Publications by authors named "Christine Stadelmann"

172 Publications

Three-dimensional virtual histology of the human hippocampus based on phase-contrast computed tomography.

Proc Natl Acad Sci U S A 2021 Nov;118(48)

Institut für Röntgenphysik, Universität Göttingen, 37077 Göttingen, Deutschland;

We have studied the three-dimensional (3D) cytoarchitecture of the human hippocampus in neuropathologically healthy and Alzheimer's disease (AD) individuals, based on phase-contrast X-ray computed tomography of postmortem human tissue punch biopsies. In view of recent findings suggesting a nuclear origin of AD, we target in particular the nuclear structure of the dentate gyrus (DG) granule cells. Tissue samples of 20 individuals were scanned and evaluated using a highly automated approach of measurement and analysis, combining multiscale recordings, optimized phase retrieval, segmentation by machine learning, representation of structural properties in a feature space, and classification based on the theory of optimal transport. Accordingly, we find that the prototypical transformation between a structure representing healthy granule cells and the pathological state involves a decrease in the volume of granule cell nuclei, as well as an increase in the electron density and its spatial heterogeneity. The latter can be explained by a higher ratio of heterochromatin to euchromatin. Similarly, many other structural properties can be derived from the data, reflecting both the natural polydispersity of the hippocampal cytoarchitecture between different individuals in the physiological context and the structural effects associated with AD pathology.
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http://dx.doi.org/10.1073/pnas.2113835118DOI Listing
November 2021

Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy.

Nat Commun 2021 11 11;12(1):6530. Epub 2021 Nov 11.

Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Georg August University, Göttingen, Germany.

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2 mice using CRISPR/Cas9-mediated genome editing. Rnaset2 mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8 effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2 mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.
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http://dx.doi.org/10.1038/s41467-021-26880-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586222PMC
November 2021

High class filtering facepiece (FFP) are fundamental and effective in protection of emergency health care workers: an observational cohort study in a German community.

Scand J Trauma Resusc Emerg Med 2021 Oct 30;29(1):155. Epub 2021 Oct 30.

Department of Anesthesiology, Emergency and Intensive Care Medicine, University Medical Centre Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a highly contagious airborne virus inducing pandemic coronavirus disease 2019 (COVID-19). This is most relevant for medical staff working under harmful conditions in emergencies often dealing with patients and an undefined SARS-CoV-2 status. We aimed to measure the effect of high-class filtering facepieces (FFP) in emergency medical service (EMS) staff by analyzing seroprevalence and history of positive polymerase chain reaction (PCR) for SARS-CoV-2.

Method: This observational cohort study included workers in EMS, who were compared with hospital staff (HS) and staff, which was not directly involved in patient care (NPC). All direct patient contacts of EMS workers were protected by FFP2/N95 (filtering face piece protection class 2/non-oil-based particulates filter efficiency 95%) masks, whereas HS was protected by FFP2/N95 exclusively when a patient had a proven or suspected SARS-CoV-2 infection. NPC was not protected by higher FFP. The seroprevalence of SARS-CoV-2 antibodies was analyzed by immunoassay by end of 12/2020 together with the history of a positive PCR. In addition, a self-assessment was performed regarding the quantity of SARS-CoV-2 positive contacts, about flu symptoms and personal belief of previous COVID-19 infections.

Results: The period in which contact to SARS-CoV-2 positive patients has been possible was 10 months (March to December 2020)-with 54,681 patient contacts documented for EMS-either emergencies (n = 33,241) or transportation services (n = 21,440). Seven hundred-thirty (n = 730) participants were included into the study (n = EMS: 325, HS: 322 and NPC: 83). The analysis of the survey showed that the exposure to patients with an unknown and consecutive positive SARS-CoV-2 result was significantly higher for EMS when compared to HS (EMS 55% vs. HS 30%, p = 0.01). The incidence of a SARS-CoV-2 infection in our cohort was 1.2% (EMS), 2.2% (HS) and 2.4% (NPC) within the three groups (ns) and lowest in EMS. Furthermore, the belief of previous COVID-19 was significant higher in EMS (19% vs. 10%), CONCLUSION: The consistent use of FFP2/N95 in EMS is able to prevent work-related SARS-CoV-2 infections in emergency situations. The significance of physical airway protection in exposed medical staff is still relevant especially under the aspect of new viral variants and unclear effectiveness of new vaccines.
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http://dx.doi.org/10.1186/s13049-021-00969-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8556778PMC
October 2021

The SARS-CoV-2 main protease M causes microvascular brain pathology by cleaving NEMO in brain endothelial cells.

Nat Neurosci 2021 11 21;24(11):1522-1533. Epub 2021 Oct 21.

Roche Pharma Research and Early Development (pRED), Roche Innovation Center, Basel, Switzerland.

Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (M) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, M induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood-brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the M-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.
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http://dx.doi.org/10.1038/s41593-021-00926-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553622PMC
November 2021

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab140. Epub 2021 Sep 20.

Max-Planck-Institute of Experimental Medicine, Department of Neurogenetics, Göttingen, Germany.

Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery.

Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis.

Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy.

Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies.
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http://dx.doi.org/10.1093/noajnl/vdab140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500692PMC
September 2021

Analyzing microglial phenotypes across neuropathologies: a practical guide.

Acta Neuropathol 2021 12 8;142(6):923-936. Epub 2021 Oct 8.

Institute of Neuropathology, Medical Faculty, University of Freiburg, Freiburg, Germany.

As extremely sensitive immune cells, microglia act as versatile watchdogs of the central nervous system (CNS) that tightly control tissue homeostasis. Therefore, microglial activation is an early and easily detectable hallmark of virtually all neuropsychiatric, neuro-oncological, neurodevelopmental, neurodegenerative and neuroinflammatory diseases. The recent introduction of novel high-throughput technologies and several single-cell methodologies as well as advances in epigenetic analyses helped to identify new microglia expression profiles, enhancer-landscapes and local signaling cues that defined diverse previously unappreciated microglia states in the healthy and diseased CNS. Here, we give an overview on the recent developments in the field of microglia biology and provide a practical guide to analyze disease-associated microglia phenotypes in both the murine and human CNS, on several morphological and molecular levels. Finally, technical limitations, potential pitfalls and data misinterpretations are discussed as well.
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http://dx.doi.org/10.1007/s00401-021-02370-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498770PMC
December 2021

Oligodendrocyte-Specific Deletion of Reduces Cerebellar Inflammation and Neurodegeneration in MOG-Induced EAE.

Int J Mol Sci 2021 Aug 31;22(17). Epub 2021 Aug 31.

Experimental Neurology, Department of Neurology, University of Giessen, Klinikstrasse 33, 35385 Giessen, Germany.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). MS commonly affects the cerebellum causing acute and chronic symptoms. Cerebellar signs significantly contribute to clinical disability, and symptoms such as tremor, ataxia, and dysarthria are difficult to treat. Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies such as MS. In autopsy tissue from patients with MS, increased expression of FGF1, FGF2, FGF9, and FGFR1 was found in lesion areas. Recent research using mouse models has focused on regions such as the spinal cord, and data on the expression of FGF/FGFR in the cerebellum are not available. In recent EAE studies, we detected that oligodendrocyte-specific deletion of results in a milder disease course, less cellular infiltrates, and reduced neurodegeneration in the spinal cord. The objective of this study was to characterize the role of in oligodendrocytes in the cerebellum. Conditional deletion of in oligodendrocytes () was achieved by tamoxifen application, EAE was induced using the MOG peptide. The cerebellum was analyzed by histology, immunohistochemistry, and western blot. At day 62 p.i., mice showed less myelin and axonal degeneration compared to FGFR1-competent mice. Infiltration of CD3(+) T cells, Mac3(+) cells, B220(+) B cells and IgG(+) plasma cells in cerebellar white matter lesions (WML) was less in mice. There were no effects on the number of OPC or mature oligodendrocytes in white matter lesion (WML). Expression of FGF2 and FGF9 associated with less myelin and axonal degeneration, and of the pro-inflammatory cytokines IL-1β, IL-6, and CD200 was downregulated in mice. The FGF/FGFR signaling protein pAkt, BDNF, and TrkB were increased in mice. These data suggest that cell-specific deletion of in oligodendrocytes has anti-inflammatory and neuroprotective effects in the cerebellum in the EAE disease model of MS.
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http://dx.doi.org/10.3390/ijms22179495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431355PMC
August 2021

Neural Injury and Repair in a Novel Neonatal Mouse Model of Listeria Monocytogenes Meningoencephalitis.

J Neuropathol Exp Neurol 2021 Sep;80(9):861-867

Department of Neuropathology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany.

To improve the therapy of neonatal central nervous system infections, well-characterized animal models are urgently needed. The present study analyzes neuropathological alterations with particular focus on neural injury and repair in brains of neonatal mice with Listeria monocytogenes (LM) meningitis/meningoencephalitis using a novel nasal infection model. The hippocampal formation and frontal cortex of 14 neonatal mice with LM meningitis/meningoencephalitis and 14 uninfected controls were analyzed by histology, immunohistochemistry, and in situ tailing for morphological alterations. In the dentate gyrus of the hippocampal formation of mice with LM meningitis/meningoencephalitis, an increased density of apoptotic neurons visualized by in situ tailing (p = 0.04) and in situ tailing plus immunohistochemistry for activated Caspase-3 (p < 0.0001) was found. A decreased density of dividing cells stained with an anti-PCNA-antibody (p < 0.0001) and less neurogenesis visualized by anti-calretinin (p < 0.0001) and anti-calbindin (p = 0.01) antibodies were detected compared to uninfected controls. The density of microglia was higher in LM meningitis (p < 0.0001), while the density of astrocytes remained unchanged. Infiltrating monocytes and neutrophilic granulocytes likely contributed to tissue damage. In conclusion, in the brains of LM-infected mice a strong immune response was observed which led to neuronal apoptosis and an impaired neural regeneration. This model appears very suitable to study therapies against long-term sequelae of neonatal LM meningitis.
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http://dx.doi.org/10.1093/jnen/nlab079DOI Listing
September 2021

Innovation in Digital Education: Lessons Learned from the Multiple Sclerosis Management Master's Program.

