TY  - THES
A1  - Schneider, Katharina
T1  - Nachweis und Analyse von Phospho-Alpha-Synuclein-Ablagerungen in Hautnerven von Patienten mit Morbus Parkinson oder Multisystematrophie
T1  - Proof and analysis of phospho-alpha-synuclein in the skin of patients with Parkinsons' disease or multiple system atrophy
N2  - Zielsetzung der Studie war es, Ablagerungen des phosphorylierten Alpha-Synucleins in der Haut von Patienten mit Morbus Parkinson und atypischen Parkinson-Syndromen zu untersuchen und deren Auswirkungen auf das periphere Nervensystem zu erforschen.
Dazu wurden Hautbiopsien von 92 Patienten mit Morbus Parkinson, 12 Patienten mit MSA und 13 Patienten mit einer Tauopathie sowie 83 gesunden Kontrollpersonen immunhisto-chemisch gefärbt und unter dem Mikroskop untersucht.
Mit einer Sensitivität von 52 % für den Morbus Parkinson und 67 % für die MSA bei hoher Spezifität stellt der Nachweis von Phospho-Alpha-Synuclein in den kleinen Nervenfasern der Haut einen geeigneten Biomarker dar. Während die Ablagerungen des phosphorylierten Alpha-Synucleins bei Patienten mit Morbus Parkinson eher in autonomen Strukturen nachweisbar waren, fanden sie sich bei Patienten mit MSA eher in sub- und intraepidermal gelegenen Nervenfasern. Phospho-Alpha-Synuclein konnte in allen untersuchten Nervenfasersubtypen nachgewiesen werden, also in CGRP-, SP-, TH- und VIP-positiven Fasern. Bei den in der vorliegenden Studie untersuchten Parkinson-Patienten waren keine Veränderungen in der sensiblen Neurographie des Nervus suralis erkennbar. Die intraepidermale Nervenfaserdichte sowie die Innervation der Schweißdrüsen waren jedoch teilweise vermindert und auch in der QST zeigten sich Auffälligkeiten. Ein Zusammenhang zu dem Vorhandensein von Phospho-Alpha-Synuclein-Ablagerungen konnte jedoch nur für die Innervation der Musculi arrectores pilorum hergestellt werden. Bei der Untersuchung der pathophysiologischen Hintergründe, durch die Phospho-Alpha-Synuclein-Ablagerungen zu Nervenfaserschädigungen führen, konnten die Hinweise auf eine Beteiligung von axonalen Transportproteinen, Mikrotubuli oder Mitochondrien nicht erhärtet werden.
N2  - The aim of this study was to examine dermal phospho-alpha-synuclein deposits of patients with Parkinson's disease or multiple system atrophy.
KW  - Synuclein <alpha->
KW  - Parkinson-Krankheit
KW  - Alpha-Synuclein
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169694
ER  - 
TY  - JOUR
A1  - Horn, Michael
A1  - Baumann, Reto
A1  - Pereira, Jorge A.
A1  - Sidiropoulos, Páris N. M.
A1  - Somandin, Christian
A1  - Welzl, Hans
A1  - Stendel, Claudia
A1  - Lühmann, Tessa
A1  - Wessig, Carsten
A1  - Toyka, Klaus V.
A1  - Relvas, João B.
A1  - Senderek, Jan
A1  - Suter, Ueli
T1  - Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells
JF  - Brain
N2  - Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.
KW  - Frabin/Fgd4
KW  - myelination
KW  - hereditary motor and sensory neuropathy
KW  - Charcot–Marie–Tooth disease
KW  - Rho-GTPase Cdc42
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125390
VL  - 135
ER  - 
TY  - JOUR
A1  - Bittner, Stefan
A1  - Bobak, Nicole
A1  - Hofmann, Majella-Sophie
A1  - Schuhmann, Michael K.
A1  - Ruck, Tobias
A1  - Göbel, Kerstin
A1  - Brück, Wolfgang
A1  - Wiendl, Heinz
A1  - Meuth, Sven G.
T1  - Murine K\(_{2P}\)5.1 Deficiency Has No Impact on Autoimmune Neuroinflammation due to Compensatory K\(_{2P}\)3.1-and K\(_{V}\)1.3-Dependent Mechanisms
JF  - International Journal of Molecular Sciences
N2  - Lymphocytes express potassium channels that regulate physiological cell functions, such as activation, proliferation and migration. Expression levels of K\(_{2P}\)5.1(TASK2; KCNK5) channels belonging to the family of two-pore domain potassium channels have previously been correlated to the activity of autoreactive T lymphocytes in patients with multiple sclerosis and rheumatoid arthritis. In humans, K\(_{2P}\)5.1 channels are upregulated upon T cell stimulation and influence T cell effector functions. However, a further clinical translation of targeting K\(_{2P}\)5.1 is currently hampered by a lack of highly selective inhibitors, making it necessary to evaluate the impact of KCNK5 in established preclinical animal disease models. We here demonstrate that K\(_{2P}\)5.1 knockout (K\(_{2P}\)5.1\(^{-/-}\) mice display no significant alterations concerning T cell cytokine production, proliferation rates, surface marker molecules or signaling pathways. In an experimental model of autoimmune neuroinflammation, K\(_{2P}\)5.1\(^{-/-}\) mice show a comparable disease course to wild-type animals and no major changes in the peripheral immune system or CNS compartment. A compensatory upregulation of the potassium channels K\(_{2P}\)3.1 and K\(_{V}\)1.3 seems to counterbalance the deletion of K\(_{2P}\)5.1. As an alternative model mimicking autoimmune neuroinflammation, experimental autoimmune encephalomyelitis in the common marmoset has been proposed, especially for testing the efficacy of new potential drugs. Initial experiments show that K\(_{2P}\)5.1 is functionally expressed on marmoset T lymphocytes, opening up the possibility for assessing future K\(_{2P}\)5.1-targeting drugs.
KW  - domain potassium channels
KW  - volume regulation
KW  - multiple-sclerosis
KW  - potassium channels
KW  - multiple sclerosis
KW  - ion channels
KW  - K+ channel
KW  - T lymphocytes
KW  - up-regulation
KW  - TASK2
KW  - K2P channels
KW  - B cells
KW  - ph
KW  - K\(_{2P}\)5.1
KW  - KCNK5
KW  - autoimmune neuroinflammation
KW  - EAE
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151454
VL  - 16
SP  - 16880
EP  - 16896
ER  - 
TY  - THES
A1  - Egenolf, Nadine
T1  - Multidimensionale morphologische und elektrophysiologische Analyse von Patienten mit Small Fiber Neuropathie
T1  - Multidimensional morphological and electrophysiological analysis of patients with small fiber neuropathy
