurotoxicity and reveal targets for more efficient therapies. [Copyright &y& Elsevier]
- Published
- 2006
- Full Text
- View/download PDF
16. Multiple Sklerose - weit mehr als eine Entmarkungskrankheit.
- Author
-
Aktas, Orhan and Zipp, Frauke
- Published
- 2004
- Full Text
- View/download PDF
17. Concurrent inflammation-related brain reorganization in multiple sclerosis and depression.
- Author
-
Molina Galindo, Lara S., Gonzalez-Escamilla, Gabriel, Fleischer, Vinzenz, Grotegerd, Dominik, Meinert, Susanne, Ciolac, Dumitru, Person, Maren, Stein, Frederike, Brosch, Katharina, Nenadić, Igor, Alexander, Nina, Kircher, Tilo, Hahn, Tim, Winter, Yaroslav, Othman, Ahmed E., Bittner, Stefan, Zipp, Frauke, Dannlowski, Udo, and Groppa, Sergiu
- Subjects
- *
MENTAL depression , *MULTIPLE sclerosis , *MAGNETIC resonance imaging , *SUPPORT vector machines , *GRAY matter (Nerve tissue) - Abstract
• Multiple sclerosis and major depression share morphologic network alterations. • The contrast between the gray and white matters may be a neuroinflammation marker. • Network alterations may underlie symptom severity and depression comorbidity in MS. Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown. We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently. MS and MDD patients showed increased modularity (ANOVA partial-η2 = 0.3) and clustering (partial-η2 = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η2 = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η2 = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %). Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
18. Meilenstein oder verpasste Chance?
- Author
-
Pape, Katrin and Zipp, Frauke
- Published
- 2019
- Full Text
- View/download PDF
19. SFB TRR43: Das Gehirn als Ziel von entzündlichen Prozessen.
- Author
-
Heppner, Frank L. and Zipp, Frauke
- Published
- 2008
- Full Text
- View/download PDF
20. Introduction
- Author
-
Zipp, Frauke and Trapp, Bruce D.
- Published
- 2007
- Full Text
- View/download PDF
21. Graduiertenkolleg 1258 Der Einfluss von Entzündung auf die Funktion des Nervensystems.
- Author
-
Kettenmann, Helmut and Zipp, Frauke
- Published
- 2006
- Full Text
- View/download PDF
22. Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.
- Author
-
Wilson, David, Chan, Dandan, Chang, Lei, Mathis, Robert, Verberk, Inge, Montalban, Xavier, Comabella, Manuel, Fissolo, Nicolas, Bielekova, Bibi, Masvekar, Ruturaj, Chitnis, Tanuja, Ziemssen, Tjalf, Akgün, Katja, Blennow, Kaj, Zetterberg, Henrik, Brück, Wolfgang, Giovannoni, Gavin, Gnanapavan, Sharmilee, Bittner, Stefan, and Zipp, Frauke
- Subjects
- *
BLOOD testing , *IMMUNOASSAY , *DIGITAL music , *CYTOPLASMIC filaments , *THERAPEUTICS , *CEREBROSPINAL fluid examination , *AXONS - Abstract
Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50–100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre–post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
23. Multiple sclerosis.
- Author
-
Jakimovski, Dejan, Bittner, Stefan, Zivadinov, Robert, Morrow, Sarah A, Benedict, Ralph HB, Zipp, Frauke, and Weinstock-Guttman, Bianca
- Subjects
- *
MULTIPLE sclerosis , *ECOLOGICAL genetics , *NATURE & nurture , *YOUNG adults , *NEURODEGENERATION - Abstract
Multiple sclerosis remains one of the most common causes of neurological disability in the young adult population (aged 18–40 years). Novel pathophysiological findings underline the importance of the interaction between genetics and environment. Improvements in diagnostic criteria, harmonised guidelines for MRI, and globalised treatment recommendations have led to more accurate diagnosis and an earlier start of effective immunomodulatory treatment than previously. Understanding and capturing the long prodromal multiple sclerosis period would further improve diagnostic abilities and thus treatment initiation, eventually improving long-term disease outcomes. The large portfolio of currently available medications paved the way for personalised therapeutic strategies that will balance safety and effectiveness. Incorporation of cognitive interventions, lifestyle recommendations, and management of non-neurological comorbidities could further improve quality of life and outcomes. Future challenges include the development of medications that successfully target the neurodegenerative aspect of the disease and creation of sensitive imaging and fluid biomarkers that can effectively predict and monitor disease changes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
24. Development and multi-center validation of a fully automated digital immunoassay for neurofilament light chain: toward a clinical blood test for neuronal injury.
