Publications by authors named "Clemens J Sommer"

19 Publications

  • Page 1 of 1

Exploiting Gangliosides for the Therapy of Ewing's Sarcoma and H3K27M-Mutant Diffuse Midline Glioma.

Cancers (Basel) 2021 Jan 29;13(3). Epub 2021 Jan 29.

Department of Pediatric Hematology/Oncology, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing's sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood-brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher's disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.
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http://dx.doi.org/10.3390/cancers13030520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7866294PMC
January 2021

Immune Cell Infiltration into the Brain After Ischemic Stroke in Humans Compared to Mice and Rats: a Systematic Review and Meta-Analysis.

Transl Stroke Res 2021 Jan 26. Epub 2021 Jan 26.

Department of Neurology with Institute of Translational Neurology, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149, Münster, Germany.

Although several studies have suggested that anti-inflammatory strategies reduce secondary infarct growth in animal stroke models, clinical studies have not yet demonstrated a clear benefit of immune modulation in patients. Potential reasons include systematic differences of post-ischemic neuroinflammation between humans and rodents. We here performed a systematic review and meta-analysis to summarize and compare the spatial and temporal distribution of immune cell infiltration in human and rodent stroke. Data on spatiotemporal distribution of immune cells (T cells, macrophages, and neutrophils) and infarct volume were extracted. Data from all rodent studies were pooled by means of a random-effect meta-analysis. Overall, 20 human and 188 rodent stroke studies were included in our analyses. In both patients and rodents, the infiltration of macrophages and neutrophils preceded the lymphocytic influx. Macrophages and neutrophils were the predominant immune cells within 72 h after infarction. Although highly heterogeneously across studies, the temporal profile of the poststroke immune response was comparable between patients and rodents. In rodent stroke, the extent of the immune cell infiltration depended on the duration and location of vessel occlusion and on the species. The density of infiltrating immune cells correlated with the infarct volume. In summary, we provide the first systematic analysis and comparison of human and rodent post-ischemic neuroinflammation. Our data suggest that the inflammatory response in rodent stroke models is comparable to that in patients with stroke. However, the overall heterogeneity of the post-ischemic immune response might contribute to the translational failure in stroke research.
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http://dx.doi.org/10.1007/s12975-021-00887-4DOI Listing
January 2021

Principles and requirements for stroke recovery science.

J Cereb Blood Flow Metab 2021 Mar 11;41(3):471-485. Epub 2020 Nov 11.

Department of Neurology, Bethel, EVKB, University of Munster, Munster, Germany.

The disappointing results in bench-to-bedside translation of neuroprotective strategies caused a certain shift in stroke research towards enhancing the endogenous recovery potential of the brain. One reason for this focus on recovery is the much wider time window for therapeutic interventions which is open for at least several months. Since recently two large clinical studies using d-amphetamine or fluoxetine, respectively, to enhance post-stroke neurological outcome failed again it is a good time for a critical reflection on principles and requirements for stroke recovery science. In principal, stroke recovery science deals with all events from the molecular up to the functional and behavioral level occurring after brain ischemia eventually ending up with any measurable improvement of various clinical parameters. A detailed knowledge of the spontaneously occurring post-ischemic regeneration processes is the indispensable prerequisite for any therapeutic approaches aiming to modify these responses to enhance post-stroke recovery. This review will briefly illuminate the molecular mechanisms of post-ischemic regeneration and the principle possibilities to foster post-stroke recovery. In this context, recent translational approaches are analyzed. Finally, the principal and specific requirements and pitfalls in stroke recovery research as well as potential explanations for translational failures will be discussed.
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http://dx.doi.org/10.1177/0271678X20970048DOI Listing
March 2021

Identification of High-Risk Atypical Meningiomas According to Semantic and Radiomic Features.

Cancers (Basel) 2020 Oct 12;12(10). Epub 2020 Oct 12.