N2  - Die Small Fiber Neuropathie (SFN) bildet eine Untergruppe der sensiblen Neuropathien, bei der die Aδ- und C-Fasern betroffen sind. Die Patienten berichten v.a. von brennenden Schmerzen und Dysästhesien, seltener auch von autonomen Funktionsstörungen. Bei fehlendem Goldstandard und normalen Nervenleitungsstudien ist die Diagnostik erschwert, da selbst nach Spezialuntersuchungen wie Hautstanzbiopsie und quantitativer sensorischer Testung (QST) viele Patienten trotz typischer Anamnese der Diagnosestellung entgehen. Wir rekrutierten 55 Patienten und 31 gesunde Kontrollen. Nach neurologischer Untersuchung und Ausschluss einer Polyneuropathie mittels Elektroneurographie wurden bei allen Studienteilnehmern Hautstanzbiopsien am Ober- und Unterschenkel zur Ermittlung der intraepidermalen Nervenfaserdichte (IENFD) entnommen sowie eine QST zur Funktionsprüfung der kleinen Nervenfasern durchgeführt. Die Studienteilnehmer wurden zudem mit cornealer confocaler Mikroskopie (CCM) und der Ableitung Schmerz-assoziierter evozierter Potentiale (PREP) untersucht. Zur autonomen Testung erfolgte die Messung der Schweißproduktion mittels quantitativem sudomotorischem Axonreflextest (QSART). Die neurologische Untersuchung zeigte in 55% der Patienten Hinweise auf eine Kleinfaserpathologie. Die distale IENFD war bei 62% der Patienten reduziert, die QST bei 22% der Patienten auffällig. Die PREP Latenzen waren in der Patientengruppe länger als bei den Kontrollen, die Amplituden niedriger. Bei der cornealen Innervation zeigte sich eine Reduktion der Nervenfaserdichte, Nervenfaserlänge und Nervenastdichte. Die in QSART gemessenen Parameter zeigten sich zu 86% unauffällig. Während nach klinischer Untersuchung, Hautbiopsie und QST in 53% der Fälle in 2 von 3 Untersuchungen eine Pathologie der kleinen Fasern festgestellt werden konnte, stieg die Rate bei zusätzlicher Anwendung von PREP und CCM auf 80% (ohne Berücksichtigung von QST). Zusammenfassend sollten die klinische Untersuchung und die Hautstanzbiopsie bei allen Patienten mit Verdacht auf SFN erfolgen. PREP und CCM sind unter den verfügbaren zusätzlichen Untersuchungen diagnostisch am wertvollsten. Wichtig ist allerdings, dass bei fehlendem Goldstandard eine SFN auch bei unauffälligen Tests nicht ausgeschlossen werden kann. Zusätzlich können die Mikroneurographie und die genetische Analyse wertvolle Hinweise auf eine Kleinfaserfunktionsstörung und deren Pathophysiologie geben.
N2  - Small fiber neuropathy (SFN) forms a subgroup of sensory neuropathies, in which the Aδ- and C-fibers are impaired. Patients mainly report burning pain and dysesthesia, less frequently also autonomic dysfunctions. In absence of a diagnostic gold standard and under normal nerve conduction studies, the diagnosis is difficult. Even after special examinations such as skin punch biopsy and quantitative sensory testing (QST), many patients are not diagnosed despite a typical pain history. We prospectively recruited 55 patients and 31 healthy controls in our study. After neurological examination and exclusion of a polyneuropathy by means of neurological examination and electroneurography, skin punch biopsies were taken from the upper and lower leg of all study participants to determine the intraepidermal nerve fiber density (IENFD). QST was performed to investigate the function of the small nerve fibers. Study participants were also examined with corneal confocal microscopy (CCM) and derivation of pain-related evoked potentials (PREP). For autonomous testing, the sweat production was measured using quantitative sudomotor axon reflex testing (QSART). Neurological examination showed hints for small fiber pathology in 55% of patients. The distal IENFD was reduced in 62% of patients, while QST was abnormal in 22% of patients. The PREP latencies were longer in the patient group than in the controls, the amplitudes were smaller. Corneal innervation showed a reduction of nerve fiber density, nerve fiber length, and nerve branch density in patients compared to controls. The parameters measured in QSART were 86% unremarkable. While after clinical examination, skin biopsy, and QST a pathology of the small fibers could be detected in 53% of the cases in 2 of 3 examinations, the rate increased to 80% with additional application of PREP and CCM (without consideration of QST). In summary, neurological examination should be performed together with skin biopsy in all patients with suspected SFN. PREP and CCM are diagnostically most valuable among the available additional examinations. However, it is important to note that in the absence of a gold standard, SFN cannot be excluded even with normal test results. In addition, microneurography and genetic analysis can provide valuable information about a small fiber dysfunction and its pathophysiology.
KW  - Neuropathischer Schmerz
KW  - Nervenfaser
KW  - Evoziertes Potenzial
KW  - Konfokale Mikroskopie
KW  - Sensorik <Neurophysiologie>
KW  - Small Fiber Neuropathie
KW  - Hautstanzbiopsie
KW  - Quantitative sensorische Testung
KW  - Mikroneurographie
KW  - Schmerz-assoziierte evozierte Potenziale
KW  - Genetik
KW  - Quantitativer sudomotorischer Axonreflextest
KW  - Corneale confocale Mikroskopie
KW  - Intraepidermale Nervenfaserdichte
KW  - small fiber neuropathy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202938
ER  - 
TY  - JOUR
A1  - Lenders, Malte
A1  - Hennermann, Julia B.
A1  - Kurschat, Christine
A1  - Rolfs, Arndt
A1  - Canaan-Kühl, Sima
A1  - Sommer, Claudia
A1  - Üçeyler, Nurcan
A1  - Kampmann, Christoph
A1  - Karabul, Nesrin
A1  - Giese, Anne-Katrin
A1  - Duning, Thomas
A1  - Stypmann, Jörg
A1  - Krämer, Johannes
A1  - Weidemann, Frank
A1  - Brand, Stefan-Martin
A1  - Wanner, Christoph
A1  - Brand, Eva
T1  - Multicenter Female Fabry Study (MFFS) - clinical survey on current treatment of females with Fabry disease
JF  - Orphanet Journal of Rare Diseases
N2  - Background
The aim of the present study was to assess manifestations of and applied treatment concepts for females with Fabry disease (FD) according to the current European Fabry Guidelines.