- Author
-
Wilson, David, Chan, Dandan, Chang, Lei, Mathis, Robert, Verberk, Inge, Montalban, Xavier, Comabella, Manuel, Fissolo, Nicolas, Bielekova, Bibi, Masvekar, Ruturaj, Chitnis, Tanuja, Ziemssen, Tjalf, Akgün, Katja, Blennow, Kaj, Zetterberg, Henrik, Brück, Wolfgang, Giovannoni, Gavin, Gnanapavan, Sharmilee, Bittner, Stefan, and Zipp, Frauke
- Subjects
- *
BLOOD testing , *IMMUNOASSAY , *DIGITAL music , *CYTOPLASMIC filaments , *THERAPEUTICS , *AXONS - Abstract
Neurofilament light chain (NfL) has emerged as a promising biomarker for detecting and monitoring axonal injury. Until recently, NfL could only be reliably measured in cerebrospinal fluid, but digital single molecule array (Simoa) technology has enabled its precise measurement in blood samples where it is typically 50–100 times less abundant. We report development and multi-center validation of a novel fully automated digital immunoassay for NfL in serum for informing axonal injury status. A 45-min immunoassay for serum NfL was developed for use on an automated digital analyzer based on Simoa technology. The analytical performance (sensitivity, precision, reproducibility, linearity, sample type) was characterized and then cross validated across 17 laboratories in 10 countries. Analytical performance for clinical NfL measurement was examined in individual patients with relapsing remitting multiple sclerosis (RRMS) after 3 months of disease modifying treatment (DMT) with fingolimod. The assay exhibited a lower limit of detection (LLoD) of 0.05 ng/L, a lower limit of quantification (LLoQ) of 0.8 ng/L, and between-laboratory imprecision <10 % across 17 validation sites. All tested samples had measurable NfL concentrations well above the LLoQ. In matched pre–post treatment samples, decreases in NfL were observed in 26/29 RRMS patients three months after DMT start, with significant decreases detected in a majority of patients. The sensitivity characteristics and reproducible performance across laboratories combined with full automation make this assay suitable for clinical use for NfL assessment, monitoring in individual patients, and cross-comparisons of results across multiple sites. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
25. Prognostic value of single-subject grey matter networks in early multiple sclerosis.
- Author
-
Fleischer, Vinzenz, Gonzalez-Escamilla, Gabriel, Pareto, Deborah, Rovira, Alex, Sastre-Garriga, Jaume, Sowa, Piotr, Høgestøl, Einar A, Harbo, Hanne F, Bellenberg, Barbara, Lukas, Carsten, Ruggieri, Serena, Gasperini, Claudio, Uher, Tomas, Vaneckova, Manuela, Bittner, Stefan, Othman, Ahmed E, Collorone, Sara, Toosy, Ahmed T, Meuth, Sven G, and Zipp, Frauke
- Subjects
- *
PROGNOSIS , *MULTIPLE sclerosis , *WHITE matter (Nerve tissue) , *MAGNETIC resonance imaging , *LARGE-scale brain networks - Abstract
The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P -values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
26. Strict blood pressure control following thrombectomy is associated with neuronal injury and poor functional outcome.
- Author
-
Hahn, Marianne, Hayani, Eyad, Bitar, Lynn, Gröschel, Sonja, Steffen, Falk, Protopapa, Maria, Othman, Ahmed, Bittner, Stefan, Zipp, Frauke, Gröschel, Klaus, and Uphaus, Timo
- Subjects
- *
BLOOD pressure , *ISCHEMIC stroke , *THROMBECTOMY , *REGRESSION analysis , *QUALITY of life - Abstract
Objective: Mechanical thrombectomy (MT) has become standard treatment in acute ischemic stroke due to large vessel occlusion (LVO). However, optimal blood pressure (BP) management following successful recanalization remains unclear. We aim to investigate the association of strictly achieving BP targets of ≤160/90 mmHg with the extent of neuronal loss and functional outcome. Methods: In patients prospectively enrolled in the Gutenberg‐Stroke‐Study (May 2018–November 2019), BP was measured half‐hourly for 24 h following MT. Based on achieving BP target of ≤160/90 mmHg, patients with successful recanalization of LVO were divided into "low‐BP" group (BP ≤ 160/90 mmHg) or "high‐BP" group (BP > 160/90 mmHg). Neuronal loss was quantified by serum‐based measurement of neurofilament light chain (sNfL) after three days. BP groups and association of BP parameters with sNfL were investigated by correlation analyses and multiple regression modeling. Results: Of 253 enrolled patients (mean age 73.1 ± 12.9 years, 53.4% female), 165 met inclusion criteria. 21.2% (n = 35) strictly achieved "low‐BP" target. "low‐BP" was associated with unfavorable functional outcome at 90‐day follow‐up (aOR [95%CI]: 5.88 [1.88–18.32], p = 0.002) and decreased health‐related quality of life (mean EQ‐5D‐index 0.45 ± 0.28 vs 0.63 ± 0.31, p = 0.009). sNfL levels were increased in "low‐BP" patients (median [IQR] 239.7 [168.4–303.4] vs 118.8 [52.5–220.5] pg/mL, p = 0.026). Hypotensive episodes were more frequent in the "low‐BP" group (48.6% vs 29.2%, p = 0.031). sNfL level could identify patients who had experienced hypotensive episodes with high discriminative ability (AUC [95%CI]: 0.68 [0.56–0.78], p = 0.007). Interpretation: Strict BP control (≤160/90 mmHg) within 24 h following successful recanalization of LVO by MT is associated with increased neuronal injury, displayed by higher sNfL levels, and poorer functional outcome, potentially indicating hypotension‐induced neuronal loss during post‐MT phase. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
27. Spatial transcriptomics and neurofilament light chain reveal changes in lesion patterns in murine autoimmune neuroinflammation.