Department of Neurosurgery, University Medical Centre, Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Up to 60% of atypical meningiomas (World Health Organization (WHO) grade II) reoccur within 5 years after resection. However, no clear radiological criteria exist to identify tumors with higher risk of relapse. In this study, we aimed to assess the association of certain radiomic and semantic features of atypical meningiomas in MRI with tumor recurrence. We identified patients operated on primary atypical meningiomas in our department from 2007 to 2017. An analysis of 13 quantitatively defined radiomic and 11 qualitatively defined semantic criteria was performed based on preoperative MRI scans. Imaging characteristics were assessed along with clinical and survival data. The analysis included 76 patients (59% women, mean age 59 years). Complete tumor resection was achieved in 65 (86%) cases, and tumor relapse occurred in 17 (22%) cases. Mean follow-up time was 41.6 (range 3-168) months. Cystic component was significantly associated with tumor recurrence (odds ratio (OR) 21.7, 95% confidence interval (CI) 3.8-124.5) and shorter progression-free survival (33.2 vs. 80.7 months, < 0.001), whereas radiomic characteristics had no predictive value in univariate analysis. However, multivariate analysis demonstrated significant predictive value of high cluster prominence (hazard ratio (HR) 5.89 (1.03-33.73) and cystic component (HR 20.21 (2.46-166.02)) for tumor recurrence. The combination of radiomic and semantic features might be an effective tool for identifying patients with high-risk atypical meningiomas. The presence of a cystic component in these tumors is associated with a high risk of tumor recurrence.
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http://dx.doi.org/10.3390/cancers12102942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599676PMC
October 2020

Quality assurance in neuropathology: Experiences from the round robin trials on mutation and promoter methylation testing launched by the Quality Assurance Initiative Pathology (QuIP) in 2018 and 2019.

Clin Neuropathol 2020 Sep/Oct;39(5):203-211

We here report on the first neuropathological round robin trials initiated by the Quality Assurance Initiative Pathology (QuIP) in Germany in the years 2018 and 2019. Testing services as external laboratory controls were offered for IDH1-R132H immunohistochemistry in 2018 followed by a molecular trial for and mutations in 2019 including the rare mutational variants. Also in 2019, a trial on promoter methylation testing was offered. On a national scale, trial offers were well received with around 40 participating institutions. The international announcement of the molecular mutational trial achieved only moderate European outspread. Success rates in all three trials were excellent (IDH1-R132H immunohistochemistry 2018: 94%, 18 out of 20 possible points required; mutational status 2019: 100%, 19 out of 20 possible points required; promoter methylation 2019: 94%, 19 out of 20 possible points required) indicating that quality standards are high in the broad majority of the institutions. Trial participation also involved filling in a questionnaire asking for background information on local testing procedures. We here present a first assessment of the information collected providing unique insights in the landscape of molecular testing in neuropathology. Derived from this information we identify future challenges and provide an outlook on the development of quality assurance in the field of neuropathology.
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http://dx.doi.org/10.5414/NP301278DOI Listing
August 2020

Decreased hippocampal cell proliferation in mice with experimental antiphospholipid syndrome.

Brain Struct Funct 2018 Sep 23;223(7):3463-3471. Epub 2018 Jun 23.

Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with β2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2'-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking.
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http://dx.doi.org/10.1007/s00429-018-1699-9DOI Listing
September 2018

Evaluation of the apparent diffusion coefficient in patients with recurrent glioblastoma under treatment with bevacizumab with radiographic pseudoresponse.

J Neuroradiol 2019 Feb 4;46(1):36-43. Epub 2018 May 4.

University Medical Center, Department of Neuroradiology, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. Electronic address:

Background: Response Assessment in Neuro-Oncology Criteria (RANO), are used to asses response to first-line treatment of glioblastoma (GBM). Differentiation between response and pseudoresponse under treatment with Bevacizumab (BVZ) remains challenging. This study evaluates ADC changes in patients with radiographic pseudoresponse under treatment with (BVZ).

Methods: Patients (n=40) with recurrent GBM under-treatment with BVZ underwent MRI before, two and four months after treatment with BVZ. In patients with radiological pseudoresponse (n=11), ADC analyses were performed. Areas with decreasing T1 contrast enhancement (CE) and FLAIR signal decrease were manually selected and compared to size and position matched healthy contralateral brain parenchyma.

Results: Histogram based ADC (10×mm/s) of these patients decreased significantly (P<0.005) from baseline MRI (T1-CE, FLAIR: 1124.9±160.3, 1098.4±226.2, respectively) to 2months (781.3±110.7, 783.3±103.3) and remained stable during 4months (777.0±138.5, 784.4±155.4, all mean±1 SD), despite progressive disease. Mean ADC values of the healthy contralateral brain tissue remained stable (P>0.05) (ADC values: baseline: 786.2±110.7, 2months: 781.1±76.2, 4months: 804.1±86.2).