Brain Sci 2021 Aug 23;11(8). Epub 2021 Aug 23.

Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, 01307 Dresden, Germany.

Since 2020, the master's program "Multiple Sclerosis Management" has been running at Dresden International University, offering structured training to become a multiple sclerosis specialist. Due to the COVID-19 pandemic, many planned teaching formats had to be changed to online teaching. The subject of this paper was the investigation of a cloud-based digital hub and student evaluation of the program. Authors analyzed use cases of computer-supported collaborative learning and student evaluation of courses and modules using the Gioia method and descriptive statistics. The use of a cloud-based digital hub as a central data platform proved to be highly successful for learning and teaching, as well as for close interaction between lecturers and students. Students rated the courses very positively in terms of content, knowledge transfer and interaction. The implementation of the master's program was successful despite the challenges of the COVID-19 pandemic. The resulting extensive use of digital tools demonstrates the "new normal" of future learning, with even more emphasis on successful online formats that also increase interaction between lecturers and students in particular. At the same time, there will continue to be tailored face-to-face events to specifically increase learning success.
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http://dx.doi.org/10.3390/brainsci11081110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393651PMC
August 2021

Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors.

Acta Neuropathol 2021 11 5;142(5):827-839. Epub 2021 Aug 5.

Institute of Neuropathology, University of Giessen, Giessen, Germany.

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
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http://dx.doi.org/10.1007/s00401-021-02356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500895PMC
November 2021

Imaging multiple sclerosis pathology at 160 μm isotropic resolution by human whole-brain ex vivo magnetic resonance imaging at 3 T.

Sci Rep 2021 07 29;11(1):15491. Epub 2021 Jul 29.

Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Gewerbestrasse 14, 4123, Allschwil, Switzerland.

Postmortem magnetic resonance imaging (MRI) of the fixed healthy and diseased human brain facilitates spatial resolutions and image quality that is not achievable with in vivo MRI scans. Though challenging-and almost exclusively performed at 7 T field strength-depicting the tissue architecture of the entire brain in fine detail is invaluable since it enables the study of neuroanatomy and uncovers important pathological features in neurological disorders. The objectives of the present work were (1) to develop a 3D isotropic ultra-high-resolution imaging approach for human whole-brain ex vivo acquisitions working on a standard clinical 3 T MRI system; and (2) to explore the sensitivity and specificity of this concept for specific pathoanatomical features of multiple sclerosis. The reconstructed images demonstrate unprecedented resolution and soft tissue contrast of the diseased human brain at 3 T, thus allowing visualization of sub-millimetric lesions in the different cortical layers and in the cerebellar cortex, as well as unique cortical lesion characteristics such as the presence of incomplete/complete iron rims, and patterns of iron accumulation. Further details such as the subpial molecular layer, the line of Gennari, and some intrathalamic nuclei are also well distinguishable.
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http://dx.doi.org/10.1038/s41598-021-94891-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322069PMC
July 2021

IDH2 R172 Mutations Across Poorly Differentiated Sinonasal Tract Malignancies: Forty Molecularly Homogenous and Histologically Variable Cases With Favorable Outcome.

Am J Surg Pathol 2021 09;45(9):1190-1204

Departments of Neuropathology.

