Papers by Michael Schroeter
Mediators of Inflammation, 2017
Background. Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently rep... more Background. Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microglia in vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after stroke in vivo, with focus on infarct demarcation. Methods. Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation. Results. After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ M1 cells while increasing M2 microglia, shifting the M1/M2 balance towards an M2 phenotype. Moreover, OPN polarized astrocytes towards the infarct. Conclusion. Microglial activation and M1 and M2 polarization have distinct but overlapping spatial patterns in permanent focal ischemia. Data suggest that OPN is involved in separating M1 and M2 subpopulations, as well as in shifting microglia polarization towards the M2 phenotype modulating beneficially inflammatory responses after focal infarction.
Journal of Neuroimmune Pharmacology, Nov 28, 2018
Cortical cerebral ischemia elicits neuroinflammation as well as secondary neuronal degeneration i... more Cortical cerebral ischemia elicits neuroinflammation as well as secondary neuronal degeneration in remote areas. Locally distinct and specific secondary neurodegeneration affecting thalamic nuclei connected to cortical areas highlights such processes. Osteopontin (OPN) is a cytokine-like glycoprotein that is excreted in high amounts after cerebral ischemia and exerts various immunomodulatory functions. We here examined putative protective effects of OPN in secondary thalamic degeneration. We subjected male Wistar rats to photothrombosis and subsequently injected OPN or placebo intracerebroventricularly. Immunohistochemical and fluorescence staining was used to detect the extent of neuronal degeneration and microglia activation. Ex vivo autoradiography with radiotracers available for human in vivo PET studies, i.e., CIS-4-[ 18 F]Fluor-D-Proline (Dcis-[ 18 F]FPRO), and [6-3 H]thymidine ([ 3 H]thymidine), confirmed degeneration and proliferation, respectively. We found secondary neurodegeneration in the thalamus characterized by microglial activation and neuronal loss. Neuronal loss was restricted to areas of microglial infiltration. Treatment with OPN significantly decreased neurodegeneration, inflammation and microglial proliferation. Microglia displayed morphological signs of activation without expressing markers of M1 or M2 polarization. D-CIS-[ 18 F]FPRO-uptake mirrored attenuated degeneration in OPN-treated animals. Notably, [ 3 H]thymidine and BrdU-staining revealed increased stem cell proliferation after treatment with OPN. The data suggest that OPN is able to ameliorate secondary neurodegeneration in thalamic nuclei. These effects can be visualized by radiotracers D-CIS-[ 18 F]FPRO and [ 3 H]thymidine, opening new vistas for translational studies.
Society of Nuclear Medicine Annual Meeting Abstracts, May 1, 2012
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Nuclear Medicine Communications, Apr 1, 2019
Text 1985 Figures / Tables 2 +1 / 2 References 14 Running title: D-cis-[ 18 F]FPro uptake in park... more Text 1985 Figures / Tables 2 +1 / 2 References 14 Running title: D-cis-[ 18 F]FPro uptake in parkinsonism 2 ABSTRACT OBJECTIVE: To investigate whether the amino acid PET-tracer cis-4-[ 18 F]fluoro-D-proline (D-cis-[ 18 F]FPro) shows increased uptake in the basal ganglia of patients with neurodegenerative akinetic-rigid parkinsonism. D-cis-[ 18 F]FPro is a sensitive PET tracer for inflammation-associated neurodegeneration in animal models. We hypothesized that D-cis-[ 18 F]FPro might also be a sensitive marker of alterations of the basal ganglia in parkinsonian syndromes. METHODS: Ten subjects with neurodegenerative akinetic-rigid parkinsonism (5 with idiopathic Parkinson's disease and 5 with atypical parkinsonian syndromes) were imaged with D-cis-[ 18 F]FPro and compared to 13 patients with brain tumors who had no basal ganglia involvement. PET images 20-50 min after injection were evaluated and tracer uptake in the basal ganglia was quantified using volume-of-interest (VOI) analysis with basal ganglia to background ratios. Disease severity was assessed with UPDRS III and correlated with D-cis-[ 18 F]FPro uptake. RESULTS: In patients with parkinsonism, VOI analysis revealed mild but significantly increased D-cis-[ 18 F]FPro uptake in the basal ganglia, pronounced in the lenticular nucleus. Disease severity correlated with D-cis-[ 18 F]FPro uptake in the right pallidum (r =-0.687, p = 0.041). CONCLUSIONS: Data suggest that D-cis-[ 18 F]FPro is a sensitive marker of inflammationassociated degenerative processes in parkinsonian syndromes.