- Author
-
Brummer, Tobias, Schillner, Miriam, Steffen, Falk, Kneilmann, Flores, Wasser, Beatrice, Uphaus, Timo, Zipp, Frauke, and Bittner, Stefan
- Subjects
- *
CYTOPLASMIC filaments , *NEUROINFLAMMATION , *WHITE matter (Nerve tissue) , *NEUROGLIA , *MYELOID cells , *PULMONARY alveolar proteinosis - Abstract
Objective: Ongoing neuroaxonal damage is a major contributor to disease progression and long-term disability in multiple sclerosis. However, spatio-temporal distribution and pathophysiological mechanisms of neuroaxonal damage during acute relapses and later chronic disease stages remain poorly understood. Methods: Here, we applied immunohistochemistry, single-molecule array, spatial transcriptomics, and microglia/axon co-cultures to gain insight into spatio-temporal neuroaxonal damage in experimental autoimmune encephalomyelitis (EAE). Results: Association of spinal cord white matter lesions and blood-based neurofilament light (sNfL) levels revealed a distinct, stage-dependent anatomical pattern of neuroaxonal damage: in chronic EAE, sNfL levels were predominately associated with anterolateral lumbar lesions, whereas in early EAE sNfL showed no correlation with lesions in any anatomical location. Furthermore, neuroaxonal damage in late EAE was largely confined to white matter lesions but showed a widespread distribution in early EAE. Following this pattern of neuroaxonal damage, spatial transcriptomics revealed a widespread cyto- and chemokine response at early disease stages, whereas late EAE was characterized by a prominent glial cell accumulation in white matter lesions. These findings were corroborated by immunohistochemistry and microglia/axon co-cultures, which further revealed a strong association between CNS myeloid cell activation and neuroaxonal damage both in vivo and in vitro. Interpretation: Our findings indicate that CNS myeloid cells may play a crucial role in driving neuroaxonal damage in EAE. Moreover, neuroaxonal damage can progress in a stage-dependent centripetal manner, transitioning from normal-appearing white matter to focal white matter lesions. These insights may contribute to a better understanding of neurodegeneration and elevated sNfL levels observed in multiple sclerosis patients at different disease stages. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
28. Implications of immunometabolism for smouldering MS pathology and therapy.
- Author
-
Bittner, Stefan, Pape, Katrin, Klotz, Luisa, and Zipp, Frauke
- Subjects
- *
PATHOLOGY , *IMMUNOLOGIC memory , *CELL metabolism , *NEUROGLIA , *IMMUNOMODULATORS - Abstract
Clinical symptom worsening in patients with multiple sclerosis (MS) is driven by inflammation compartmentalized within the CNS, which results in chronic neuronal damage owing to insufficient repair mechanisms. The term 'smouldering inflammation' summarizes the biological aspects underlying this chronic, non-relapsing and immune-mediated mechanism of disease progression. Smouldering inflammation is likely to be shaped and sustained by local factors in the CNS that account for the persistence of this inflammatory response and explain why current treatments for MS do not sufficiently target this process. Local factors that affect the metabolic properties of glial cells and neurons include cytokines, pH value, lactate levels and nutrient availability. This Review summarizes current knowledge of the local inflammatory microenvironment in smouldering inflammation and how it interacts with the metabolism of tissue-resident immune cells, thereby promoting inflammatory niches within the CNS. The discussion highlights environmental and lifestyle factors that are increasingly recognized as capable of altering immune cell metabolism and potentially responsible for smouldering pathology in the CNS. Currently approved MS therapies that target metabolic pathways are also discussed, along with their potential for preventing the processes that contribute to smouldering inflammation and thereby to progressive neurodegenerative damage in MS. Smouldering inflammation encompasses all non-relapsing aspects of inflammatory pathobiology in multiple sclerosis. Here, Bittner and colleagues describe the mechanisms that underlie CNS-compartmentalized smouldering inflammation and review evidence indicating that immunometabolic reprogramming driven by the CNS tissue microenvironment shapes these inflammatory responses. Potential treatments are also discussed. Key points: The term 'smouldering inflammation' summarizes the biological aspects that underlie compartmentalized CNS inflammation and chronic neuronal damage, which are insufficiently targeted by currently approved therapies. The chronically inflamed CNS provides a unique tissue microenvironment characterized by alterations in nutrient availability, pH value, lactate levels and cytokine profiles. Tissue-resident memory T cells, microglia and astrocytes are key immune cells in smouldering inflammation that can adapt their metabolic profiles in response to the inflamed microenvironment. Environmental and lifestyle factors are increasingly recognized as modulators of immune cell metabolism. Modulation of immune cell metabolism and the inflammatory microenvironment might foster novel treatment approaches in smouldering inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
29. SFB-TR 128: Multiple Sklerose: Von einem neuen Verständnis der Pathogenese zur Therapie.
- Author
-
Zipp, Frauke and Wiendl, Heinz
- Published
- 2013
- Full Text
- View/download PDF
30. Novel therapeutic options and drug targets in MS.
- Author
-
Methner, Axel and Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis treatment , *CLINICAL trials , *DRUG efficacy , *ESTERS , *IMMUNOLOGICAL adjuvants , *NEURODEGENERATION , *IMMUNE system , *SINGLE nucleotide polymorphisms , *THERAPEUTICS - Abstract
The article looks at important therapeutic developments aimed at multiple sclerosis (MS). In 2012, three clinical trials were conducted to describe the efficacy of dimethyl fumarate (BG12) and laquinimod in relapsing-remitting MS. Results of these studies showed that BG12 can address the neurodegenerative pathology of MS, as well as its dysregulated immune system. Another study examined a single nucleotide polymorphism in a gene associated with MS.
- Published
- 2013
- Full Text
- View/download PDF
31. Erratum to: Dendritic cells as therapeutic targets in neuroinflammation.
- Author
-
Luessi, Felix, Zipp, Frauke, and Witsch, Esther
- Subjects
- *
NEUROLOGICAL disorders , *THERAPEUTICS , *DENDRITIC cells , *ANTI-inflammatory agents - Published
- 2016
- Full Text
- View/download PDF
32. Bilateral meralgia paresthetica after cesarian section with epidural analgesia.
- Author
-
Paul, Friedemann and Zipp, Frauke
- Subjects
- *
LETTERS to the editor , *CESAREAN section - Abstract
A letter to the editor is presented discussing the issue of bilateral meralgia paresthetica after cesarean section with epidural analgesia.