Methods
Between 10/2008 and 12/2014, data from the most recent visit of 261 adult female FD patients from six German Fabry centers were retrospectively analyzed. Clinical presentation and laboratory data, including plasma lyso-Gb3 levels were assessed.

Results
Fifty-five percent of females were on enzyme replacement therapy (ERT), according to recent European FD guidelines. Thirty-three percent of females were untreated although criteria for ERT initiation were fulfilled. In general, the presence of left ventricular hypertrophy (LVH) seemed to impact more on ERT initiation than impaired renal function. In ERT-naïve females RAAS blockers were more often prescribed if LVH was present rather than albuminuria. Affected females with missense mutations showed a similar disease burden compared to females with nonsense mutations. Elevated plasma lyso-Gb3 levels in ERT-naïve females seem to be a marker of disease burden, since patients showed comparable incidences of organ manifestations even if they were ~8 years younger than females with normal lyso-Gb3 levels.

Conclusion
The treatment of the majority of females with FD in Germany is in line with the current European FD guidelines. However, a relevant number of females remain untreated despite organ involvement, necessitating a careful reevaluation of these females.
KW  - Fabry disease
KW  - females
KW  - lyso-Gb3
KW  - enzyme replacement therapy
KW  - guidelines
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166543
VL  - 11
IS  - 88
ER  - 
TY  - JOUR
A1  - Norrmen, Camilla
A1  - Figlia, Gianluca
A1  - Lebrun-Julien, Frederic
A1  - Pereira, Jorge A.
A1  - Trötzmüller, Martin
A1  - Köfeler, Harald C.
A1  - Rantanen, Ville
A1  - Wessig, Carsten
A1  - van Deijk, Anne-Lieke F.
A1  - Smit, August B.
A1  - Verheijen, Mark H. G.
A1  - Rüegg, Markus A.
A1  - Hall, Michael N.
A1  - Suter, Ueli
T1  - mTORC1 Controls PNS Myelination along the mTORC1-RXR gamma-SREBP-Lipid Biosynthesis Axis in Schwann Cells
JF  - Cell Reports
N2  - Myelin formation during peripheral nervous system (PNS) development, and reformation after injury and in disease, requires multiple intrinsic and extrinsic signals. Akt/mTOR signaling has emerged as a major player involved, but the molecular mechanisms and downstream effectors are virtually unknown. Here, we have used Schwann-cell-specific conditional gene ablation of raptor and rictor, which encode essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2), respectively, to demonstrate that mTORC1 controls PNS myelination during development. In this process, mTORC1 regulates lipid biosynthesis via sterol regulatory element-binding proteins (SREBPs). This course of action is mediated by the nuclear receptor RXRg, which transcriptionally regulates SREBP1c downstream of mTORC1. Absence of mTORC1 causes delayed myelination initiation as well as hypomyelination, together with abnormal lipid composition and decreased nerve conduction velocity. Thus, we have identified the mTORC1-RXR gamma-SREBP axis controlling lipid biosynthesis as a major contributor to proper peripheral nerve function.
KW  - axonal integrity
KW  - peripheral nervous-system
KW  - COMPLEX 1
KW  - rat hepatocytes
KW  - SREBP
KW  - mice
KW  - growth
KW  - protein
KW  - element
KW  - CNS Myelination
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114847
SN  - 2211-1247
VL  - 9
IS  - 2
ER  - 
TY  - JOUR
A1  - Herm, Juliane
A1  - Schurig, Johannes
A1  - Martinek, Martin R.
A1  - Höltgen, Reinhard
A1  - Schirdewan, Alexander
A1  - Kirchhof, Paulus
A1  - Wieczorek, Marcus
A1  - Pürerfellner, Helmut
A1  - Heuschmann, Peter U.
A1  - Fiebach, Jochen B.
A1  - Haeusler, Karl Georg
T1  - MRI-detected brain lesions in AF patients without further stroke risk factors undergoing ablation - a retrospective analysis of prospective studies
JF  - BMC Cardiovascular Disorders
N2  - Background
Atrial fibrillation (AF) without other stroke risk factors is assumed to have a low annual stroke risk comparable to patients without AF. Therefore, current clinical guidelines do not recommend oral anticoagulation for stroke prevention of AF in patients without stroke risk factors. We analyzed brain magnetic resonance imaging (MRI) imaging to estimate the rate of clinically inapparent (“silent”) ischemic brain lesions in these patients.

Methods
We pooled individual patient-level data from three prospective studies comprising stroke-free patients with symptomatic AF. All study patients underwent brain MRI within 24–48 h before planned left atrial catheter ablation. MRIs were analyzed by a neuroradiologist blinded to clinical data.

Results
In total, 175 patients (median age 60 (IQR 54–67) years, 32% female, median CHA\(_2\)DS\(_2\)-VASc = 1 (IQR 0–2), 33% persistent AF) were included. In AF patients without or with at least one stroke risk factor, at least one silent ischemic brain lesion was observed in 4 (8%) out of 48 and 10 (8%) out of 127 patients, respectively (p > 0.99). Presence of silent ischemic brain lesions was related to age (p = 0.03) but not to AF pattern (p = 0.77). At least one cerebral microbleed was detected in 5 (13%) out of 30 AF patients without stroke risk factors and 25 (25%) out of 108 AF patients with stroke risk factors (p = 0.2). Presence of cerebral microbleeds was related to male sex (p = 0.04) or peripheral artery occlusive disease (p = 0.03).