IDH2 R172 mutations occur in sinonasal undifferentiated carcinoma (SNUC), large-cell neuroendocrine carcinoma (LCNEC), sinonasal adenocarcinomas, and olfactory neuroblastoma (ONB). We performed a clinical, pathologic, and genetic/epigenetic analysis of a large IDH2-mutated sinonasal tumor cohort to explore their distinct features. A total 165 sinonasal/skull base tumors included 40 IDH2 mutants studied by light microscopy, immunohistochemistry, and genome-wide DNA methylation, and 125 IDH2 wild-type tumors used for comparison. Methylation profiles were analyzed by unsupervised hierarchical clustering, t-distributed stochastic neighbor embedding dimensionality reduction and assessed for copy number alterations (CNA). Thirty-nine histologically assessable cases included 25 (64.1%) SNUC, 8 (20.5%) LCNEC, 2 (5.1%) poorly differentiated adenocarcinomas, 1 (2.7%) ONB, and 3 (7.7%) IDH2-mutated tumors with ONB features. All cases were high-grade showing necrosis (82.4%), prominent nucleoli (88.9%), and median 21 mitoses/10 HPFs. AE1/AE3 and/or CAM 5.2 were positive in all and insulinoma-associated protein 1 (INSM1) in 80% cases. All IDH2 mutants formed one distinct group by t-distributed stochastic neighbor embedding dimensionality reduction separating from all IDH2 wild-type tumors. There was no correlation between methylation clusters and histopathologic diagnoses. Recurrent CNA included 1q gain (79.3%), 17p loss (75.9%), and 17q gain (58.6%). No CNA differences were observed between SNUC and LCNEC. IDH2 mutants showed better disease-specific survival than SMARCB1-deficient (P=0.027) and IDH2 wild-type carcinomas overall (P=0.042). IDH2-mutated sinonasal tumors are remarkably homogeneous at the molecular level and distinct from IDH2 wild-type sinonasal malignancies. Biology of IDH2-mutated sinonasal tumors might be primarily defined by their unique molecular fingerprint rather than by their respective histopathologic diagnoses.
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http://dx.doi.org/10.1097/PAS.0000000000001697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373679PMC
September 2021

An unusual lymphoid lesion mimicking meningioma.

Brain Pathol 2021 09 13;31(5):e12995. Epub 2021 Jul 13.

Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.

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http://dx.doi.org/10.1111/bpa.12995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412078PMC
September 2021

Deep spatial profiling of human COVID-19 brains reveals neuroinflammation with distinct microanatomical microglia-T-cell interactions.

Immunity 2021 07 9;54(7):1594-1610.e11. Epub 2021 Jun 9.

Faculty of Medicine, Clinic for Internal Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Disease, University Medical Center Freiburg, Freiburg, Germany; Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany. Electronic address:

COVID-19 can cause severe neurological symptoms, but the underlying pathophysiological mechanisms are unclear. Here, we interrogated the brain stems and olfactory bulbs in postmortem patients who had COVID-19 using imaging mass cytometry to understand the local immune response at a spatially resolved, high-dimensional, single-cell level and compared their immune map to non-COVID respiratory failure, multiple sclerosis, and control patients. We observed substantial immune activation in the central nervous system with pronounced neuropathology (astrocytosis, axonal damage, and blood-brain-barrier leakage) and detected viral antigen in ACE2-receptor-positive cells enriched in the vascular compartment. Microglial nodules and the perivascular compartment represented COVID-19-specific, microanatomic-immune niches with context-specific cellular interactions enriched for activated CD8 T cells. Altered brain T-cell-microglial interactions were linked to clinical measures of systemic inflammation and disturbed hemostasis. This study identifies profound neuroinflammation with activation of innate and adaptive immune cells as correlates of COVID-19 neuropathology, with implications for potential therapeutic strategies.
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http://dx.doi.org/10.1016/j.immuni.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188302PMC
July 2021

Concurrent axon and myelin destruction differentiates X-linked adrenoleukodystrophy from multiple sclerosis.

Glia 2021 Oct 17;69(10):2362-2377. Epub 2021 Jun 17.

Institute of Neuropathology, University Medical Center Göttingen, Göttingen, Germany.

Cerebral disease manifestation occurs in about two thirds of males with X-linked adrenoleukodystrophy (CALD) and is fatally progressive if left untreated. Early histopathologic studies categorized CALD as an inflammatory demyelinating disease, which led to repeated comparisons to multiple sclerosis (MS). The aim of this study was to revisit the relationship between axonal damage and myelin loss in CALD. We applied novel immunohistochemical tools to investigate axonal damage, myelin loss and myelin repair in autopsy brain tissue of eight CALD and 25 MS patients. We found extensive and severe acute axonal damage in CALD already in prelesional areas defined by microglia loss and relative myelin preservation. In contrast to MS, we did not observe selective phagocytosis of myelin, but a concomitant decay of the entire axon-myelin unit in all CALD lesion stages. Using a novel marker protein for actively remyelinating oligodendrocytes, breast carcinoma-amplified sequence (BCAS) 1, we show that repair pathways are activated in oligodendrocytes in CALD. Regenerating cells, however, were affected by the ongoing disease process. We provide evidence that-in contrast to MS-selective myelin phagocytosis is not characteristic of CALD. On the contrary, our data indicate that acute axonal injury and permanent axonal loss are thus far underestimated features of the disease that must come into focus in our search for biomarkers and novel therapeutic approaches.
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http://dx.doi.org/10.1002/glia.24042DOI Listing
October 2021

Urinary Levels of SARS-CoV-2 Nucleocapsid Protein Associate With Risk of AKI and COVID-19 Severity: A Single-Center Observational Study.

Front Med (Lausanne) 2021 25;8:644715. Epub 2021 May 25.

Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.