Conclusion: Treatment of GBM with BVZ leads to a decrease of ADC values in areas of pre-treatment T1-CE/FLAIR signal hyperintensity to levels of comparable with normal brain tissue. ADC values remained stable, even when progressive tumor growth was reported.
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http://dx.doi.org/10.1016/j.neurad.2018.04.002DOI Listing
February 2019

Neuronal Growth and Behavioral Alterations in Mice Deficient for the Psychiatric Disease-Associated Gene.

Front Mol Neurosci 2018 9;11:30. Epub 2018 Feb 9.

Department of Anesthesiology, University Medical Center, Johannes Gutenberg-University Mainz, Mainz, Germany.

Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been implicated in neuronal growth and connectivity. In addition, genetic variants in or near the NEGR1 locus have been associated with obesity and more recently with learning difficulties, intellectual disability and psychiatric disorders. However, experimental evidence is lacking to support a possible link between NEGR1, neuronal growth and behavioral abnormalities. Initial expression analysis of NEGR1 mRNA in C57Bl/6 wildtype (WT) mice by hybridization demonstrated marked expression in the entorhinal cortex (EC) and dentate granule cells. In co-cultures of cortical neurons and NSC-34 cells overexpressing NEGR1, neurite growth of cortical neurons was enhanced and distal axons occupied an increased area of cells overexpressing NEGR1. Conversely, in organotypic slice co-cultures, -knockout (KO) hippocampus was less permissive for axons grown from EC of β-actin-enhanced green fluorescent protein (EGFP) mice compared to WT hippocampus. Neuroanatomical analysis revealed abnormalities of EC axons in the hippocampal dentate gyrus (DG) of -KO mice including increased numbers of axonal projections to the hilus. Neurotransmitter receptor ligand binding densities, a proxy of functional neurotransmitter receptor abundance, did not show differences in the DG of -KO mice but altered ligand binding densities to NMDA receptor and muscarinic acetylcholine receptors M1 and M2 were found in CA1 and CA3. Activity behavior, anxiety-like behavior and sensorimotor gating were not different between genotypes. However, -KO mice exhibited impaired social behavior compared to WT littermates. Moreover, -KO mice showed reversal learning deficits in the Morris water maze and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures. Thus, our results from neuronal growth assays, neuroanatomical analyses and behavioral assessments provide first evidence that deficiency of the psychiatric disease-associated gene may affect neuronal growth and behavior. These findings might be relevant to further evaluate the role of NEGR1 in cognitive and psychiatric disorders.
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http://dx.doi.org/10.3389/fnmol.2018.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811522PMC
February 2018

Fostering Poststroke Recovery: Towards Combination Treatments.

Stroke 2017 04 6;48(4):1112-1119. Epub 2017 Mar 6.

From the Institute of Neuropathology, Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany (C.J.S.); and Department of Neurology, Bethel, EVKB, University of Munster, Germany (W.-R.S.).

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http://dx.doi.org/10.1161/STROKEAHA.116.013324DOI Listing
April 2017

Ischemic stroke: experimental models and reality.

Authors:
Clemens J Sommer

Acta Neuropathol 2017 02 7;133(2):245-261. Epub 2017 Jan 7.

Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University Mainz; Focus Program Translational Neuroscience (FTN) and Rhine Main Neuroscience Network (rmn2), Langenbeckstrasse 1, 55131, Mainz, Germany.