Conclusion
In patients with symptomatic AF scheduled for ablation, brain MRI detected silent ischemic brain lesions in approximately one in 12 patients, and microbleeds in one in 5 patients. The prevalence of silent ischemic brain lesions did not differ in AF patients with or without further stroke risk factors.
KW  - Clinically silent stroke
KW  - atrial fibrillation
KW  - magnetic resonance imaging
KW  - cerebral microbleeds
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201226
VL  - 19
ER  - 
TY  - THES
A1  - Hillerer, Claudia
T1  - MR-Protonen-Spektroskopie des Linsenkerns bei idiopathischen Handdystonien
T1  - H Magnetic Resonance Spectroscopy of the Lentiform Nucleus in Idiopathic Focal Hand Dystonia
N2  - Die Pathogenese der idiopathischen Handdystonie ist bis heute nicht abschließend geklärt. Verschiedene Befunde sprechen für eine Läsion der Basalganglien, insbesondere des Linsenkerns. Insbesondere bildgebende Verfahren wie MRT, Sonographie, PET oder SPECT, und Untersuchungen bei sekundären Dystonieformen weisen in diese Richtung. Trotz vielfacher Anstrengungen, den zugrunde liegenden Pathomechanismus aufzudecken, ist es bis heute noch nicht gelungen, ein einheitliches anatomisches oder biochemisches Korrelat für die Störung verantwortlich zu machen: So bieten einige pathoanatomische Studien Hinweise auf Zellverlust und Gliose im Striatum, andere zeigten Veränderungen in der Konzentration verschiedener Neurotransmitter. Jüngere Untersuchungen lassen einen gestörten Komplex I der mitochondrialen Atmungskette vermuten. Da die Ätiologie der Dystonien bisher letztlich nicht geklärt ist, bietet die Protonenspektroskopie die Möglichkeit, Stoffwechselveränderungen sowie Änderungen der Gewebszusammensetzung und der Konzentrationen darin enthaltener Stoffe zu untersuchen und so Hypothesen zur Genese der idiopathischen Dystonie herauszuarbeiten. Wir untersuchten 14 Patienten mit idiopathischem Schreibkrampf und 11 gesunde, altersentsprechende Probanden, die nachweislich an keiner zentral-neurologischen Erkrankung litten. Zur Messung wurde eine Standard-Kopfspule ( 1,5 T Ganzkörper MR-Tomograph, Siemens Magnetom Vision, Erlangen) verwendet. Die Spektrenerhebung erfolgte mit Hilfe einer PRESS-Sequenz (TR= 1365 ms, TE= 135 ms), das Voxel war auf das Gebiet des Linsenkerns zentriert. Die anhand der Spektren ermittelten Metabolitenverhältnisse von NAA:Cho, NAA:Crea, Cho:Crea und Lac:Crea ergaben keine statistisch signifikante Seitendifferenz innerhalb der Patientengruppe, auch ein Vergleich zwischen Patienten- und Kontrollgruppe blieb ohne statistische Differenz (p>0,05). Somit konnten durch die Protonenspektroskopie keine Veränderungen der Metabolitenkonzentrationen bei der idiopathischen Handdystonie festgestellt werden. Es ergibt sich damit kein Hinweis darauf, daß idiopathischen Dystonien ein meßbarer Verlust von Neuronen, eine damit einhergehende sekundäre Gliose oder eine meßbare Störung des Energiehaushalts, sei es durch erhöhte Umsatzraten oder eine fehlerhafte oxidative Phosphorylierung, zugrunde liegt. Eine mögliche Erklärung dieser unauffälligen Befunde bei Dystoniepatienten könnte die Annahme einer Störung des Stoffwechsels in nur wenigen Neuronen bieten, was sich der Sensitivität der Methode entziehen kann. Denkbar sind auch Konzentrationsänderungen von Neurotransmittern, Einlagerungen von Schwermetallen (z.B.Kupfer), Veränderungen der oxidativen Phosphorylierung oder Änderungen der Rezeptordichte. Generalisierte Dystonien müßten eine eventuell vorhandene Pathologie am deutlichsten aufweisen und wären deshalb ebenfalls ein interessantes Krankheitsbild. Die spektroskopische Untersuchung gestaltet sich aber wegen des bei dieser Form zu erwartenden erhöhten Auftretens von Bewegungsartefakten schwierig. Auch das Verwenden veränderter Meßparameter (TE, TR) oder einer höheren Tesla-Zahl bei einem größeren Patientenkollektiv wäre zur weiteren Abklärung anzustreben. Insbesondere sollten Schreibkrampf-Patienten mit Hilfe der funktionellen MR-Spektroskopie während des Auftretens dystoner Verkrampfungen oder auch während der Durchführung willkürlicher Fingerbewegungen untersucht werden. Bisher latente Veränderungen könnten sich dann, unter der so erzeugten motorischen Aktivierung, manifestieren.
N2  - The pathogenesis of primary focal hand dystonia is still unknown. Several radiologic findings and also findings by studies in patients with secondary dystonia point toward the basal ganglia, especially the lentiform nucleus as a possible site of the lesion. There are also abnormalities in histopathologic and biochemical examinations: cell loss and gliosis in the striatum are described as well as an imbalance of neurotransmitters or defects of the complex I of the respiratory chain. But all these results are inconsistent, so the question is open as to whether neurodegeneration occurs in basal ganglia of primary dystonia. H-magnetic resonance spectroscopy (MRS) in vivo is a non-invasive technique for the examination of brain metabolites. It has proved helpful to assess neuronal degeneration and loss or changes in the tissue composition in various basal ganglia disorders, but data of dystonia patients is lacking so far. We have examinated 14 patients with primary focal hand dystonia and 11 healthy control subjects. For the examination a standard quadrature head coil was used (1.5-T MR whole body imager, Siemens AG, Erlangen, Germany). Single volume spectra were obtained using a PRESS sequenz (TR=1365ms, TE=135ms). The voxels (3.375 or 8.0 cm³) were centered on the lentiform nucleus. No statistically significant difference of the measured metabolite ratios of N-acetylaspartate (NAA)/creatine, NAA/choline, choline/creatine or lactate/creatine were found, neither by the intraindividual comparison between the left and right sided lentiform nucleus of the patient group nor by the comparison between patient and control group. So we found no evidence that primary focal dystonia is associated with a conspicuous loss of neurons with secondary gliosis or a marked disturbance of the energy metabolism caused by defects of the respiratory chain or an increased turnover. A possible reason for the normal findings is the limited sensitivity of the method, so minor abnormalities cannot be excluded. For future investigations it will be interesting to examinate patients with generalised dystonia or patients with focal dystonia at the time of a dystonic contraction or active finger movement, because if there are just small changes in the metabolite ratios, it should be recognizable in this cases first. Also changes in the study protocol (p.e. other TE or TR) or examinations with a 3-T imager could bring a benefit.
KW  - Dystonie
KW  - Protonenspektroskopie
KW  - Basalganglien
KW  - Dystonia
KW  - Proton Magnetic Resonance Spectroscopy
KW  - Basal ganglia
Y1  - 2001
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-1182401
ER  - 
TY  - JOUR
A1  - Pötter-Nerger, Monika
A1  - Reese, Rene
A1  - Steigerwald, Frank
A1  - Heiden, Jan Arne
A1  - Herzog, Jan
A1  - Moll, Christian K. E.
A1  - Hamel, Wolfgang
A1  - Ramirez-Pasos, Uri
A1  - Falk, Daniela
A1  - Mehdorn, Maximilian
A1  - Gerloff, Christian
A1  - Deuschl, Günther
A1  - Volkmann, Jens
T1  - Movement-Related Activity of Human Subthalamic Neurons during a Reach-to-Grasp Task