Acute kidney injury (AKI) is very common in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) disease 2019 (COVID-19) and considered as a risk factor for COVID-19 severity. SARS-CoV-2 renal tropism has been observed in COVID-19 patients, suggesting that direct viral injury of the kidneys may contribute to AKI. We examined 20 adult cases with confirmed SARS-CoV-2 infection requiring ICU supportive care in a single-center prospective observational study and investigated whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19. The objective of the study was to evaluate whether urinary markers for viral infection (SARS-CoV-2 N) and shedded cellular membrane proteins (ACE2, TMPRSS2) allow identification of patients at risk for AKI and outcome of COVID-19. Urinary SARS-CoV-2 N measured at ICU admission identified patients at risk for AKI in COVID-19 (HR 5.9, 95% CI 1.4-26, = ). In addition, the combination of urinary SARS-CoV-2 N and plasma albumin measurements further improved the association with AKI (HR 11.4, 95% CI 2.7-48, = ). Finally, combining urinary SARS-CoV-2 N and plasma albumin measurements associated with the length of ICU supportive care (HR 3.3, 95% CI 1.1-9.9, = ) and premature death (HR 7.6, 95% CI 1.3-44, = ). In contrast, urinary ACE2 and TMPRSS2 did not correlate with AKI in COVID-19. In conclusion, urinary SARS-CoV-2 N levels associate with risk for AKI and correlate with COVID-19 severity.
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http://dx.doi.org/10.3389/fmed.2021.644715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185060PMC
May 2021

Chronic White Matter Inflammation and Serum Neurofilament Levels in Multiple Sclerosis.

Neurology 2021 08 4;97(6):e543-e553. Epub 2021 Jun 4.

From the Department of Neurology (P.M., V.v.P.), Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium; Departments of Neurology (P.M., A.M., M.T., C.P., R.D.P.) and Radiology (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.), Lausanne University Hospital and Lausanne University; Departments of Medicine, Clinical Research, and Biomedical Engineering (J.K., M.W., R.G., P.-J.L., R.R., D.L., L.K., C.G.) and Translational Imaging in Neurology (ThINk), Department of Biomedical Engineering Basel (M.W., R.G., R.G., P.-J.L., R.R., C.G.), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), and Clinical Trial Unit, Department of Clinical Research (S.S., P.B.), University Hospital Basel and University of Basel, Switzerland; Institute of Neuropathology (F.v.d.M., C.S.), University Medical Center Göttingen, Germany; Radiological Physics, Department of Radiology (M.W.), University Hospital Basel; Signal Processing Laboratory (LTS5) (F.L.R., M.B.C.), Ecole Polytechnique Fédérale de Lausanne; CIBM Center for Biomedical Imaging (F.L.R., M.B.C.), Lausanne, Switzerland; Department of Neurology (P.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Translational Neuroradiology Section (P.S., D.S.R., M.A.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; and Department of Neurology (D.S.R., M.A.), Johns Hopkins University, Baltimore, MD.

Objective: To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage.

Methods: In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases.

Results: In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (β, 16.3; 95% confidence interval [CI], 4.6-28.0; < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; β, 30.4; 95% CI, 15.6-45.2; < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (β, 1.1; 95% CI, 0.3-1.9; < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: = 0.004 and = 0.0002, respectively).

Conclusion: Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.
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http://dx.doi.org/10.1212/WNL.0000000000012326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424501PMC
August 2021

Effects of FGFR Tyrosine Kinase Inhibition in OLN-93 Oligodendrocytes.

Cells 2021 05 25;10(6). Epub 2021 May 25.

Experimental Neurology, Department of Neurology, Justus Liebig University of Giessen, 35385 Giessen, Germany.

Fibroblast growth factor (FGF) signaling is involved in the pathogenesis of multiple sclerosis (MS). Data from neuropathology studies suggest that FGF signaling contributes to the failure of remyelination in MS. In MOG-induced EAE, oligodendrocyte-specific deletion of and resulted in a less severe disease course, reduced inflammation, myelin and axon degeneration and changed FGF/FGFR and BDNF/TrkB signaling. Since signaling cascades in oligodendrocytes could not be investigated in the EAE studies, we here aimed to characterize FGFR-dependent oligodendrocyte-specific signaling in vitro. FGFR inhibition was achieved by application of the multi-kinase-inhibitor dovitinib and the FGFR1/2/3-inhibitor AZD4547. Both substances are potent inhibitors of FGF signaling; they are effective in experimental tumor models and patients with malignancies. Effects of FGFR inhibition in oligodendrocytes were studied by immunofluorescence microscopy, protein and gene analyses. Application of the tyrosine kinase inhibitors reduced FGFR1, phosphorylated ERK and Akt expression, and it enhanced BDNF and TrkB expression. Furthermore, the myelin proteins CNPase and PLP were upregulated by FGFR inhibition. In summary, inhibition of FGFR signaling in oligodendrocytes can be achieved by application of tyrosine kinase inhibitors. Decreased phosphorylation of ERK and Akt is associated with an upregulation of BDNF/TrkB signaling, which may be responsible for the increased production of myelin proteins. Furthermore, these data suggest that application of FGFR inhibitors may have the potential to promote remyelination in the CNS.
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http://dx.doi.org/10.3390/cells10061318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228431PMC
May 2021

FGF/FGFR Pathways in Multiple Sclerosis and in Its Disease Models.