Journal of Neurology, Sep 27, 2022
Background Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 cours... more Background Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. Methods Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. Results Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. Discussion In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. Trial registration information German clinical trial registry (https:// www. drks. de), DRKS00024099, first patient enrolled: February 4th, 2019.
Journal of Neurology, Neurosurgery & Psychiatry, 2022
ObjectiveMyasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscula... more ObjectiveMyasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies.MethodsIn this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model.ResultsBoth groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated...
DGNeurologie, 2021
Die Kommission 1.4 Anhaltszahlen und Qualitätssicherung der Deutschen Gesellschaft für Neurologie... more Die Kommission 1.4 Anhaltszahlen und Qualitätssicherung der Deutschen Gesellschaft für Neurologie führt alle 2 Jahre eine Umfrage unter den an der Akutversorgung neurologischer Patienten teilnehmenden neurologischen Kliniken in Deutschland durch. Anhaltszahlen zur akutneurologischen Versorgung in Deutschland, der Infrastruktur der Krankenhäuser und der neurologischen Fachabteilungen aus dem Jahr 2019 wurden 2020 erfragt und mit den Ergebnissen der Vorumfragen verglichen. Bei hoher Antwortquote von 67 % gehörte zu den wesentlichen Ergebnissen, dass die Größe der Kliniken und deren Ertragsstärke seit 2015 weitgehend stagnieren. Dies korreliert zeitlich mit dem seit 2015 anhaltenden, die Versorgung einschränkenden Pflegepersonalmangel und dem im Vergleich zu 2017 leicht gemilderten Ärztemangel. Der Ärztemangel konnte durch Rekrutierung von Ärzten aus dem Ausland abgemildert werden. Mindestens einen Arzt mit einem Examen von außerhalb der Europäischen Union beschäftigten 71 % der Klinik...
Neurology - Neuroimmunology Neuroinflammation, 2020
ObjectiveTo provide first real-world experience on patients with MS treated with the B cell–deple... more ObjectiveTo provide first real-world experience on patients with MS treated with the B cell–depleting antibody ocrelizumab.MethodsWe retrospectively collected data of patients who had received at least 1 treatment cycle (2 infusions) of ocrelizumab at 3 large neurology centers. Patients' characteristics including premedication, clinical disease course, and documented side effects were analyzed.ResultsWe could identify 210 patients (125 women, mean age ± SD, 42.1 ± 11.4 years) who had received ocrelizumab with a mean disease duration of 7.3 years and a median Expanded Disability Status Scale score of 3.75 (interquartile range 2.5–5.5; range 0–8). Twenty-six percent of these patients had a primary progressive MS (PPMS), whereas 74% had a relapsing-remitting (RRMS) or active secondary progressive (aSPMS) disease course. Twenty-four percent of all patients were treatment naive, whereas 76% had received immune therapies before. After ocrelizumab initiation (median follow-up was 200 d...
Journal of Neuroinflammation, 2020
Background In cerebral ischemia, microglia have a dichotomous role in keeping the balance between... more Background In cerebral ischemia, microglia have a dichotomous role in keeping the balance between pro- and anti-inflammatory mediators to avoid deleterious chronic inflammation and to leverage repair processes. Methods We examined functional and inflammatory markers in primary rat microglia in vitro after oxygen-glucose deprivation (OGD) or glucose deprivation (aglycemia). We then investigated the preconditioning effect of OGD or aglycemia upon a subsequent strong inflammatory stimulus, here lipopolysaccharides (LPS). Moreover, an “in vitro brain model” of neurons and glia, differentiated from primary rat neural stem cells, was exposed to OGD or aglycemia. Conditioned medium (CM) of this neuronal/glial co-culture was then used to condition microglia, followed by LPS as a “second hit.” Results OGD or aglycemia at sublethal doses did not significantly affect microglia function, including the expression of inflammatory markers. However, preconditioning with either OGD or aglycemia led ...