- Published
- 2006
- Full Text
- View/download PDF
33. No increase in demyelinating diseases after hepatitis B vaccination.
- Author
-
Zipp, Frauke, Weil, John G., and Einhäupl, Karl M.
- Subjects
- *
HEPATITIS B vaccines , *DEMYELINATION - Abstract
Reports that hepatitis B vaccination does not induce demyelination. Molecular features of both the virus and the vaccine that could theoretically account for the assumed connection; Rate of central nervous system demyelinating episodes in individuals vaccinated against hepatitis B.
- Published
- 1999
- Full Text
- View/download PDF
34. Interleukin-4 as a therapeutic target.
- Author
-
Gärtner, Yvonne, Bitar, Lynn, Zipp, Frauke, and Vogelaar, Christina Francisca
- Subjects
- *
INTERLEUKIN-4 , *SPINAL cord injuries , *IMMUNE response , *ATOPIC dermatitis , *MULTIPLE sclerosis - Abstract
Interleukin-4 (IL-4) is a pleiotropic cytokine mainly known for its role in type 2 immunity. Therapies antagonizing or blocking IL-4 activity have been developed to counteract diseases such as atopic dermatitis and asthma. In contrast, other disorders experimentally benefit from IL-4-related effects and IL-4 recently demonstrated beneficial activity in experimental stroke, spinal cord injury and the animal model of multiple sclerosis. To exploit IL-4-related activity for therapeutic concepts, current experimental efforts include modifying the pathway without inducing type 2 immune response and targeting of the cytokine to specific tissues. Here, we review different activities of IL-4 as well as therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
35. EGFL7 loss correlates with increased VEGF-D expression, upregulating hippocampal adult neurogenesis and improving spatial learning and memory.
- Author
-
Barth, Kathrin, Vasić, Verica, McDonald, Brennan, Heinig, Nora, Wagner, Marc-Christoph, Schumann, Ulrike, Röhlecke, Cora, Bicker, Frank, Schumann, Lana, Radyushkin, Konstantin, Baumgart, Jan, Tenzer, Stefan, Zipp, Frauke, Meinhardt, Matthias, Alitalo, Kari, Tegeder, Irmgard, and Schmidt, Mirko H. H.
- Abstract
Neural stem cells reside in the subgranular zone, a specialized neurogenic niche of the hippocampus. Throughout adulthood, these cells give rise to neurons in the dentate gyrus, playing an important role in learning and memory. Given that these core cognitive processes are disrupted in numerous disease states, understanding the underlying mechanisms of neural stem cell proliferation in the subgranular zone is of direct practical interest. Here, we report that mature neurons, neural stem cells and neural precursor cells each secrete the neurovascular protein epidermal growth factor-like protein 7 (EGFL7) to shape this hippocampal niche. We further demonstrate that EGFL7 knock-out in a Nestin-CreERT2-based mouse model produces a pronounced upregulation of neurogenesis within the subgranular zone. RNA sequencing identified that the increased expression of the cytokine VEGF-D correlates significantly with the ablation of EGFL7. We substantiate this finding with intraventricular infusion of VEGF-D upregulating neurogenesis in vivo and further show that VEGF-D knock-out produces a downregulation of neurogenesis. Finally, behavioral studies in EGFL7 knock-out mice demonstrate greater maintenance of spatial memory and improved memory consolidation in the hippocampus by modulation of pattern separation. Taken together, our findings demonstrate that both EGFL7 and VEGF-D affect neurogenesis in the adult hippocampus, with the ablation of EGFL7 upregulating neurogenesis, increasing spatial learning and memory, and correlating with increased VEGF-D expression. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. Early spinal cord pseudoatrophy in interferon‐beta‐treated multiple sclerosis.
- Author
-
Matusche, Britta, Litvin, Ludmila, Schneider, Ruth, Bellenberg, Barbara, Mühlau, Mark, Pongratz, Viola, Berthele, Achim, Groppa, Sergiu, Muthuraman, Muthuraman, Zipp, Frauke, Paul, Friedemann, Wiendl, Heinz, Meuth, Sven G., Sämann, Philipp, Weber, Frank, Linker, Ralf A., Kümpfel, Tania, Gold, Ralf, and Lukas, Carsten
- Subjects
- *
SPINAL cord , *MULTIPLE sclerosis , *CERVICAL cord , *CEREBRAL atrophy , *MAGNETIC resonance imaging - Abstract
Background and purpose: Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease‐modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain. Methods: A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon‐beta therapy (n = 84) and untreated patients (n = 45). Results: Patients treated with interferon‐beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year. Conclusions: These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon‐beta treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
37. Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects.