The vast majority of cerebral stroke cases are caused by transient or permanent occlusion of a cerebral blood vessel ("ischemic stroke") eventually leading to brain infarction. The final infarct size and the neurological outcome depend on a multitude of factors such as the duration and severity of ischemia, the existence of collateral systems and an adequate systemic blood pressure, etiology and localization of the infarct, but also on age, sex, comorbidities with the respective multimedication and genetic background. Thus, ischemic stroke is a highly complex and heterogeneous disorder. It is immediately obvious that experimental models of stroke can cover only individual specific aspects of this multifaceted disease. A basic understanding of the principal molecular pathways induced by ischemia-like conditions comes already from in vitro studies. One of the most frequently used in vivo models in stroke research is the endovascular suture or filament model in rodents with occlusion of the middle cerebral artery (MCA), which causes reproducible infarcts in the MCA territory. It does not require craniectomy and allows reperfusion by withdrawal of the occluding filament. Although promptly restored blood flow is far from the pathophysiology of spontaneous human stroke, it more closely mimics the therapeutic situation of mechanical thrombectomy which is expected to be increasingly applied to stroke patients. Direct transient or permanent occlusion of cerebral arteries represents an alternative approach but requires craniectomy. Application of endothelin-1, a potent vasoconstrictor, allows induction of transient focal ischemia in nearly any brain region and is frequently used to model lacunar stroke. Circumscribed and highly reproducible cortical lesions are characteristic of photothrombotic stroke where infarcts are induced by photoactivation of a systemically given dye through the intact skull. The major shortcoming of this model is near complete lack of a penumbra. The two models mimicking human stroke most closely are various embolic stroke models and spontaneous stroke models. Closeness to reality has its price and goes along with higher variability of infarct size and location as well as unpredictable stroke onset in spontaneous models versus unpredictable reperfusion in embolic clot models.
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http://dx.doi.org/10.1007/s00401-017-1667-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5250659PMC
February 2017

Functional Improvement after Photothrombotic Stroke in Rats Is Associated with Different Patterns of Dendritic Plasticity after G-CSF Treatment and G-CSF Treatment Combined with Concomitant or Sequential Constraint-Induced Movement Therapy.

PLoS One 2016 11;11(1):e0146679. Epub 2016 Jan 11.

Department of Neurology, University of Münster, Münster, Germany.

We have previously shown that granulocyte-colony stimulating factor (G-CSF) treatment alone, or in combination with constraint movement therapy (CIMT) either sequentially or concomitantly, results in significantly improved sensorimotor recovery after photothrombotic stroke in rats in comparison to untreated control animals. CIMT alone did not result in any significant differences compared to the control group (Diederich et al., Stroke, 2012;43:185-192). Using a subset of rat brains from this former experiment the present study was designed to evaluate whether dendritic plasticity would parallel improved functional outcomes. Five treatment groups were analyzed (n = 6 each) (i) ischemic control (saline); (ii) CIMT (CIMT between post-stroke days 2 and 11); (iii) G-CSF (10 μg/kg G-CSF daily between post-stroke days 2 and 11); (iv) combined concurrent group (CIMT plus G-CSF) and (v) combined sequential group (CIMT between post-stroke days 2 and 11; 10 μg/kg G-CSF daily between post-stroke days 12 and 21, respectively). After impregnation of rat brains with a modified Golgi-Cox protocol layer V pyramidal neurons in the peri-infarct cortex as well as the corresponding contralateral cortex were analyzed. Surprisingly, animals with a similar degree of behavioral recovery exhibited quite different patterns of dendritic plasticity in both peri-lesional and contralesional areas. The cause for these patterns is not easily to explain but puts the simple assumption that increased dendritic complexity after stroke necessarily results in increased functional outcome into perspective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713830PMC
July 2016

Systemic PaO2 Oscillations Cause Mild Brain Injury in a Pig Model.

Crit Care Med 2016 May;44(5):e253-63

1Department of Anaesthesiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 2Department of Anaesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria. 3Department of Anaesthesia and Critical Care, University Hospitals, Wuerzburg, Germany. 4Institute of Neuropathology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 5Core Facility Bioinformatics, Division Biostatistics and Bioinformatics, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany. 6Division Biostatistics and Bioinformatics, Institute of Medical Biostatistics, Epidemiology and Informatics, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.

Objective: Systemic PaO2 oscillations occur during cyclic recruitment and derecruitment of atelectasis in acute respiratory failure and might harm brain tissue integrity.

Design: Controlled animal study.

Setting: University research laboratory.

Subjects: Adult anesthetized pigs.

Interventions: Pigs were randomized to a control group (anesthesia and extracorporeal circulation for 20 hr with constant PaO2, n = 10) or an oscillation group (anesthesia and extracorporeal circulation for 20 hr with artificial PaO2 oscillations [3 cycles min⁻¹], n = 10). Five additional animals served as native group (n = 5).

