Publications by authors named "Klaudia Lepka"

10 Publications

  • Page 1 of 1

Association of Retinal Layer Thickness With Cognition in Patients With Multiple Sclerosis.

Neurol Neuroimmunol Neuroinflamm 2021 Jul 27;8(4). Epub 2021 May 27.

From the Cogito Center for Applied Neurocognition and Neuropsychological Research (S.J.B., M.F., A.R., N.S., I.-K.P.); Department of Neurology (M.D., M.G., M.W., K.L., J.G., N.G., H.-P.H., O.A., S.M., P.A., I.-K.P.), Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Brain and Mind Centre (H.-P.H.), Department of Neurology, University of Sydney; and Department of Neurology (H.-P.H.), Medical University of Vienna, Austria.

Objective: Retinal layer thickness (RLT) measured by optical coherence tomography (OCT) is considered a noninvasive, cost-efficient marker of neurodegeneration in multiple sclerosis (MS). We aimed to investigate associations of RLT with cognitive performance and its potential as indicator of cognitive status in patients with MS by performing generalized estimating equation (GEE) analyses.

Methods: In this cross-sectional study, patients with at least mild signs of cognitive impairment were examined by OCT as well as by the Brief International Cognitive Assessment for MS and tests assessing attention and executive functions (Trail Making Test [TMT] A and B). Associations of these factors were investigated using GEE models controlling for demographic and disease-related factors and correcting for multiple testing.

Results: A total of 64 patients entered the study. In the final sample (n = 50 [n = 14 excluded due to missing data or drop-outs]; n = 44 relapsing-remitting MS and n = 6 secondary progressive MS, mean Expanded Disability Status Scale score = 2.59 [SD = 1.17], disease duration [median] = 7.34 [interquartile range = 12.1]), 36.0% were cognitively impaired. RLT of the macular retinal nerve fiber layer was associated with performance in TMT-B (β = -0.259). Analyses focusing on the upper and lower tertile of RLT additionally revealed associations between macular ganglion cell-inner plexiform layer and TMT-B and verbal short-term memory and learning, respectively.

Conclusion: In patients with MS, at less advanced disease stages, RLT was especially associated with cognitive flexibility promoting OCT as a potential marker advocating further extensive neuropsychological examination.
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http://dx.doi.org/10.1212/NXI.0000000000001018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161541PMC
July 2021

Serum neurofilament light chain: No clear relation to cognition and neuropsychiatric symptoms in stable MS.

Neurol Neuroimmunol Neuroinflamm 2020 11 24;7(6). Epub 2020 Sep 24.

From the Department of Neurology (O.A., M.G., K.L., N.G., J.G., H.-P.H., P.A., I.-K.P.), Medical Faculty, University Düsseldorf, Germany; Cogito Center for Applied Neurocognition and Neuropsychological Research (A.R., M.F., S.B., N.S., I.-K.P.), Düsseldorf, Germany; Department of Neurology (A.H., M.S., M.O., H.T.), University Hospital Ulm, Germany; Department of Neurology (C.E., D.P.), Research Unit for Neuronal Plasticity and Repair, Medical University of Graz, Austria; Division of Neuroradiology, Vascular and Interventional Radiology (C.E.), Department of Radiology, Medical University of Graz, Austria; Department of Diagnostic and Interventional Radiology (G.A., B.T.), Medical Faculty, University Düsseldorf, Germany; and Department of Neurology (H.T.), Dietenbronn, Germany.

Objective: To explore the hypothesis that serum neurofilament light chain (sNfL) indicative of neuroaxonal damage may improve precise disease profiling with regard to cognition and neuropsychiatric symptoms, we analyzed potential associations of sNfL levels with cognitive test scores, fatigue, depression, and anxiety.

Methods: Patients with relapsing-remitting and secondary progressive MS (SPMS) underwent an elaborated assessment including MRI, various cognitive tests, and patient-reported outcomes. We determined sNfL levels by single molecule array (Simoa) assay. Relationships between sNfL, cognition, neuropsychiatric symptoms, and demographical data were analyzed using correlations, group comparisons, and regressions.