- Author
-
Daguano Gastaldi, Vinicius, BH Wilke, Justus, Weidinger, Cosima A., Walter, Carolin, Barnkothe, Nadine, Teegen, Bianca, Luessi, Felix, Stöcker, Winfried, Lühder, Fred, Begemann, Martin, Zipp, Frauke, Nave, Klaus-Armin, and Ehrenreich, Hannelore
- Subjects
- *
AUTOIMMUNE diseases , *HUMORAL immunity , *AUTOANTIBODY analysis , *AUTOIMMUNITY , *LOGISTIC regression analysis , *FISHER exact test , *BRAIN injuries - Abstract
• A selection of 49 anti-brain autoantibodies was analyzed in > 7000 subjects. • Brain-directed autoantibodies are frequent across health and disease. • Neither seroprevalence nor immunoglobulin class nor titers alone predict disease. • Age, gender, genetic factors, and brain injury emerge as predictors of serum AB. Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in > 7000 individuals. Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher's exact tests and logistic regression analyses were used. Study of N = 7025 subjects (55.8 % male; 41 ± 16 years) revealed N = 1133 (16.13 %) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR = 1.018/year; 95 % CI [1.015–1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR = 1.303; 95 % CI [1.144–1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7 %). Low seroprevalence (1.25 %-0.02 %) was seen for most AB (e.g., amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3 , previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR = 1.55; 95 % CI [1.058–2.271]) and disease likelihood (OR = 1.43; 95 % CI [1.032–1.985]). APOE4 carriers (∼19 %) had lower seropositivity (OR = 0.766; 95 % CI [0.625–0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR = 1.599; 95 % CI [1.022–2.468]). Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
38. Elevated neurofilament light chain CSF/serum ratio indicates impaired CSF outflow in idiopathic intracranial hypertension.
- Author
-
Engel, Sinah, Halcour, Johannes, Ellwardt, Erik, Uphaus, Timo, Steffen, Falk, Zipp, Frauke, Bittner, Stefan, and Luessi, Felix
- Subjects
- *
INTRACRANIAL hypertension , *GLIAL fibrillary acidic protein , *CYTOPLASMIC filaments - Abstract
Background: Impaired cerebrospinal fluid (CSF) homeostasis is central to the pathogenesis of idiopathic intracranial hypertension (IIH), although the precise mechanisms involved are still not completely understood. The aim of the current study was to assess the CSF/serum ratio of neurofilament light chain levels (QNfL) as a potential indicator of functional CSF outflow obstruction in IIH patients. Methods: NfL levels were measured by single molecule array in CSF and serum samples of 87 IIH patients and in three control groups, consisting of 52 multiple sclerosis (MS) patients with an acute relapse, 21 patients with an axonal polyneuropathy (PNP), and 41 neurologically healthy controls (HC). QNfL was calculated as the ratio of CSF and serum NfL levels. Similarly, we also assessed the CSF/serum ratio of glial fibrillary acidic protein (QGFAP) levels to validate the QNfL data. Routine CSF parameters including the CSF/serum albumin ratio (QAlb) were determined in all groups. Lumbar puncture opening pressure of IIH patients was measured by manometry. Results: CSF-NfL levels (r = 0.29, p = 0.008) and QNfL (0.40, p = 0.0009), but not serum NfL (S-NfL) levels, were associated with lumbar puncture opening pressure in IIH patients. CSF-NfL levels were increased in IIH patients, MS patients, and PNP patients, whereas sNfL levels were normal in IIH, but elevated in MS and PNP. Remarkably, QNfL (p < 0.0001) as well as QGFAP (p < 0.01) were only increased in IIH patients. QNfL was positively correlated with CSF-NfL levels (r = 0.51, p = 0.0012) and negatively correlated with S-NfL levels (r = − 0.51, p = 0.0012) in HC, while it was only positively associated with CSF-NfL levels in IIH patients (r = 0.71, p < 0.0001). An increase in blood-CSF barrier permeability assessed by QAlb did not lead to a decrease in QNfL in any cohort. Conclusions: The observed elevation of QNfL in IIH patients, which was associated with lumbar puncture opening pressure, indicates a reduced NfL transition from the CSF to serum compartment. This supports the hypothesis of a pressure-dependent CSF outflow obstruction to be critically involved in IIH pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
39. A new window in multiple sclerosis pathology: non-conventional quantitative magnetic resonance imaging outcomes
- Author
-
Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis diagnosis , *NEURODEGENERATION , *MAGNETIC resonance imaging , *PATHOLOGY , *INFLAMMATION , *OPTICAL coherence tomography , *BIOMARKERS , *DIFFUSION tensor imaging - Abstract
Summary: Recent findings suggest that neuronal pathology occurs early in the course of multiple sclerosis and seems to be responsible for accumulation of disability. Nonetheless, the nervous system has an intrinsic potential for repair and compensation in the neuronal component. Disease-modifying drugs such as glatiramer acetate interfere with, and down-regulate, inflammatory pathology and slow neurodegeneration. Moreover, certain regulatory cytokines and neurotrophic factors have the capacity to promote neuronal and axonal repair. Given the importance of neuronal injury in multiple sclerosis and the potential of certain treatments for neuronal repair, it is important to possess adequate and sensitive tools to visualise the pathology in the neuronal compartment. The most promising tools to measure neuronal and axonal damage in multiple sclerosis, as well as neu-roprotection and repair, are whole brain volume change for quantification of general brain atrophy, and T1 hypointensity (black holes) and magnetisation transfer ratio for measuring evolution of lesion damage. Other promising techniques, such as diffusion tensor imaging-based fibre tracking and magnetic resonance spectroscopy may allow detailed analyses, but these are still in the experimental stage and are not available for routine clinical practice. Further paraclinical measurements such as optical coherence tomography for the evaluation of the anterior visual pathway may have potential as objective surrogate markers for neurodegeneration in multiple sclerosis. [Copyright &y& Elsevier]
- Published
- 2009
- Full Text
- View/download PDF
40. Altered grey matter integrity and network vulnerability relate to epilepsy occurrence in patients with multiple sclerosis.