Measurements And Main Results: Outcome following exposure to artificial PaO2 oscillations compared with constant PaO2 levels was measured using 1) immunohistochemistry, 2) real-time polymerase chain reaction for inflammatory markers, 3) receptor autoradiography, and 4) transcriptome analysis in the hippocampus. Our study shows that PaO2 oscillations are transmitted to brain tissue as detected by novel ultrarapid oxygen sensing technology. PaO2 oscillations cause significant decrease in NISSL-stained neurons (p < 0.05) and induce inflammation (p < 0.05) in the hippocampus and a shift of the balance of hippocampal neurotransmitter receptor densities toward inhibition (p < 0.05). A pathway analysis suggests that cerebral immune and acute-phase response may play a role in mediating PaO2 oscillation-induced brain injury.

Conclusions: Artificial PaO2 oscillations cause mild brain injury mediated by inflammatory pathways. Although artificial PaO2 oscillations and endogenous PaO2 oscillations in lung-diseased patients have different origins, it is likely that they share the same noxious effect on the brain. Therefore, PaO2 oscillations might represent a newly detected pathway potentially contributing to the crosstalk between acute lung and remote brain injury.
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http://dx.doi.org/10.1097/CCM.0000000000001399DOI Listing
May 2016

Prevention of an increase in cortical ligand binding to AMPA receptors may represent a novel mechanism of endogenous brain protection by G-CSF after ischemic stroke.

Restor Neurol Neurosci 2016 08;34(4):665-75

Institute of Neuropathology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Purpose: Using G-CSF deficient mice we recently demonstrated neuroprotective properties of endogenous G-CSF after ischemic stroke. The present follow-up study was designed to check, whether specific alterations in ligand binding densities of excitatory glutamate or inhibitory GABAA receptors may participate in this effect.

Methods: Three groups of female mice were subjected to 45 minutes of MCAO: wildtype, G-CSF deficient and G-CSF deficient mice substituted with G-CSF. Infarct volumes were determined after 24 hours and quantitative in vitro receptor autoradiography was performed using [3H]MK-801, [3H]AMPA and [3H]muscimol for labeling of NMDA, AMPA and GABAA receptors, respectively. Ligand binding densities were analyzed in regions in the ischemic core, peri-infarct areas and corresponding contralateral regions.

Results: Infarct volumes did not significantly differ between the experimental groups. Ligand binding densities of NMDA and GABAA receptors were widely in the same range. However, AMPA receptor binding densities in G-CSF deficient mice were substantially enhanced compared to wildtype mice. G-CSF substitution in mice lacking G-CSF largely reversed this effect.

Conclusions: Although infarct volumes did not differ 24 hours after ischemia the increase of AMPA receptor binding densities in G-CSF deficient mice may explain the bigger infarcts previously observed at later time-points with the same stroke model.
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http://dx.doi.org/10.3233/RNN-150543DOI Listing
August 2016

Mice with experimental antiphospholipid syndrome display hippocampal dysfunction and a reduction of dendritic complexity in hippocampal CA1 neurones.

Neuropathol Appl Neurobiol 2015 Aug 30;41(5):657-71. Epub 2015 Apr 30.

Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Aims: The antiphospholipid syndrome (APS) is an autoimmune disease characterized by high titres of auto-antibodies (aPL) leading to thrombosis and consequent infarcts. However, many affected patients develop neurological symptoms in the absence of stroke. Similarly, in a mouse model of this disease (eAPS), animals consistently develop behavioural abnormalities despite lack of ischemic brain injury. Therefore, the present study was designed to identify structural alterations of hippocampal neurones underlying the neurological symptoms in eAPS.

Methods: Adult female Balb/C mice were subjected to either induction of eAPS by immunization with β2-Glycoprotein 1 or to a control group. After sixteen weeks animals underwent behavioural and cognitive testing using Staircase test (experiment 1 and 2) and Y-maze alternation test (experiment 1) and were tested for serum aPL levels (both experiments). Animals of experiment 1 (n = 7/group) were used for hippocampal neurone analysis using Golgi-Cox staining. Animals of experiment 2 (n = 7/group) were used to analyse molecular markers of total dendritic integrity (MAP2), presynaptic plasticity (synaptobrevin 2/VAMP2) and dendritic spines (synaptopodin) using immunohistochemistry.