Frontiers in Neurology, 2019
Autoimmune encephalitis often causes acute psychiatric symptoms and epileptic seizures. However, ... more Autoimmune encephalitis often causes acute psychiatric symptoms and epileptic seizures. However, it is becoming increasingly clear that depending on the target antigen both symptoms and disease severity may vary. Furthermore, the identification and characterization of antibody subtypes are highly relevant for personalizing the treatment and to prevent relapses. Here we present an atypical case of encephalitis with cerebellar and temporal dysfunction but without seizures associated with high levels of cerebrospinal fluid neuropil antibodies against a yet unknown epitope on the neuronal surface in the cerebellum, hippocampus, thalamus, and the olfactory bulb. We treated the patient successfully with corticosteroids, plasmapheresis, and rituximab.
Journal of the Peripheral Nervous System, 2019
In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglob... more In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), intravenous immunoglobulin (IVIG) is recommended to be periodically reduced to assess the need for ongoing therapy. However, little is known about the effectiveness of restabilization with IVIG in patients who worsen after IVIG withdrawal. In the Polyneuropathy And Treatment with Hizentra (PATH) study, the pre‐randomization period included sudden stopping of IVIG followed by 12 weeks of observation. Those deteriorating were then restabilized with IVIG. Of 245 subjects who stopped IVIG, 28 did not show signs of clinical deterioration within 12 weeks. Two hundred and seven received IVIG restabilization with an induction dose of 2 g/kg bodyweight (bw) IgPro10 (Privigen, CSL Behring, King of Prussia, Pennsylvania) and maintenance doses of 1 g/kg bw every 3 weeks for up to 13 weeks. Signs of clinical improvement were seen in almost all (n = 188; 91%) subjects. During IVIG restabilization, 35 subjects either did no...
Stem Cell Research & Therapy, 2018
Background: Osteopontin (OPN), an acidic phosphoglycoprotein, is upregulated in the brain after c... more Background: Osteopontin (OPN), an acidic phosphoglycoprotein, is upregulated in the brain after cerebral ischemia. We previously reported that OPN supports migration, survival, and proliferation of neural stem cells (NSC) in primary cell culture, as well as their differentiation into neurons. We here analyzed the effects of OPN on neuroblasts in vivo in the context of cerebral ischemia. Methods: Transgenic mice expressing luciferase under the control of the neuroblast-specific doublecortin (DCX)promoter, allowing visualization of neuroblasts in vivo using bioluminescence imaging (BLI), were injected with OPN intracerebroventricularly while control mice were injected with vehicle buffer. To assess the effects of OPN after ischemia, additional mice were subjected to photothrombosis and injected with either OPN or vehicle. Results: OPN enhanced the migration of neuroblasts both in the healthy brain and after ischemia, as quantified by BLI in vivo. Moreover, the number of neural progenitors was increased following OPN treatment, with the maximum effect on the second day after OPN injection into the healthy brain, and 14 days after OPN injection following ischemia. After ischemia, OPN quantitatively promoted the endogenous, ischemia-induced neuroblast expansion, and additionally recruited progenitors from the contralateral hemisphere. Conclusions: Our results strongly suggest that OPN constitutes a promising substance for the targeted activation of neurogenesis in ischemic stroke.
Neurology International Open, 2018
Myasthenic exacerbation and crisis are most critical incidences in myasthenia gravis. Even nowada... more Myasthenic exacerbation and crisis are most critical incidences in myasthenia gravis. Even nowadays myasthenic crisis is a life-threatening condition, with a lethality of 2–3%. We review means of avoiding myasthenic exacerbation and crisis, elaborate on red flags and how to establish highly-active therapy in a timely manner. This includes the reasonable use of cholinesterase inhibitors, immunoadsorption or plasma exchange, as well as immunoglobulins and steroids. Immunosuppressive agents and monoclonal antibody therapy add to the therapeutic options.Intensive care of myasthenic patients includes the management of dysphagia and delirium. Importantly, the perioperative management of patients undergoing thymectomy and weaning are specific challenges in the treatment of myasthenic patients in the ICU.Establishing timely consequent immunosuppression and treatment of myasthenic patients in specialized outpatient centres help to avoid repetitive exacerbations and crises.
Mediators of Inflammation, 2017
Background.Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently repo... more Background.Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microgliain vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after strokein vivo, with focus on infarct demarcation.Methods.Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation.Results.After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ ...