- Author
-
Ciolac, Dumitru, Gonzalez‐Escamilla, Gabriel, Winter, Yaroslav, Melzer, Nico, Luessi, Felix, Radetz, Angela, Fleischer, Vinzenz, Groppa, Stanislav A., Kirsch, Michael, Bittner, Stefan, Zipp, Frauke, Muthuraman, Muthuraman, Meuth, Sven G., Grothe, Matthias, and Groppa, Sergiu
- Subjects
- *
PEOPLE with epilepsy , *MULTIPLE sclerosis , *MAGNETIC resonance imaging , *AGE groups , *HIDRADENITIS suppurativa , *DISEASE duration - Abstract
Background and purpose: The aim of this study was to investigate the relevance of compartmentalized grey matter (GM) pathology and network reorganization in multiple sclerosis (MS) patients with concomitant epilepsy. Methods: From 3‐T magnetic resonance imaging scans of 30 MS patients with epilepsy (MSE group; age 41 ± 15 years, 21 females, disease duration 8 ± 6 years, median Expanded Disability Status Scale [EDSS] score 3), 60 MS patients without epilepsy (MS group; age 41 ± 12 years, 35 females, disease duration 6 ± 4 years, EDSS score 2), and 60 healthy subjects (HS group; age 40 ± 13 years, 27 females) the regional volumes of GM lesions and of cortical, subcortical and hippocampal structures were quantified. Network topology and vulnerability were modelled within the graph theoretical framework. Receiver‐operating characteristic (ROC) curve analysis was applied to assess the accuracy of GM pathology measures to discriminate between MSE and MS patients. Results: Higher lesion volumes within the hippocampus, mesiotemporal cortex and amygdala were detected in the MSE compared to the MS group (all p < 0.05). The MSE group had lower cortical volumes mainly in temporal and parietal areas compared to the MS and HS groups (all p < 0.05). Lower hippocampal tail and presubiculum volumes were identified in both the MSE and MS groups compared to the HS group (all p < 0.05). Network topology in the MSE group was characterized by higher transitivity and assortativity, and higher vulnerability compared to the MS and HS groups (all p < 0.05). Hippocampal lesion volume yielded the highest accuracy (area under the ROC curve 0.80 [0.67–0.91]) in discriminating between MSE and MS patients. Conclusions: High lesion load, altered integrity of mesiotemporal GM structures, and network reorganization are associated with a greater propensity for epilepsy occurrence in people with MS. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
41. Network alterations underlying anxiety symptoms in early multiple sclerosis.
- Author
-
Ellwardt, Erik, Muthuraman, Muthuraman, Gonzalez-Escamilla, Gabriel, Chirumamilla, Venkata Chaitanya, Luessi, Felix, Bittner, Stefan, Zipp, Frauke, Groppa, Sergiu, and Fleischer, Vinzenz
- Subjects
- *
MULTIPLE sclerosis , *TRANSCRANIAL magnetic stimulation , *LARGE-scale brain networks , *CEREBRAL atrophy , *PATHOLOGY , *MULTIPLE personality , *APATHY - Abstract
Background: Anxiety, often seen as comorbidity in multiple sclerosis (MS), is a frequent neuropsychiatric symptom and essentially affects the overall disease burden. Here, we aimed to decipher anxiety-related networks functionally connected to atrophied areas in patients suffering from MS.Methods: Using 3-T MRI, anxiety-related atrophy maps were generated by correlating longitudinal cortical thinning with the severity of anxiety symptoms in MS patients. To determine brain regions functionally connected to these maps, we applied a technique termed "atrophy network mapping". Thereby, the anxiety-related atrophy maps were projected onto a large normative connectome (n = 1000) performing seed-based functional connectivity. Finally, an instructed threat paradigm was conducted with regard to neural excitability and effective connectivity, using transcranial magnetic stimulation combined with high-density electroencephalography.Results: Thinning of the left dorsal prefrontal cortex was the only region that was associated with higher anxiety levels. Atrophy network mapping identified functional involvement of bilateral prefrontal cortex as well as amygdala and hippocampus. Structural equation modeling confirmed that the volumes of these brain regions were significant determinants that influence anxiety symptoms in MS. We additionally identified reduced information flow between the prefrontal cortex and the amygdala at rest, and pathologically increased excitability in the prefrontal cortex in MS patients as compared to controls.Conclusion: Anxiety-related prefrontal cortical atrophy in MS leads to a specific network alteration involving structures that resemble known neurobiological anxiety circuits. These findings elucidate the emergence of anxiety as part of the disease pathology and might ultimately enable targeted treatment approaches modulating brain networks in MS. [ABSTRACT FROM AUTHOR]- Published
- 2022
- Full Text
- View/download PDF
42. Two laboratory-confirmed cases of Japanese encephalitis imported to Germany by travelers returning from Southeast Asia
- Author
-
Tappe, Dennis, Nemecek, Andrea, Zipp, Frauke, Emmerich, Petra, Gabriel, Martin, Günther, Stephan, Dobler, Gerhard, Schmidt-Chanasit, Jonas, and Stich, August
- Subjects
- *
JAPANESE encephalitis viruses , *ENCEPHALITIS vaccines , *BRAIN diseases , *VIROLOGY - Abstract
Abstract: Japanese encephalitis virus is the leading cause of encephalitis in Asia and parts of the Pacific. Despite the high number of symptomatic infections in endemic countries, clinical disease in travelers is rare. However, an increasing number of imported infections from popular holiday destinations in Southeast Asia have been recorded in the past few years, including serious disease courses in short-term travelers. Here we report two severe, non-fatal cases in tourists, who returned from a long-time stay in Thailand and a short-term trip to Bali, Indonesia, respectively. Recommendations for vaccination and pre-travel advice are discussed. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
43. Cerebral blood perfusion changes in multiple sclerosis
- Author
-
Wuerfel, Jens, Paul, Friedemann, and Zipp, Frauke
- Subjects
- *
BLOOD vessels , *MULTIPLE sclerosis , *MICROCIRCULATION , *CEREBRAL circulation - Abstract