Cells 2021 04 13;10(4). Epub 2021 Apr 13.

Experimental Neurology, Department of Neurology, University of Giessen, Klinikstrasse 33, 35385 Giessen, Germany.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS.
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http://dx.doi.org/10.3390/cells10040884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068804PMC
April 2021

TSPO PET imaging of natalizumab-associated progressive multifocal leukoencephalopathy.

Brain 2021 Oct;144(9):2683-2695

Institute of Clinical Neuroimmunology, University Hospital, Ludwig-Maximilians-Universität Munich, Munich, Germany.

Progressive multifocal leukoencephalopathy (PML) is a severe infection of the CNS caused by the polyomavirus JC that can occur in multiple sclerosis patients treated with natalizumab. Clinical management of patients with natalizumab-associated PML is challenging not least because current imaging tools for the early detection, longitudinal monitoring and differential diagnosis of PML lesions are limited. Here we evaluate whether translocator protein (TSPO) PET imaging can be applied to monitor the inflammatory activity of PML lesions over time and differentiate them from multiple sclerosis lesions. For this monocentre pilot study we followed eight patients with natalizumab-associated PML with PET imaging using the TSPO radioligand 18F-GE-180 combined with frequent 3 T MRI. In addition we compared TSPO PET signals in PML lesions with the signal pattern of multiple sclerosis lesions from 17 independent multiple sclerosis patients. We evaluated the standardized uptake value ratio as well as the morphometry of the TSPO uptake for putative PML and multiple sclerosis lesions areas compared to a radiologically unaffected pseudo-reference region in the cerebrum. Furthermore, TSPO expression in situ was immunohistochemically verified by determining the density and cellular identity of TSPO-expressing cells in brain sections from four patients with early natalizumab-associated PML as well as five patients with other forms of PML and six patients with inflammatory demyelinating CNS lesions (clinically isolated syndrome/multiple sclerosis). Histological analysis revealed a reticular accumulation of TSPO expressing phagocytes in PML lesions, while such phagocytes showed a more homogeneous distribution in putative multiple sclerosis lesions. TSPO PET imaging showed an enhanced tracer uptake in natalizumab-associated PML lesions that was present from the early to the chronic stages (up to 52 months after PML diagnosis). While gadolinium enhancement on MRI rapidly declined to baseline levels, TSPO tracer uptake followed a slow one phase decay curve. A TSPO-based 3D diagnostic matrix taking into account the uptake levels as well as the shape and texture of the TSPO signal differentiated >96% of PML and multiple sclerosis lesions. Indeed, treatment with rituximab after natalizumab-associated PML in three patients did not affect tracer uptake in the assigned PML lesions but reverted tracer uptake to baseline in the assigned active multiple sclerosis lesions. Taken together our study suggests that TSPO PET imaging can reveal CNS inflammation in natalizumab-associated PML. TSPO PET may facilitate longitudinal monitoring of disease activity and help to distinguish recurrent multiple sclerosis activity from PML progression.
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http://dx.doi.org/10.1093/brain/awab127DOI Listing
October 2021

Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration.

J Clin Invest 2021 03;131(5)

Institute of Neuropathology and.

Approximately 80% of neuromyelitis optica spectrum disorder (NMOSD) patients harbor serum anti-aquaporin-4 autoantibodies targeting astrocytes in the CNS. Crucial for NMOSD lesion initiation is disruption of the blood-brain barrier (BBB), which allows the entrance of Abs and serum complement into the CNS and which is a target for new NMOSD therapies. Astrocytes have important functions in BBB maintenance; however, the influence of their loss and the role of immune cell infiltration on BBB permeability in NMOSD have not yet been investigated. Using an experimental model of targeted NMOSD lesions in rats, we demonstrate that astrocyte destruction coincides with a transient disruption of the BBB and a selective loss of occludin from tight junctions. It is noteworthy that BBB integrity is reestablished before astrocytes repopulate. Rather than persistent astrocyte loss, polymorphonuclear leukocytes (PMNs) are the main mediators of BBB disruption, and their depletion preserves BBB integrity and prevents astrocyte loss. Inhibition of PMN chemoattraction, activation, and proteolytic function reduces lesion size. In summary, our data support a crucial role for PMNs in BBB disruption and NMOSD lesion development, rendering their recruitment and activation promising therapeutic targets.
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http://dx.doi.org/10.1172/JCI141694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919716PMC
March 2021

Case Report: Findings Suggestive of Paraclinical Progressive Multifocal Leukoencephalopathy and Lung Cancer-Derived Brain Metastases in an MS Patient Treated With Fingolimod.