Results: In 45 clinically stable patients with MS (Expanded Disability Status Scale = 2.73 ± 1.12, disease duration = 10.03 ± 7.49 years), 40.0% were cognitively impaired. Mean sNfL levels were 16.02 ± 10.39 pg/mL, with higher levels in the SPMS subgroup ( = 0.038). sNfL levels did reliably link neither with the investigated cognitive and affective parameters nor with fatigue levels. The only relationship found in a small subgroup of patients with SPMS (n = 7) with visuospatial learning ( = -0.950, = 0.001) and memory ( = -0.813; = 0.026) disappeared when further controlling for age, educational level, and sex.

Conclusions: In patients with stable MS at less advanced disease stages, sNfL did not convincingly relate to cognitive performance, fatigue, depression, or anxiety and thus may not serve as a surrogate biomarker for neuropsychological status in such populations.
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http://dx.doi.org/10.1212/NXI.0000000000000885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673283PMC
November 2020

Protective effects of 4-aminopyridine in experimental optic neuritis and multiple sclerosis.

Brain 2020 04;143(4):1127-1142

NeuroCure Clinical Research Center and Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health and Max Delbrueck Center for Molecular Medicine, Berlin, Germany.

Chronic disability in multiple sclerosis is linked to neuroaxonal degeneration. 4-aminopyridine (4-AP) is used and licensed as a symptomatic treatment to ameliorate ambulatory disability in multiple sclerosis. The presumed mode of action is via blockade of axonal voltage gated potassium channels, thereby enhancing conduction in demyelinated axons. In this study, we provide evidence that in addition to those symptomatic effects, 4-AP can prevent neuroaxonal loss in the CNS. Using in vivo optical coherence tomography imaging, visual function testing and histologic assessment, we observed a reduction in retinal neurodegeneration with 4-AP in models of experimental optic neuritis and optic nerve crush. These effects were not related to an anti-inflammatory mode of action or a direct impact on retinal ganglion cells. Rather, histology and in vitro experiments indicated 4-AP stabilization of myelin and oligodendrocyte precursor cells associated with increased nuclear translocation of the nuclear factor of activated T cells. In experimental optic neuritis, 4-AP potentiated the effects of immunomodulatory treatment with fingolimod. As extended release 4-AP is already licensed for symptomatic multiple sclerosis treatment, we performed a retrospective, multicentre optical coherence tomography study to longitudinally compare retinal neurodegeneration between 52 patients on continuous 4-AP therapy and 51 matched controls. In line with the experimental data, during concurrent 4-AP therapy, degeneration of the macular retinal nerve fibre layer was reduced over 2 years. These results indicate disease-modifying effects of 4-AP beyond symptomatic therapy and provide support for the design of a prospective clinical study using visual function and retinal structure as outcome parameters.
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http://dx.doi.org/10.1093/brain/awaa062DOI Listing
April 2020

Factors associated with headache in intravenous immunoglobulin treatment for neurological diseases.

Acta Neurol Scand 2019 Oct 23;140(4):290-295. Epub 2019 Jul 23.

Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.

Objectives: To identify possible risk factors influencing the incidence of intravenous immunoglobulin (IVIg) treatment-related cephalalgia in neurological diseases.

Materials & Methods: Retrospective chart review of neurological patients receiving IVIg treatment between July 13, 2017, and August 14, 2017. Patients with MS receiving natalizumab in the same setting were observed as a reference group.

Results: Patients with headache after IVIg infusion (n = 22 infusions) showed a reduced heart rate (by 6.0 ± 8.5 beats per minute [bpm]), but no significant difference in blood pressure. Patients without headache after IVIg infusion (n = 69 infusions) showed a higher systolic blood pressure increase and a stronger reduction in the heart rate (by 5.7 ± 8.6 bpm), compared to patients with headache after IVIg infusion. The infusion rate was significantly slower and age significantly lower in patients developing headache after IVIg infusion. Body temperature was unchanged in both groups. Binary logistic regression analysis revealed that blood pressure at baseline and age significantly influence the occurrence of cephalalgia. In reference, patients receiving natalizumab (ie, shorter infusions/smaller infusion volume), systolic blood pressure, and heart rate decreased, while body temperature increased. Here, one patient developed headache.