JF  - Frontiers in Human Neuroscience
N2  - The aim of the study was to record movement-related single unit activity (SUA) in the human subthalamic nucleus (STN) during a standardized motor task of the upper limb. We performed microrecordings from the motor region of the human STN and registered kinematic data in 12 patients with Parkinson’s disease (PD) undergoing deep brain stimulation surgery (seven women, mean age 62.0 ± 4.7 years) while they intraoperatively performed visually cued reach-to-grasp movements using a grip device. SUA was analyzed offline in relation to different aspects of the movement (attention, start of the movement, movement velocity, button press) in terms of firing frequency, firing pattern, and oscillation. During the reach-to-grasp movement, 75/114 isolated subthalamic neurons exhibited movement-related activity changes. The largest proportion of single units showed modulation of firing frequency during several phases of the reach and grasp (polymodal neurons, 45/114), particularly an increase of firing rate during the reaching phase of the movement, which often correlated with movement velocity. The firing pattern (bursting, irregular, or tonic) remained unchanged during movement compared to rest. Oscillatory single unit firing activity (predominantly in the theta and beta frequency) decreased with movement onset, irrespective of oscillation frequency. This study shows for the first time specific, task-related, SUA changes during the reach-to-grasp movement in humans.
KW  - subthalamic nucleus
KW  - deep brain stimulation
KW  - Parkinson’s disease
KW  - neurophysiology
KW  - beta oscillation
KW  - reach-to-grasp movement
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170361
VL  - 11
IS  - 436
ER  - 
TY  - JOUR
A1  - Meziane, Hadj Boumediene
A1  - Moisello, Clara
A1  - Perfetti, Bernardo
A1  - Kvint, Svetlana
A1  - Isaias, Ioannis Ugo
A1  - Quartarone, Angelo
A1  - Di Rocco, Alessandro
A1  - Ghilardi, Maria Felice
T1  - Movement preparation and bilateral modulation of beta activity in aging and Parkinson's disease
JF  - PLoS ONE
N2  - In previous studies of young subjects performing a reaction-time reaching task, we found that faster reaction times are associated with increased suppression of beta power over primary sensorimotor areas just before target presentation. Here we ascertain whether such beta decrease similarly occurs in normally aging subjects and also in patients with Parkinson's disease (PD), where deficits in movement execution and abnormalities of beta power are usually present. We found that in both groups, beta power decreased during the motor task in the electrodes over the two primary sensorimotor areas. However, before target presentation, beta decreases in PD were significantly smaller over the right than over the left areas, while they were symmetrical in controls. In both groups, functional connectivity between the two regions, measured with imaginary coherence, increased before the target appearance; however, in PD, it decreased immediately after, while in controls, it remained elevated throughout motor planning. As in previous studies with young subjects, the degree of beta power before target appearance correlated with reaction time. The values of coherence during motor planning, instead, correlated with movement time, peak velocity and acceleration. We conclude that planning of prompt and fast movements partially depends on coordinated beta activity of both sensorimotor areas, already at the time of target presentation. The delayed onset of beta decreases over the right region observed in PD is possibly related to a decreased functional connectivity between the two areas, and this might account for deficits in force programming, movement duration and velocity modulation.
KW  - event-related desynchronization
KW  - reaction-time tasks
KW  - brain dynamics
KW  - coherence
KW  - bradykinesia
KW  - activation
KW  - cortical oscillatory activity
KW  - voluntary movement
KW  - EEG data
KW  - L-DOPA
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144147
VL  - 10
IS  - 1
ER  - 
TY  - THES
A1  - Kißner [geb. Stenger], Stefanie Martina
T1  - Morphologische Untersuchungen an Myoblasten von Patienten, die an facioscapulohumeraler Muskeldystrophie (FSHD) leiden
T1  - Morphological studies on myoblasts of patients with facioscapulohumeral muscular dystrophy
N2  - Die autosomal-dominant vererbte facioscapulohumerale Muskeldystrophie (FSHD) ist mit einer Prävalenz von etwa 1:20.000 die dritthäufigste Form der hereditären Myopathien. Erste Beschwerden werden meist in der zweiten Lebensdekade beobachtet. Betroffen sind vor allem die Muskulatur von Gesicht, Schultern, Oberarmen, die Fußhebermuskulatur und die Muskeln des Hüftgürtels.
FSHD wird durch einen Gendefekt ausgelöst, der den langen Arm des Chromosoms vier (4q35) betrifft, wobei es zur teilweisen Deletion des polymorphen Abschnitts D4Z4, der für das Protein DUX4 codiert, kommt. Dabei treten unter anderem Störungen in der DUX4-Expression, Veränderungen der myogenen Genexpression, eine Unterdrückung der Muskelzelldifferenzierung und eine Inhibition der Muskelbildung auf.
FSHD und eine andere Form der Muskeldystrophie, die Emery-Dreifuss-Muskeldystrophie (EDMD), zeigen trotz unterschiedlicher genetischer Ursachen phänotypisch Ähnlichkeiten in der Ausprägung der Erkrankungen. In früheren Studien zeigte die Kernhülle von EDMD-Myoblasten morphologische Auffälligkeiten. In anderen Untersuchungen waren morphologische Veränderungen der Mitochondrien von FSHD-Patienten festzustellen.
Daher wurden elektronenmikroskopische Untersuchungen der Kernhülle und der Mitochondrien von FSHD-Myoblasten durchgeführt und mit der entsprechenden Kontrolle verglichen.
Hierfür wurden drei verschiedene Zelllinien-Paare in unterschiedlichen Passagen, das heißt unterschiedlicher Anzahl an Subkultivierungen, eingesetzt, wobei in den höheren Passagen vermehrt morphologische Atypien beobachtet werden konnten.
Die eingesetzten Zelllinien differenzieren sich durch verschiedene Parameter wie beispielsweise Alter und Geschlecht der Patienten. Dabei zeigten sich sowohl zwischen den Kontrollzellen als auch zwischen den FSHD-Myoblasten Unterschiede.
Im Rahmen der Probenvorbereitung für die Elektronenmikroskopie kamen zwei verschiedene Fixierungsmethoden zum Einsatz: die konventionelle chemische Fixierung, Entwässerung und Flacheinbettung von Kulturzellen und die Hochdruckgefrierung mit anschließender Gefriersubstitution. In Bezug auf die Qualität des Strukturerhalts, die beim Hochdruckgefrieren erreicht wird, wird dieser Art der Fixierung eine Überlegenheit gegenüber allen anderen Verfahren zugeschrieben. Diese allgemeine Aussage kann nicht vollständig auf die Untersuchungen an den Myoblasten übertragen werden.
Für die Untersuchung der Kernmembranen sind beide Methoden geeignet, wobei der Abstand zwischen innerer und äußerer Kernmembran nach der HPF-Fixierung schärfer abgebildet wurde. Bei der Darstellung der Mitochondrien zeigten die elektronenmikroskopischen Aufnahmen nach dem Hochdruckgefrieren bessere und schärfere Ergebnisse. Die Kernporen waren bei beiden Fixierungsmethoden gut erkennbar. 
Beim Vergleich der gesunden und erkrankten Myoblasten wiesen die Kontrollzellen deutlich weniger Auffälligkeiten auf als die Myoblasten von FSHD-Patienten. 