Front Neurol 2021 3;12:561158. Epub 2021 Feb 3.

Department of Neurology, University Medical Center Göttingen, Göttingen, Germany.

Fingolimod represents a highly effective disease-modifying drug in patients with active relapsing-remitting multiple sclerosis (RRMS). Its immunosuppressive effects can mediate adverse events like increased risk of cancer development or appearance of opportunistic infections. Progressive multifocal leukoencephalopathy (PML)-representing a severe opportunistic infection-has been only infrequently described during Fingolimod treatment. Here, we present a case of a 63-year-old women with pre-diagnosed RRMS who presented with new multiple cerebral lesions in a routine MRI scan, also including a tumefactive lesion in the left parietal lobe, eventually leading to the diagnosis of brain metastases derived by an adenocarcinoma of the lung. Additionally, a JCV-DNA-PCR in the cerebrospinal fluid revealed positive results, corresponding to a paraclinical progressive multifocal leukoencephalopathy. In conclusion, adverse events potentially associated with immunosuppression can occur during Fingolimod treatment. In this context, the occurrence of cancer and opportunistic infections should be carefully monitored. Here, we report a case in which JCV-DNA-PCR in the cerebrospinal fluid suggests asymptomatic PML and simultaneously lung cancer brain metastases developed. While it is rather unlikely that either event occurred as an adverse event of fingolimod treatment, a contributing effect cannot be formally excluded.
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http://dx.doi.org/10.3389/fneur.2021.561158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886972PMC
February 2021

The impact of transcranial direct current stimulation on cerebral vasospasm in a rat model of subarachnoid hemorrhage.

J Cereb Blood Flow Metab 2021 08 27;41(8):2000-2009. Epub 2021 Jan 27.

Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany.

Transcranial direct current stimulation (tDCS) has been shown to induce changes in cortical excitability and perfusion in a rat ischemic stroke model. Since perfusion disturbances are a common phenomenon, not only in ischemic but also in hemorrhagic stroke, tDCS might have a possible beneficial effect on cerebral perfusion in hemorrhagic stroke as well. We applied tDCS in a rat model of subarachnoid hemorrhage (SAH) and evaluated its impact on vasospasm. SAH was induced using the double-hemorrhage rat model. TDCS was applied on day 3 and 4. For vasospasm assessment magnetic resonance angiography was performed on day 1, day 2 and day 5. A total of 147 rats were operated, whereat 72 rats died before day 5 and 75 rats survived the whole experiment and could be analyzed. The cathodal group consisted of 26 rats, the anodal group included 24 rats. Thirteen rats served as controls without tDCS, and twelve rats underwent a sham operation. The cathodal group revealed the lowest incidence of new vasospasm on day 5 ( = 0.01), and the lowest mean number of vasospastic vessels per rat ( = 0.02). TDCS influences the vasospasm incidence in an SAH-model in rats, where cathodal-tDCS was associated with a lower vasospasm incidence and severity.
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http://dx.doi.org/10.1177/0271678X21990130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323336PMC
August 2021

Neuropathology associated with SARS-CoV-2 infection.

Lancet 2021 01;397(10271):276-277

Department of Pathology and Immunology, Division of Clinical Pathology, Geneva University Hospitals, Geneva 1211, Switzerland. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(21)00095-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825940PMC
January 2021

Endoscope-assisted fluorescence-guided resection allowing supratotal removal in glioblastoma surgery.

Neurosurg Focus 2021 01;50(1):E3

Departments of1Neurosurgery.

Objective: Several studies have proven the benefits of a wide extent of resection (EOR) of contrast-enhancing tumor in terms of progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma (GBM). Thus, gross-total resection (GTR) is the main surgical goal in noneloquently located GBMs. Complete tumor removal can be almost doubled by microscopic fluorescence guidance. Recently, a study has shown that an endoscope with a light source capable of inducing fluorescence allows visualization of remnant fluorescent tumor tissue even after complete microscopic fluorescence-guided (FG) resection, thereby increasing the rate of GTR. Since tumor infiltration spreads beyond the borders of contrast enhancement on MRI, the aim of this study was to determine via volumetric analyses of the EOR whether endoscope-assisted FG resection enables supratotal resection beyond the borders of contrast enhancement.