Conclusions: Intravenous immunoglobulin-associated headache is not associated with an increased blood pressure after infusion but with a reduced heart rate, a slower infusion rate, female sex and seems to be influenced by baseline systolic blood pressure and age. A reaction to immunoglobulin aggregates, stabilizers, or vasoactive mediators are possible explanations. The absence of an association with body temperature does not suggest a systemic immune response as a cause for headache.
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http://dx.doi.org/10.1111/ane.13144DOI Listing
October 2019

The metalloprotease ADAMTS4 generates N-truncated Aβ4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease.

Acta Neuropathol 2019 02 13;137(2):239-257. Epub 2018 Nov 13.

Department of Neuropathology, Heinrich-Heine University, Moorenstrasse 5, 40225, Düsseldorf, Germany.

Brain accumulation and aggregation of amyloid-β (Aβ) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length Aβ peptides (mainly Aβ1-40 and Aβ1-42) are produced through sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. However, studies of autopsy brain samples from AD patients have demonstrated that a large fraction of insoluble Aβ peptides are truncated at the N-terminus, with Aβ4-x peptides being particularly abundant. Aβ4-x peptides are highly aggregation prone, but their origin and any proteases involved in their generation are unknown. We have identified a recognition site for the secreted metalloprotease ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4) in the Aβ peptide sequence, which facilitates Aβ4-x peptide generation. Inducible overexpression of ADAMTS4 in HEK293 cells resulted in the secretion of Aβ4-40 but unchanged levels of Aβ1-x peptides. In the 5xFAD mouse model of amyloidosis, Aβ4-x peptides were present not only in amyloid plaque cores and vessel walls, but also in white matter structures co-localized with axonal APP. In the ADAMTS4 knockout background, Aβ4-40 levels were reduced confirming a pivotal role of ADAMTS4 in vivo. Surprisingly, in the adult murine brain, ADAMTS4 was exclusively expressed in oligodendrocytes. Cultured oligodendrocytes secreted a variety of Aβ species, but Aβ4-40 peptides were absent in cultures derived from ADAMTS4 mice indicating that the enzyme was essential for Aβ4-x production in this cell type. These findings establish an enzymatic mechanism for the generation of Aβ4-x peptides. They further identify oligodendrocytes as a source of these highly amyloidogenic Aβ peptides.
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http://dx.doi.org/10.1007/s00401-018-1929-5DOI Listing
February 2019

Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment.

Mult Scler 2018 11 11;24(13):1776-1778. Epub 2018 Oct 11.

Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

Background: Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial.

Objective: To report a case of acute sarcoidosis (Löfgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment.

Case Report: Sarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased).

Conclusion: Our case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications.
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http://dx.doi.org/10.1177/1352458518771276DOI Listing
November 2018

Iron-sulfur glutaredoxin 2 protects oligodendrocytes against damage induced by nitric oxide release from activated microglia.

Glia 2017 09 15;65(9):1521-1534. Epub 2017 Jun 15.

Department of Neurology, Medical Faculty, Heinrich-Heine Universität, Düsseldorf, 40225, Germany.

Demyelinated brain lesions, a hallmark of autoimmune neuroinflammatory diseases like multiple sclerosis, result from oligodendroglial cell damage. Activated microglia are considered a major source of nitric oxide and subsequent peroxynitrite-mediated damage of myelin. Here, we provide biochemical and biophysical evidence that the oxidoreductase glutaredoxin 2 inhibits peroxynitrite formation by transforming nitric oxide into dinitrosyl-diglutathionyl-iron-complexes. Glutaredoxin 2 levels influence both survival rates of primary oligodendrocyte progenitor cells and preservation of myelin structure in cerebellar organotypic slice cultures challenged with activated microglia or nitric oxide donors. Of note, glutaredoxin 2-mediated protection is not linked to its enzymatic activity as oxidoreductase, but to the disassembly of its uniquely coordinated iron-sulfur cluster using glutathione as non-protein ligand. The protective effect of glutaredoxin 2 is connected to decreased protein carbonylation and nitration. In line, brain lesions of mice suffering from experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, show decreased glutaredoxin 2 expression and increased nitrotyrosine formation indicating that this type of protection is missing in the inflamed central nervous system. Our findings link inorganic biochemistry to neuroinflammation and identify glutaredoxin 2 as a protective factor against neuroinflammation-mediated myelin damage. Thus, improved availability of glutathione-coordinated iron-sulfur clusters emerges as a potential therapeutic approach in inflammatory demyelination.
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http://dx.doi.org/10.1002/glia.23178DOI Listing
September 2017

Redox Events As Modulators of Pathology and Therapy of Neuroinflammatory Diseases.