Abstract: The proximity of immune cell aggregations to the vasculature is a hallmark of multiple sclerosis. Furthermore, it is widely accepted that inflammation is able to modulate the microcirculation. Until recently, the detection of cerebral blood perfusion changes was technically challenging, and perfusion studies in multiple sclerosis patients yielded contradictory results. However, new developments in fast magnetic resonance imaging have enabled us to image the cerebral hemodynamics based on the dynamic tracking of a bolus of paramagnetic contrast agents (dynamic susceptibility contrast). This review discusses the technical principles, possible pitfalls, and potential for absolute quantification of cerebral blood volume and flow in a clinical setting. It also outlines recent findings on inflammation associated perfusion changes, which are inseparable from pathological considerations in multiple sclerosis. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
44. High-field diffusion tensor imaging of mouse brain in vivo using single-shot STEAM MRI
- Author
-
Boretius, Susann, Würfel, Jens, Zipp, Frauke, Frahm, Jens, and Michaelis, Thomas
- Subjects
- *
MEDICAL imaging systems , *RESONANCE , *ATOMS , *FIELD theory (Physics) - Abstract
Abstract: Information about the microstructural organization of cerebral white matter that is accessible by magnetic resonance diffusion tensor imaging (DTI) gains increasing importance for studies of animal brain. Particular challenges occur for in vivo conditions as well as at high magnetic fields. Here, we have employed a diffusion-weighted (DW) single-shot STEAM MRI sequence for DTI of mouse brain in vivo at 7T. The approach exploits the increased longitudinal magnetization and prolonged T 1 relaxation times of water protons at higher magnetic field strengths without suffering from susceptibility-induced artifacts. When compared to studies at 2.35T, half Fourier DW STEAM MRI at 7T yielded a substantial gain in signal-to-noise ratio (SNR) that could be invested either in a reduction of the measurement time or an increase of the spatial resolution. Thus, for a measurement time of 3h, DTI with a voxel size of 117μm×117μm×720μm not only resulted in high-quality maps of the fractional anisotropy and main diffusion direction (MDD), but also allowed for fiber tracking of major mouse brain structures in vivo. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
45. Neurodegeneration in autoimmune demyelination: Recent mechanistic insights reveal novel therapeutic targets
- Author
-
Aktas, Orhan, Waiczies, Sonia, and Zipp, Frauke
- Subjects
- *
NEURODEGENERATION , *DEMYELINATION , *MULTIPLE sclerosis , *AUTOIMMUNE diseases - Abstract
Abstract: Multiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system (CNS) and the major cause of neurological disability in young adults in Western countries. In spite of intensive research efforts, treatment options established to date do not sufficiently prevent the accumulation of tissue damage and clinical disability in patients with MS. We here describe recently identified molecules responsible for the inflammatory and the neurodegenerative processes in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), and review new treatment options targeting both aspects of this disease. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
46. Serum levels of soluble CD95 are not associated with amelioration of multiple sclerosis during pregnancy
- Author
-
Ehrlich, Stefan, Haas, Judith, Zipp, Frauke, and Infante-Duarte, Carmen
- Subjects
- *
MULTIPLE sclerosis , *VIRUS diseases , *PREGNANT women , *STEROID hormones - Abstract
Abstract: Multiple sclerosis (MS) is considered an autoimmune disease of the central nervous system. Like various other autoimmune disorders, MS normally improves during pregnancy. Pregnant MS patients experience a significant reduction in relapse rates and magnetic resonance (MR) disease activity. How sex steroid hormones affect disease course remains unclear. We hypothesized that hormonal changes during pregnancy might modulate the autoimmune response by enhancing apoptosis of autoreactive T lymphocytes. One of the most important effectors of apoptosis in T cells is the CD95/CD95L system. We have previously reported that the soluble form of CD95 (sCD95) can block CD95-mediated apoptosis and that MS patients show elevated levels of sCD95. Therefore, we considered whether gravidity might influence serum levels of sCD95 in patients, and analyzed the concentration of sCD95 in the sera of 61 patients with relapsing-remitting (RR) MS before, during and after pregnancy. We found no association between serum levels of sCD95 and pregnancy-related immune suppression in MS patients. Thus, sex steroid hormones do not seem to affect the production of anti-apoptotic sCD95. [Copyright &y& Elsevier]
- Published
- 2007
- Full Text
- View/download PDF
47. Death Ligands and Autoimmune Demyelination.
- Author
-
Aktas, Orhan, Prozorovski, Timour, and Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis , *DEMYELINATION , *APOPTOSIS , *TUMOR necrosis factors , *ENCEPHALOMYELITIS - Abstract
Death ligands induce apoptosis, which is a cell suicide program leading mainly to selective elimination of an organism's useless cells. Importantly, the dying cell is an active participant in its own demise ("cellular suicide"). Under physiological conditions, apoptosis is most often found during normal cell turnover and tissue homeostasis, embryogenesis, induction and maintenance of immune tolerance, development of the nervous system, and endocrine-dependent tissue atrophy. However, apoptotic processes have also been suggested to contribute to the pathology of the autoimmune demyelinating disease multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis. Here, apoptosis plays a double role. On one hand, impaired apoptosis may result in increased numbers or persistence of activated myelin-specific T cells. On the other hand, local tissue damage involves apoptosis of oligodendrocytes and neurons, leading to the clinical symptoms. In this article, an overview is given of the current knowledge of the roles of apoptosis-mediating and immune regulatory death ligands of the tumor necrosis factor (TNF) family (TNF, lymphotoxin-beta, OX40L [CD134L], CD154 [CD40L], CD95L, CD70 [CD27L], CD153 [CD30L], 4-1BBL [CD137L], TRAIL, TWEAK, BAFF, GITRL) in the pathogenesis of MS and of their implications for related therapeutic strategies. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
48. Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity.