Innere und äußere Kernmembran verliefen bei den Kontrollzellen meist parallel und die Mitochondrien zeigten in den meisten Fällen eine typische wurmartige, längliche Form mit Cristae. Dies traf sowohl für die konventionelle Fixierung als auch für das Hochdruckgefrieren zu.
Die erkrankten Myoblasten wiesen im Vergleich zur Kontrolle bei beiden Fixierungsmethoden deutliche Auffälligkeiten in der Mitochondrien-Morphologie auf. Neben einer oft großen Variationsbreite hinsichtlich Form und Länge war auch das teilweise Fehlen der Cristae festzustellen.
Bei Betrachtung der Kernhülle fielen jedoch deutliche Unterschiede zwischen konventioneller und HPF-Fixierung auf. Die äußere Kernmembran der konventionell fixierten FSHD-Myoblasten verlief unregelmäßig und gewellt. Im Gegensatz dazu wies die Kernhülle der HPF-fixierten erkrankten Myoblasten einen erstaunlich parallelen Verlauf auf.
Da bei EDMD in vorangegangenen Untersuchungen auch fluoreszenzmikroskopisch Veränderungen der erkrankten Zellen auffällig waren, wurde neben den Methoden der Elektronenmikroskopie das Vorliegen und die Verteilung verschiedener Proteine in FSHD-Myoblasten mittels indirekter Immunfluoreszenz untersucht und mit den Kontrollzellen verglichen.
Zur Beurteilung der Kernhülle wurden Antikörper gegen Lamin A/C und Nukleoporine eingesetzt. Die Mitochondrien wurden mithilfe des Antikörpers ANT1/2, der an den Adenin-Nukleotid-Translokator der inneren Mitochondrienmembran bindet, untersucht.
Im Gegensatz zu den Untersuchungen an EDMD-Myoblasten waren die Lamine A und C sowie die Kernporen sowohl bei den Myoblasten der FSHD-Patienten als auch bei den Kontrollzellen nachweisbar und gleichmäßig verteilt.
Bei der indirekten Immunfluoreszenz mit ANT1/2 zeigten sich Unterschiede zwischen den untersuchten Myoblasten-Paaren.
Durch die vorliegenden Ergebnisse ist darauf zu schließen, dass die Myoblasten von FSHD-Patienten Veränderungen Mitochondrien aufweisen. Die Untersuchungen der Kernhülle liefern abhängig von der Fixierungsmethode unterschiedliche Ergebnisse.
N2  - The autosomal dominant facioscapulohumeral muscular dystrophy (FSHD), with a prevalence of about 1:20,000, is the third most common form of hereditary myopathy. First complaints are usually observed in the second decade of life. Most affected are the muscles of the face, shoulders, upper arms, lower legs and girdle.
FSHD is triggered by a gene defect affecting the long arm of chromosome four (4q35), resulting in the partial deletion of polymorphic portion D4Z4 encoding the protein DUX4. This leads to disorders in DUX4 expression, changes in myogenic gene expression, suppression of muscle cell differentiation and inhibition of muscle formation.
FSHD and another form of muscular dystrophy, the Emery-Dreifuss muscular dystrophy (EDMD), show phenotypic similarities in the severity of the disease, despite different genetic causes. In previous studies, the nuclear envelope of EDMD myoblasts showed morphological abnormalities. Other studies revealed morphological changes in the mitochondria of FSHD patients.
Therefore, electron micrographs of the nuclear envelope and mitochondria of FSHD myoblasts were performed and compared to the corresponding control.
For this purpose, three different pairs of myoblasts were used in different passages, that is, different numbers of subcultures, with increased morphological atypia being observed in the higher passages.
The cell lines used differentiate by several parameters such as age and sex of the patients. There were differences between the control cells as well as between the FSHD myoblasts.
Two different fixation methods were used in sample preparation for electron microscopy: conventional chemical fixation, drainage and flat embedding of cultured cells and high-pressure freezing with subsequent freeze substitution. In terms of the quality of structure preservation achieved in high pressure freezing, this type of fixation is attributed superiority over all other methods. This general statement cannot be completely applied to the investigations on the myoblasts.
For the investigation of the nuclear membranes both methods are suitable, whereby the distance between inner and outer nuclear membrane after the HPF fixation was more sharply mapped. In the representation of mitochondria, the electron micrographs after high pressure freezing showed better and sharper results. The nuclear pores were easily recognizable in both fixation methods.
When comparing the healthy and diseased myoblasts, the control cells showed significantly less abnormalities than the myoblasts of FSHD patients.
The inner and outer nuclear membrane were mostly parallel in the control cells, and the mitochondria in most cases showed a typical worm-like elongated form with cristae. This was true for both conventional fixation and high pressure freezing.
FSHD myoblasts exhibited marked abnormalities in mitochondrial morphology compared to controls in both fixation methods. In addition to an often wide range of variation in shape and length there was also noted the partial absence of cristae.
When looking at the nuclear envelope, however, there were clear differences between conventional and HPF fixation. The outer nuclear membrane of the conventionally fixed FSHD myoblasts was irregular and wavy. In contrast, the nuclear envelope of HPF fixed diseased myoblasts showed an astonishingly parallel course.
Since in EDMD changes in the diseased cells were also noticeable by fluorescence microscopy, in addition to the methods of electron microscopy, the presence and distribution of various proteins in FSHD myoblasts was examined by indirect immunofluorescence and compared with the control cells.
To assess the nuclear envelope, antibodies against lamin A/C and nucleoporins were used. The mitochondria were examined using the antibody ANT1 / 2, which binds to the adenine nucleotide translocator of the inner mitochondrial membrane.
In contrast to the studies on EDMD myoblasts, the lamins A and C as well as the nuclear pores were detectable and evenly distributed both in the myoblasts of the FSHD patients and in the control cells.
Indirect immunofluorescence with ANT1 / 2 showed differences between the investigated myoblasts.
The present results suggest that the myoblasts of FSHD patients have changes in mitochondria. The investigations of the nuclear envelope provide different results depending on the fixation method.
KW  - Landouzy-Déjerine-Atrophie
KW  - Facioscapulohumeral muscular dystrophy
KW  - Myoblast
KW  - Morphologie <Biologie>
KW  - FSHD
KW  - myoblast
KW  - Myoblasten
KW  - HPF
KW  - morphology
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-156676
ER  - 
TY  - JOUR
A1  - Silwedel, Christine
A1  - Haarmann, Axel
A1  - Fehrholz, Markus
A1  - Claus, Heike
A1  - Speer, Christian P.
A1  - Glaser, Kirsten
T1  - More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells
JF  - Journal of Neuroinflammation
N2  - Background
Ureaplasma species (spp.) are commonly regarded as low-virulent commensals but may cause invasive diseases in immunocompromised adults and in neonates, including neonatal meningitis. The interactions of Ureaplasma spp. with host defense mechanisms are poorly understood. This study addressed Ureaplasma-driven cell death, concentrating on apoptosis as well as inflammatory cell death.