Methods: The authors conducted a retrospective single-center analysis of a consecutive series of patients with primary GBM presumed to be noneloquently located and routinely operated on at their institution between January 2015 and February 2018 using a combined microscopic and endoscopic FG resection. A 20-mg/kg dose of 5-aminolevulinic acid (5-ALA) was administered 4 hours before surgery. After complete microscopic FG resection, the resection cavity was scanned using the endoscope. Detected residual fluorescent tissue was resected and embedded separately for histopathological examination. Nonenhanced and contrast-enhanced 3D T1-weighted MR images acquired before and within 48 hours after tumor resection were analyzed using 3D Slicer. Bias field-corrected data were used to segment brain parenchyma, contrast-enhancing tumor, and the resection cavity for volume definition. The difference between the pre- and postoperative brain parenchyma volume was considered to be equivalent to the resected nonenhancing but fluorescent tumor tissue. The volume of resected tumor tissue was calculated from the sum of resected contrast-enhancing tumor tissue and resected nonenhancing tumor tissue.

Results: Twelve patients with GBM were operated on using endoscopic after complete microscopic FG resection. In all cases, residual fluorescent tissue not visualized with the microscope was detected. Histopathological examination confirmed residual tumor tissue in all specimens. The mean preoperative volume of brain parenchyma without contrast-enhancing tumor was 1213.2 cm3. The mean postoperative volume of brain parenchyma without the resection cavity was 1151.2 cm3, accounting for a mean volume of nonenhancing but fluorescent tumor tissue of 62.0 cm3. The mean relative rate of the overall resected volume compared to the contrast-enhancing tumor volume was 244.7% (p < 0.001).

Conclusions: Combined microscopic and endoscopic FG resection of GBM significantly increases the EOR and allows the surgeon to achieve a supratotal resection beyond the borders of contrast enhancement in noneloquently located GBM.
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http://dx.doi.org/10.3171/2020.10.FOCUS20560DOI Listing
January 2021

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination.

Acta Neuropathol Commun 2020 12 24;8(1):224. Epub 2020 Dec 24.

Institute of Neuropathology, University Medical Center Göttingen, 37075, Göttingen, Germany.

Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2 OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1 oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.
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http://dx.doi.org/10.1186/s40478-020-01105-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761156PMC
December 2020

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19.

Nat Neurosci 2021 02 30;24(2):168-175. Epub 2020 Nov 30.

Department of Neurology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.
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http://dx.doi.org/10.1038/s41593-020-00758-5DOI Listing
February 2021

Oligodendrocyte-specific deletion of FGFR2 ameliorates MOG -induced EAE through ERK and Akt signalling.

Brain Pathol 2021 03 4;31(2):297-311. Epub 2021 Jan 4.

Department of Neurology, University of Giessen, Giessen, Germany.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) are involved in demyelinating pathologies including multiple sclerosis (MS). In our recent study, oligodendrocyte-specific deletion of FGFR1 resulted in a milder disease course, less inflammation, reduced myelin and axon damage in EAE. The objective of this study was to elucidate the role of oligodendroglial FGFR2 in MOG -induced EAE. Oligodendrocyte-specific knockout of FGFR2 (Fgfr2 ) was achieved by application of tamoxifen; EAE was induced using the MOG peptide. EAE symptoms were monitored over 62 days. Spinal cord tissue was analysed by histology, immunohistochemistry and western blot. Fgfr2 mice revealed a milder disease course, less myelin damage and enhanced axonal density. The number of oligodendrocytes was not affected in demyelinated areas. However, protein expression of FGFR2, FGF2 and FGF9 was downregulated in Fgfr2 mice. FGF/FGFR dependent signalling proteins were differentially regulated; pAkt was upregulated and pERK was downregulated in Fgfr2 mice. The number of CD3(+) T cells, Mac3(+) cells and B220(+) B cells was less in demyelinated lesions of Fgfr2  mice. Furthermore, expression of IL-1β, TNF-α and CD200 was less in Fgfr2  mice than controls. Fgfr2  mice showed an upregulation of PLP and downregulation of the remyelination inhibitors SEMA3A and TGF-β expression. These data suggest that cell-specific deletion of FGFR2 in oligodendrocytes has anti-inflammatory and neuroprotective effects accompanied by changes in FGF/FGFR dependent signalling, inflammatory cytokines and expression of remyelination inhibitors. Thus, FGFRs in oligodendrocytes may represent potential targets for the treatment of inflammatory and demyelinating diseases including MS.
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http://dx.doi.org/10.1111/bpa.12916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018040PMC
March 2021

Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity.

Science 2020 11 20;370(6518):856-860. Epub 2020 Oct 20.

Institute of Neuronal Cell Biology, Technical University Munich, Munich, Germany.

The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
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http://dx.doi.org/10.1126/science.abd2985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857391PMC
November 2020

MOG-expressing teratoma followed by MOG-IgG-positive optic neuritis.

Acta Neuropathol 2021 01 19;141(1):127-131. Epub 2020 Oct 19.

Institute of Neuropathology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany.

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http://dx.doi.org/10.1007/s00401-020-02236-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785547PMC
January 2021
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