Front Cell Dev Biol 2016 23;4:63. Epub 2016 Jun 23.

Department of Neurology, Medical Faculty, Heinrich-Heine University Düsseldorf Düsseldorf, Germany.

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http://dx.doi.org/10.3389/fcell.2016.00063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917551PMC
July 2016

Redox regulation of cytoskeletal dynamics during differentiation and de-differentiation.

Biochim Biophys Acta 2015 Aug 8;1850(8):1575-87. Epub 2014 Nov 8.

Institut für Biochemie und Molekularbiologie, Universitätsmedizin Greifswald, Ernst-Moritz-Arndt-Universität, Greifswald, Germany. Electronic address:

Background: The cytoskeleton, unlike the bony vertebrate skeleton or the exoskeleton of invertebrates, is a highly dynamic meshwork of protein filaments that spans through the cytosol of eukaryotic cells. Especially actin filaments and microtubuli do not only provide structure and points of attachments, but they also shape cells, they are the basis for intracellular transport and distribution, all types of cell movement, and--through specific junctions and points of adhesion--join cells together to form tissues, organs, and organisms.

Scope Of Review: The fine tuned regulation of cytoskeletal dynamics is thus indispensible for cell differentiation and all developmental processes. Here, we discussed redox signalling mechanisms that control this dynamic remodeling. Foremost, we emphasised recent discoveries that demonstrated reversible thiol and methionyl switches in the regulation of actin dynamics.

Major Conclusions: Thiol and methionyl switches play an essential role in the regulation of cytoskeletal dynamics.

General Significance: The dynamic remodeling of the cytoskeleton is controlled by various redox switches. These mechanisms are indispensible during development and organogenesis and might contribute to numerous pathological conditions. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation.
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http://dx.doi.org/10.1016/j.bbagen.2014.10.030DOI Listing
August 2015

Glutaredoxin regulates vascular development by reversible glutathionylation of sirtuin 1.

Proc Natl Acad Sci U S A 2013 Dec 25;110(50):20057-62. Epub 2013 Nov 25.

Department of Medical Biochemistry and Biophysics, Department of Molecular Tumor and Cell Biology, and Institute of Environmental Medicine, Karolinska Institutet, 17177, Stockholm, Sweden.

Embryonic development depends on complex and precisely orchestrated signaling pathways including specific reduction/oxidation cascades. Oxidoreductases of the thioredoxin family are key players conveying redox signals through reversible posttranslational modifications of protein thiols. The importance of this protein family during embryogenesis has recently been exemplified for glutaredoxin 2, a vertebrate-specific glutathione-disulfide oxidoreductase with a critical role for embryonic brain development. Here, we discovered an essential function of glutaredoxin 2 during vascular development. Confocal microscopy and time-lapse studies based on two-photon microscopy revealed that morpholino-based knockdown of glutaredoxin 2 in zebrafish, a model organism to study vertebrate embryogenesis, resulted in a delayed and disordered blood vessel network. We were able to show that formation of a functional vascular system requires glutaredoxin 2-dependent reversible S-glutathionylation of the NAD(+)-dependent protein deacetylase sirtuin 1. Using mass spectrometry, we identified a cysteine residue in the conserved catalytic region of sirtuin 1 as target for glutaredoxin 2-specific deglutathionylation. Thereby, glutaredoxin 2-mediated redox regulation controls enzymatic activity of sirtuin 1, a mechanism we found to be conserved between zebrafish and humans. These results link S-glutathionylation to vertebrate development and successful embryonic angiogenesis.
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http://dx.doi.org/10.1073/pnas.1313753110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3864331PMC
December 2013