Trials, Jul 25, 2016
Subcutaneous administration of Ig (SCIg) has gained popularity as an alternative route of adminis... more Subcutaneous administration of Ig (SCIg) has gained popularity as an alternative route of administration but has never been rigorously examined in chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of the PATH study (Polyneuropathy and Treatment with Hizentra) is to determine the efficacy of two different doses of SCIg IgPro20 (0.2 g/kg bw or 0.4 g/kg bw) in a 24-week maintenance treatment of CIDP in comparison to placebo. The primary efficacy endpoint will be the proportion of patients who show CIDP relapse (1-point deterioration on the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score) or are withdrawn within 24 weeks after randomization for any reason. IVIg-dependent adult patients with definite or probable CIDP according to the European Federation of Neurological Societies/Peripheral Nerve Society who fulfil the inclusion and exclusion criteria will be eligible. Based on sample-size calculation and relapse assumptions in t...
Journal of Experimental Stroke and Translational Medicine, 2009
Over the past years, severe difficulties in translating experimental stroke research from bench-t... more Over the past years, severe difficulties in translating experimental stroke research from bench-to-bedside have become apparent, and call for fresh ideas on why bench results get "lost in translation". In an attempt to close this gap, we suggest to perform experimental stroke studies in an intraindividual, longitudinal and translational way using multi-modal in vivo imaging protocols. Besides allowing us to stratify experimental animals in vivo, non-invasive imaging can also generate specific read-outs that allow monitoring the efficiency of individual treatments. Such an experimental design may specifically overcome the disadvantageous effects of increased variability in embolic stroke models. The quite novel "macrosphere model" of embolic stroke comprises a number of advantages, both regarding its particular usefulness for longitudinal imaging as well as its interesting pathophysiological aspects linking it to human stroke.
Experimental & translational stroke medicine, Jan 20, 2010
Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia. It involves ac... more Neuroinflammation evolves as a multi-facetted response to focal cerebral ischemia. It involves activation of resident glia cell populations, recruitment of blood-derived leucocytes as well as humoral responses. Among these processes, phagocyte accumulation has been suggested to be a surrogate marker of neuroinflammation. We previously assessed phagocyte accumulation in human stroke by MRI. We hypothesize that phagocyte accumulation in the macrosphere model may resemble the temporal and spatial patterns observed in human stroke. In a rat model of permanent focal ischemia by embolisation of TiO2-spheres we assessed key features of post-ischemic neuroinflammation by the means of histology, immunocytochemistry of glial activation and influx of hematogeneous cells, and quantitative PCR of TNF-α, IL-1, IL-18, and iNOS mRNA. In the boundary zone of the infarct, a transition of ramified microglia into ameboid phagocytic microglia was accompanied by an up-regulation of MHC class II on the ce...
World Journal of Stem Cells, 2015
The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their abi... more The discovery of endogenous neural stem cells (eNSCs) in the adult mammalian brain with their ability to self-renew and differentiate into functional neurons, astrocytes and oligodendrocytes has raised the hope for novel therapies of neurological diseases. Experimentally, those eNSCs can be mobilized in vivo , enhancing regeneration and accelerating functional recovery after, e.g., focal cerebral
Personalakquise im Krankenhaus, 2012
Stroke, 2007
Background and Purpose— Inflammation contributes to brain damage caused by ischemic stroke. Ultra... more Background and Purpose— Inflammation contributes to brain damage caused by ischemic stroke. Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI allows noninvasive monitoring of macrophage recruitment into ischemic brain lesions. In this study, we determined the extent of USPIO enhancement during early stages of ischemic stroke. Methods— Twelve consecutive patients with typical clinical signs of stroke underwent multimodal stroke imaging at 1.5-T within 24 hours of symptom onset. They received intravenous USPIO (ferumoxtran) infusion at 26 to 96 hours (mean, 44 hours) after stroke. A total of four follow-up MRI scans were performed 24 to 36 hours, 48 to 72 hours, 7 to 8 days, and 10 to 11 days after USPIO infusion. Results— Nine patients were included in the final analysis. Parenchymal USPIO enhancement occurred in 3 of 9 analyzed patients and was mainly evident on T1-weighted spin-echo images. USPIO-dependent signal changes were spatially heterogeneous, reflecting the disti...
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Papers by Michael Schroeter