- Author
-
Liebmann, Marie, Korn, Lisanne, Janoschka, Claudia, Albrecht, Stefanie, Lauks, Sarah, Herrmann, Alexander M, Schulte-Mecklenbeck, Andreas, Schwab, Nicholas, Schneider-Hohendorf, Tilman, Eveslage, Maria, Wildemann, Brigitte, Luessi, Felix, Schmidt, Stephan, Diebold, Martin, Bittner, Stefan, Gross, Catharina C, Kovac, Stjepana, Zipp, Frauke, Derfuss, Tobias, and Kuhlmann, Tanja
- Subjects
- *
DIMETHYL fumarate , *T cells , *OXYGEN consumption , *REACTIVE oxygen species , *AUTOIMMUNITY , *GLUTATHIONE , *THERAPEUTIC use of antioxidants , *MULTIPLE sclerosis , *RESEARCH , *ANIMAL experimentation , *RESEARCH methodology , *ANTIOXIDANTS , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *IMMUNITY , *RESEARCH funding , *IMMUNOSUPPRESSIVE agents , *MICE , *LONGITUDINAL method , *PHARMACODYNAMICS - Abstract
Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
49. The potential of serum neurofilament as biomarker for multiple sclerosis.
- Author
-
Bittner, Stefan, Oh, Jiwon, Havrdová, Eva Kubala, Tintoré, Mar, and Zipp, Frauke
- Subjects
- *
MULTIPLE sclerosis , *BIOMARKERS , *CYTOPLASMIC filaments , *TREATMENT effectiveness , *MEDICAL protocols , *NEUROMYELITIS optica , *RESEARCH , *NERVE tissue proteins , *RESEARCH methodology , *MAGNETIC resonance imaging , *PROGNOSIS , *MEDICAL cooperation , *EVALUATION research , *COMPARATIVE studies , *LONGITUDINAL method - Abstract
Multiple sclerosis is a highly heterogeneous disease, and the detection of neuroaxonal damage as well as its quantification is a critical step for patients. Blood-based serum neurofilament light chain (sNfL) is currently under close investigation as an easily accessible biomarker of prognosis and treatment response in patients with multiple sclerosis. There is abundant evidence that sNfL levels reflect ongoing inflammatory-driven neuroaxonal damage (e.g. relapses or MRI disease activity) and that sNfL levels predict disease activity over the next few years. In contrast, the association of sNfL with long-term clinical outcomes or its ability to reflect slow, diffuse neurodegenerative damage in multiple sclerosis is less clear. However, early results from real-world cohorts and clinical trials using sNfL as a marker of treatment response in multiple sclerosis are encouraging. Importantly, clinical algorithms should now be developed that incorporate the routine use of sNfL to guide individualized clinical decision-making in people with multiple sclerosis, together with additional fluid biomarkers and clinical and MRI measures. Here, we propose specific clinical scenarios where implementing sNfL measures may be of utility, including, among others: initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
50. High anti-JCPyV serum titers coincide with high CSF cell counts in RRMS patients.
- Author
-
Schneider-Hohendorf, Tilman, Schulte-Mecklenbeck, Andreas, Ostkamp, Patrick, Janoschka, Claudia, Pawlitzki, Marc, Luessi, Felix, Zipp, Frauke, Meuth, Sven G, Klotz, Luisa, Wiendl, Heinz, Gross, Catharina C, and Schwab, Nicholas
- Subjects
- *
PROGRESSIVE multifocal leukoencephalopathy , *CEREBROSPINAL fluid , *TITERS , *NATALIZUMAB , *CENTRAL nervous system , *THROMBOTIC thrombocytopenic purpura - Abstract
Background: Progressive multifocal leukoencephalopathy (PML) can in rare cases occur in natalizumab-treated patients with high serum anti-JCPyV antibodies, hypothetically due to excessive blockade of immune cell migration. Objective: Immune cell recruitment to the central nervous system (CNS) was assessed in relapsing-remitting multiple sclerosis (RRMS) patients stratified by low versus high anti-JCPyV antibody titers as indicator for PML risk. Methods: Cerebrospinal fluid (CSF) cell counts of 145 RRMS patients were quantified by flow cytometry. Generalized linear models were employed to assess influence of age, sex, disease duration, Expanded Disability Status Scale (EDSS), clinical/radiological activity, current steroid or natalizumab treatment, as well as anti-JCPyV serology on CSF cell subset counts. Results: While clinical/radiological activity was associated with increased CD4, natural killer (NK), B and plasma cell counts, natalizumab therapy reduced all subpopulations except monocytes. With and without natalizumab therapy, patients with high anti-JCPyV serum titers presented with increased CSF T-cell counts compared to patients with low anti-JCPyV serum titers. In contrast, PML patients assessed before (n = 2) or at diagnosis (n = 5) presented with comparably low CD8 and B-cell counts, which increased after plasma exchange (n = 4). Conclusion: High anti-JCPyV indices, which could be indicative of increased viral activity, are associated with elevated immune cell recruitment to the CNS. Its excessive impairment in conjunction with viral activity could predispose for PML development. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.