Results: eAPS mice developed increased aPL titres and presented with abnormal behaviour and impaired short term memory. Further, they revealed a reduction of dendritic complexity of hippocampal CA1 neurones as reflected by decreased dendritic length, arborization and spine density, respectively. Additional decrease of the spine-associated protein expression of Synaptopodin points to dendritic spines as major targets in the pathological process.

Conclusion: Reduction of hippocampal dendritic complexity may represent the structural basis for the behavioural and cognitive abnormalities of eAPS mice.
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http://dx.doi.org/10.1111/nan.12180DOI Listing
August 2015

Distribution of the hematopoietic growth factor G-CSF and its receptor in the adult human brain with specific reference to Alzheimer's disease.

J Anat 2014 Apr 5;224(4):377-91. Epub 2014 Jan 5.

Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

The granulocyte colony-stimulating factor (G-CSF), being a member of the hematopoietic growth factor family, is also critically involved in controlling proliferation and differentiation of neural stem cells. Treatment with G-CSF has been shown to result in substantial neuroprotective and neuroregenerative effects in various experimental models of acute and chronic diseases of the central nervous system. Although G-CSF has been tested in a clinical study for treatment of acute ischemic stroke, there is only fragmentary data on the distribution of this cytokine and its receptor in the human brain. Therefore, the present study was focused on the immunohistochemical analysis of the protein expression of G-CSF and its receptor (G-CSF R) in the adult human brain. Since G-CSF has been shown not only to exert neuroprotective effects in animal models of Alzheimer's disease (AD) but also to be a candidate for clinical treatment, we have also placed an emphasis on the regulation of these molecules in this neurodegenerative disease. One major finding is that both G-CSF and G-CSF R were ubiquitously but not uniformly expressed in neurons throughout the CNS. Protein expression of G-CSF and G-CSF R was not restricted to neurons but was also detectable in astrocytes, ependymal cells, and choroid plexus cells. However, the distribution of G-CSF and G-CSF R did not substantially differ between AD brains and control, even in the hippocampus, where early neurodegenerative changes typically occur.
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http://dx.doi.org/10.1111/joa.12154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098674PMC
April 2014

Altered receptor binding densities in experimental antiphospholipid syndrome despite only moderately enhanced autoantibody levels and absence of behavioral features.

Immunobiology 2014 May 28;219(5):341-9. Epub 2013 Nov 28.

Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

Experimental antiphospholipid syndrome (eAPS) in Balb/c mice causes neuropsychiatric abnormalities including hyperactivity, increased explorative behavior and cognitive deficits. Recently, we have demonstrated that these behavioral changes were linked to an upregulation of serotonergic 5-HT1A receptor binding densities in cortical and hippocampal regions while excitatory and inhibitory neurotransmitter receptors remain largely unchanged. To examine whether the observed behavioral features depend on a critical antibody concentration, mice with only moderately enhanced antiphospholipid antibodies (aPL), about 50-80% of high levels, were analyzed and compared to controls. The staircase test was used to test animals for hyperactivity and explorative behavior. The brains were analyzed for tissue integrity and inflammation. Ligand binding densities of NMDA, AMPA, GABAA, 5-HT1A, M1 and M2 muscarinic acetylcholine receptors, respectively, were analyzed by in vitro receptor autoradiography and compared to brains of mice from our previous study with high levels of aPL. Mice with only moderately enhanced aPL did not develop significant behavioral changes. Brain parenchyma remained intact and neither inflammation nor glial activation was detectable. However, there was a significant decrease of NMDA receptor binding densities in the motor cortex as well as an increase in M1 binding densities in cortical and hippocampal regions, whereas the other receptors analyzed were not altered. Lack of neuropsychiatric symptoms may be due to modulations of receptors resulting in normal behavior. In conclusion, our results support the hypothesis that high levels of aPL are required for the manifestation of neuropsychiatric involvement while at lower antibody levels compensatory mechanisms may preserve normal behavior.
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http://dx.doi.org/10.1016/j.imbio.2013.11.006DOI Listing
May 2014

Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic 5-HT1A receptors.

Immunobiology 2013 Apr 27;218(4):517-26. Epub 2012 Jun 27.

Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany.