Methods
Human brain microvascular endothelial cells (HBMEC) were exposed to Ureaplasma (U.) urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). Resulting numbers of dead cells as well as mRNA levels and enzyme activity of key agents in programmed cell death were assessed by flow cytometry, RNA sequencing, and qRT-PCR, respectively. xCELLigence data were used for real-time monitoring of changes in cell adhesion properties.

Results
Both Ureaplasma isolates induced cell death (p < 0.05, vs. broth). Furthermore, Ureaplasma spp. enhanced mRNA levels for genes in apoptosis, including caspase 3 (Up3 p < 0.05, vs. broth), caspase 7 (p < 0.01), and caspase 9 (Up3 p < 0.01). Caspase 3 activity was increased upon Uu8 exposure (p < 0.01). Vice versa, Ureaplasma isolates downregulated mRNA levels for proteins involved in inflammatory cell death, namely caspase 1 (Uu8 p < 0.01, Up3 p < 0.001), caspase 4 (Uu8 p < 0.05, Up3 p < 0.01), NOD-like receptor pyrin domain-containing 3 (Uu8 p < 0.05), and receptor-interacting protein kinase 3 (p < 0.05).

Conclusions
By inducing apoptosis in HBMEC as main constituents of the blood-brain barrier, Ureaplasma spp. may provoke barrier breakdown. Simultaneous suppression of inflammatory cell death may additionally attenuate host defense strategies. Ultimate consequence could be invasive and long-term CNS infections by Ureaplasma spp.
KW  - Ureaplasma urealyticum
KW  - Ureaplasma parvum
KW  - Neuroinflammation
KW  - Meningitis
KW  - Caspase
KW  - Apoptosis
KW  - HBMEC
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200711
VL  - 16
ER  - 
TY  - JOUR
A1  - Arlotti, Mattia
A1  - Palmisano, Chiara
A1  - Minafra, Brigida
A1  - Todisco, Massimiliano
A1  - Pacchetti, Claudio
A1  - Canessa, Andrea
A1  - Pozzi, Nicoló G.
A1  - Cilia, Roberto
A1  - Prenassi, Marco
A1  - Marceglia, Sara
A1  - Priori, Alberto
A1  - Rampini, Paolo
A1  - Barbieri, Sergio
A1  - Servello, Domenico
A1  - Volkmann, Jens
A1  - Pezzoli, Gianni
A1  - Isaias, Ioannis U.
T1  - Monitoring subthalamic oscillations for 24 hours in a freely moving Parkinson's disease patient
JF  - Movement Disorders
N2  - No abstract available
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221249
VL  - 34
ER  - 
TY  - JOUR
A1  - Jarius, Sven
A1  - Kleiter, Ingo
A1  - Ruprecht, Klemens
A1  - Asgari, Nasrin
A1  - Pitarokoili, Kalliopi
A1  - Borisow, Nadja
A1  - Hümmert, Martin W.
A1  - Trebst, Corinna
A1  - Pache, Florence
A1  - Winkelmann, Alexander
A1  - Beume, Lena-Alexandra
A1  - Ringelstein, Marius
A1  - Stich, Oliver
A1  - Aktas, Orhan
A1  - Korporal-Kuhnke, Mirjam
A1  - Schwarz, Alexander
A1  - Lukas, Carsten
A1  - Haas, Jürgen
A1  - Fechner, Kai
A1  - Buttmann, Mathias
A1  - Bellmann-Strobl, Judith
A1  - Zimmermann, Hanna
A1  - Brandt, Alexander U.
A1  - Franciotta, Diego
A1  - Schanda, Kathrin
A1  - Paul, Friedemann
A1  - Reindl, Markus
A1  - Wildemann, Brigitte
T1  - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 3: Brainstem involvement - frequency, presentation and outcome
JF  - Journal of Neuroinflammation
N2  - Background
Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) are present in a subset of aquaporin-4 (AQP4)-IgG-negative patients with optic neuritis (ON) and/or myelitis. Little is known so far about brainstem involvement in MOG-IgG-positive patients.

Objective
To investigate the frequency, clinical and paraclinical features, course, outcome, and prognostic implications of brainstem involvement in MOG-IgG-positive ON and/or myelitis.

Methods
Retrospective case study.

Results
Among 50 patients with MOG-IgG-positive ON and/or myelitis, 15 (30 %) with a history of brainstem encephalitis were identified. All were negative for AQP4-IgG. Symptoms included respiratory insufficiency, intractable nausea and vomiting (INV), dysarthria, dysphagia, impaired cough reflex, oculomotor nerve palsy and diplopia, nystagmus, internuclear ophthalmoplegia (INO), facial nerve paresis, trigeminal hypesthesia/dysesthesia, vertigo, hearing loss, balance difficulties, and gait and limb ataxia; brainstem involvement was asymptomatic in three cases. Brainstem inflammation was already present at or very shortly after disease onset in 7/15 (47 %) patients. 16/21 (76.2 %) brainstem attacks were accompanied by acute myelitis and/or ON. Lesions were located in the pons (11/13), medulla oblongata (8/14), mesencephalon (cerebral peduncles; 2/14), and cerebellar peduncles (5/14), were adjacent to the fourth ventricle in 2/12, and periaqueductal in 1/12; some had concomitant diencephalic (2/13) or cerebellar lesions (1/14). MRI or laboratory signs of blood-brain barrier damage were present in 5/12. Cerebrospinal fluid pleocytosis was found in 11/14 cases, with neutrophils in 7/11 (3-34 % of all CSF white blood cells), and oligoclonal bands in 4/14. Attacks were preceded by acute infection or vaccination in 5/15 (33.3 %). A history of teratoma was noted in one case. The disease followed a relapsing course in 13/15 (87 %); the brainstem was involved more than once in 6. Immunosuppression was not always effective in preventing relapses. Interferon-beta was followed by new attacks in two patients. While one patient died from central hypoventilation, partial or complete recovery was achieved in the remainder following treatment with high-dose steroids and/or plasma exchange. Brainstem involvement was associated with a more aggressive general disease course (higher relapse rate, more myelitis attacks, more frequently supratentorial brain lesions, worse EDSS at last follow-up).

Conclusions
Brainstem involvement is present in around one third of MOG-IgG-positive patients with ON and/or myelitis. Clinical manifestations are diverse and may include symptoms typically seen in AQP4-IgG-positive neuromyelitis optica, such as INV and respiratory insufficiency, or in multiple sclerosis, such as INO. As MOG-IgG-positive brainstem encephalitis may take a serious or even fatal course, particular attention should be paid to signs or symptoms of additional brainstem involvement in patients presenting with MOG-IgG-positive ON and/or myelitis.
KW  - Myelin oligodendrocyte glycoprotein (MOG) antibodies
KW  - MOG-IgG
KW  - Neuromyelitis optica spectrum disorders (NMOSD)
KW  - Brainstem encephalitis
KW  - Rhombencephalitis
KW  - Optic neuritis
KW  - Myelitis
KW  - Longitudinally extensive transverse myelitis (LETM)
KW  - Cerebellitis
KW  - Ataxia
KW  - Respiratory insufficiency
KW  - Intractable nausea and vomiting
KW  - Facial nerve palsy
KW  - Diplopia Internuclear ophthalmoplegia (INO)
KW  - Hearing loss
KW  - Aquaporin-4 antibodies (AQP4-Ig, NMO-IgG)G
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165543
VL  - 13
IS  - 281
ER  - 
TY  - JOUR
A1  - Jarius, Sven
A1  - Ruprecht, Klemens
A1  - Kleiter, Ingo
A1  - Borisow, Nadja
A1  - Asgari, Nasrin
A1  - Pitarokoili, Kalliopi
A1  - Pache, Florence
A1  - Stich, Oliver
A1  - Beume, Lena-Alexandra
A1  - Hümmert, Martin W.
A1  - Ringelstein, Marius
A1  - Trebst, Corinna
A1  - Winkelmann, Alexander
A1  - Schwarz, Alexander
A1  - Buttmann, Mathias
A1  - Zimmermann, Hanna
A1  - Kuchling, Joseph
A1  - Franciotta, Diego
A1  - Capobianco, Marco
A1  - Siebert, Eberhard
A1  - Lukas, Carsten
A1  - Korporal-Kuhnke, Mirjam
A1  - Haas, Jürgen
A1  - Fechner, Kai
A1  - Brandt, Alexander U.
A1  - Schanda, Kathrin
A1  - Aktas, Orhan
A1  - Paul, Friedemann
A1  - Reindl, Markus
A1  - Wildemann, Brigitte
T1  - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome
JF  - Journal of Neuroinflammation
N2  - Background
A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).

Objective
To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.

Methods
Retrospective multicenter study.

Results
The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk’s 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases.