The antiphospholipid syndrome (APS) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts. In experimental APS (eAPS), a mouse model of APS, behavioral abnormalities develop in the absence of vessel occlusion or infarcts. Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits, we checked for lymphocytic infiltration, activation of glia and macrophages, as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior. Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3, CD4, CD8 and forkhead box P3 (Foxp3), respectively. GFAP, Iba1 and CD68-immunohistochemistry was performed, to check for activation of astrocytes, microglia and macrophages. Ligand binding densities of NMDA, AMPA, GABAA and 5-HT1A receptors were analyzed by in vitro receptor autoradiography. No significant inflammatory reaction occurred in eAPS mice. There was neither activation of astrocytes or microglia nor accumulation of macrophages. Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged. However, ligand binding densities of the modulatory serotonergic 5-HT1A receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed.
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http://dx.doi.org/10.1016/j.imbio.2012.06.011DOI Listing
April 2013

Citicoline enhances neuroregenerative processes after experimental stroke in rats.

Stroke 2012 Jul 10;43(7):1931-40. Epub 2012 May 10.

Department of Neurology, University of Münster, Münster, Germany.

Background And Purpose: The neuroprotective potential of citicoline in acute ischemic stroke has been shown in many experimental studies and, although the exact mechanisms are still unknown, a clinical Phase III trial is currently underway. Our present study was designed to check whether citicoline also enhances neuroregeneration after experimental stroke.

Methods: Forty Wistar rats were subjected to photothrombotic stroke and treated either with daily injections of citicoline (100 mg/kg) or vehicle for 10 consecutive days starting 24 hours after ischemia induction. Sensorimotor tests were performed after an adequate training period at Days 1, 10, 21, and 28 after stroke. Then brains were removed and analyzed for infarct size, glial scar formation, neurogenesis, and ligand binding densities of excitatory and inhibitory neurotransmitter receptors.

Results: Animals treated with citicoline showed a significantly better neurological outcome at Days 10, 21, and 28 after ischemia, which could not be attributed to differences in infarct volumes or glial scar formation. However, neurogenesis in the dentate gyrus, subventricular zone, and peri-infarct area was significantly increased by citicoline. Furthermore, enhanced neurological outcome after citicoline treatment was associated with a shift toward excitation in the perilesional cortex.

Conclusions: Our present data demonstrate that, apart from the well-known neuroprotective effects in acute ischemic stroke, citicoline also possesses a substantial neuroregenerative potential. Thanks to its multimodal effects, easy applicability, and history as a well-tolerated drug, promising possibilities of neurological treatment including chronic stroke open up.
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http://dx.doi.org/10.1161/STROKEAHA.112.654806DOI Listing
July 2012

Distribution of granulocyte-monocyte colony-stimulating factor and its receptor α-subunit in the adult human brain with specific reference to Alzheimer's disease.

J Neural Transm (Vienna) 2012 Nov 20;119(11):1389-406. Epub 2012 Mar 20.

Department of Neuropathology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.

Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a member of the hematopoietic growth factor family, promoting proliferation and differentiation of hematopoietic progenitor cells of the myeloid lineage. In recent years, GM-CSF has also proved to be an important neurotrophic factor in the central nervous system (CNS) via binding to the GM-CSF receptor (GM-CSF R). Furthermore, studies on rodent CNS revealed a wide distribution of both the major binding α-subunit of the GM-CSF R (GM-CSF Rα) and its ligand. Since respective data on the expression pattern of these two molecules are still lacking, the present study has been designed to systematically analyze the protein expression of GM-CSF and GM-CSF Rα in the human brain, with particular emphasis on their regulation in Alzheimer's disease (AD). One major finding is that both GM-CSF and GM-CSF Rα were ubiquitously but not uniformly expressed in neurons throughout the CNS. Protein expression of GM-CSF and GM-CSF Rα was not restricted to neurons but also detectable in astrocytes, ependymal cells and choroid plexus cells. Interestingly, distribution and intensity of immunohistochemical staining for GM-CSF did not differ among AD brains and age-matched controls. Concerning GM-CSF Rα, a marked reduction of protein expression was predominantly detected in the hippocampus although a slight reduction was also found in various cortical regions, thalamic nuclei and some brainstem nuclei. Since the hippocampus is one of the target regions of neurodegenerative changes in AD, reduction of GM-CSF Rα, with consecutive downregulation of GM-CSF signaling, may contribute to in the progressive course of neurodegeneration in AD.
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http://dx.doi.org/10.1007/s00702-012-0794-yDOI Listing
November 2012