Conclusion
Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course and the short median time to second attack support the use of prophylactic long-term treatments in patients with MOG-IgG-positive ON and/or myelitis.
KW  - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG)
KW  - Aquaporin-4 antibodies (AQP4-IgG, NMO-IgG)
KW  - Optic neuritis
KW  - Transverse myelitis
KW  - Longitudinally extensive transverse myelitis
KW  - Magnetic resonance imaging
KW  - Autoantibodies
KW  - Neuromyelitis optica spectrum disorders (NMOSD)
KW  - Cerebrospinal fluid
KW  - Oligoclonal bands
KW  - Electrophysiology
KW  - Evoked potentials
KW  - Treatment
KW  - Therapy
KW  - Methotrexate
KW  - Azathioprine
KW  - Rituximab
KW  - Ofatumumab
KW  - Interferon beta
KW  - Glatiramer acetate
KW  - Natalizumab
KW  - Outcome
KW  - Pregnancy
KW  - Infections
KW  - Vaccination
KW  - Multiple sclerosis
KW  - Barkhof criteria
KW  - McDonald criteria
KW  - Wingerchuk criteria 2006 and 2015
KW  - IPND criteria
KW  - International consensus diagnostic criteria for neuromyelitis optica spectrum disorders
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165570
VL  - 13
IS  - 280
ER  - 
TY  - JOUR
A1  - Jarius, Sven
A1  - Ruprecht, Klemens
A1  - Kleiter, Ingo
A1  - Borisow, Nadja
A1  - Asgari, Nasrin
A1  - Pitarokoili, Kalliopi
A1  - Pache, Florence
A1  - Stich, Oliver
A1  - Beume, Lena-Alexandra
A1  - Hümmert, Martin W.
A1  - Trebst, Corinna
A1  - Ringelstein, Marius
A1  - Aktas, Orhan
A1  - Winkelmann, Alexander
A1  - Buttmann, Mathias
A1  - Schwarz, Alexander
A1  - Zimmermann, Hanna
A1  - Brandt, Alexander U.
A1  - Franciotta, Diego
A1  - Capobianco, Marco
A1  - Kuchling, Joseph
A1  - Haas, Jürgen
A1  - Korporal-Kuhnke, Mirjam
A1  - Lillevang, Soeren Thue
A1  - Fechner, Kai
A1  - Schanda, Kathrin
A1  - Paul, Friedemann
A1  - Wildemann, Brigitte
A1  - Reindl, Markus
T1  - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin
JF  - Journal of Neuroinflammation
N2  - Background
Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders.

Objective
To assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers.

Methods
614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells.

Results
MOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7%) patients with a history of both ON and myelitis, 22/103 (21.4%) with a history of ON but no myelitis and 6/45 (13.3%) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67%) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89%) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment.

Conclusions
To date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.
KW  - Neuromyelitis optica (NMO)
KW  - Devic’s syndrome
KW  - Optic neuritis
KW  - Transverse Myelitis
KW  - Longitudinally extensive transverse myelitis (LETM)
KW  - Neuromyelitis optica spectrum disorders (NMOSD)
KW  - Multiple sclerosis
KW  - Autoantibodies
KW  - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG)
KW  - Neuromyelitis optica antibodies (NMO-IgG)
KW  - Aquaporin-4 antibodies (AQP4-IgG)
KW  - Cell-based assays
KW  - Cerebrospinal fluid
KW  - Antibody index
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165659
VL  - 13
IS  - 279
ER  - 
TY  - THES
A1  - Merzyn, Cornelia
T1  - Modulation systemischer Chemokinspiegel durch rekombinantes Interferon-beta bei Patienten mit multipler Sklerose
T1  - Modulation of systemic chemokine levels by recombinant interferon-beta in patients with multiple sclerosis
N2  - Multiple Sklerose (MS) ist eine chronisch-entzündliche Erkrankung des Zentralen Nervensystems mit deutlich ausgeprägten Autoimmunphänomenen. Das derzeit meistverwendete Therapeutikum zur Sekundärprophylaxe von Krankheitsschüben ist rekombinantes Interferon-&#946; (IFN-&#946;). Wirk- und Nebenwirkungsmechanismen des Medikaments werden bisher nur partiell verstanden. In der Pathogenese der MS spielt eine Familie chemotaktisch wirksamer Zytokine, der Chemokine, eine entscheidende Rolle. Ziel dieser Studie war zu untersuchen, ob IFN-&#946; die systemischen Konzentrationen der Pathogenese-relevanten Chemokine CXCL10, CCL2 und außerdem des endogenen Pyrogens IL-6 verändert, und ob diese Veränderungen mit dem Auftreten grippeartiger Nebenwirkungen korrelieren. Zu diesem Zweck wurden bei 37 Patienten mit schubförmiger MS zu drei Zeitpunkten – vor sowie 6 und 24 Stunden nach der Applikation von IFN-&#946; – die genannten Botenstoffe im Blut bestimmt. Parallel wurden subjektiv empfundene grippeartige Nebenwirkungen mit Hilfe eines standardisierten Fragebogens abgefragt, und die Körperkerntemperatur wurde gemessen. Als Kontrollen dienten gesunde Probanden, derzeit nicht immunmodulatorisch behandelte MS-Patienten und MS-Patienten unter Therapie mit Glatirameracetat. Nur bei den mit IFN-&#946; behandelten Patienten zeigte sich nach 6 Stunden ein signifikanter transienter Anstieg der Konzentrationen von CXCL10, CCL2. Der Anstieg der Chemokinkonzentrationen korrelierte mit einem transienten IL-6-Anstieg und dem Auftreten grippeartiger Nebenwirkungen. Chemokine, unter denen sich zahlreiche starke endogene Pyrogene befinden, könnten somit für die häufig zu beobachtenden grippeartigen Nebenwirkungen mit verantwortlich sein. Die Ergebnisse werfen die weiterführende Frage auf, ob die beobachtete Chemokininduktion auch relevant für den therapeutischen Effekt von IFN-&#61538; ist. Ob Chemokine sich erfolgreich als Biomarker zur Prädiktion des Therapieerfolgs einsetzen lassen, wird derzeit in einem weiterführenden Projekt untersucht.
N2  - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with clear autoimmune phenomena. Recombinant Interferon-&#946; (IFN-&#946;) is currently the most widely used treatment to prevent relapses. The mechanisms and side effects of the drug are only partially understood. A family of chemotactical active cytokines, the chemokines, play a decisive role in the pathogenesis of MS. The aim of this study was to examine if IFN-&#946; alters the systemic concentrations of CXCL10 and CCL2, two chemokines that are relevant in the pathogenesis, and of IL-6, an endogenous pyrogen. A further aim was to discover whether these concentrations correlate with the appearance of flu-like symptoms, a common adverse effect of IFN-&#946;. 37 patients with relapsing-remitting MS were tested three times to measure the chemokine concentrations in their blood – prior to IFN-&#946; application, and again 6 and 24 hours after application. Concurrently, the occurrence of flu-like symptoms was recorded with the help of a standardized questionnaire and through body temperature measurements. The control groups consisted of healthy subjects, MS patients not receiving any treatment, and MS patients treated with glatiramer acetate. After 6 hours, only the MS patients treated with IFN-&#946; showed a significant transient elevation in the concentrations of CXCL10 and CCL2. This elevation correlated with a transient increase in the IL-6 concentration and the appearance of flu-like symptoms. Among the chemokines there are many strong endogenous pyrogens, which might be responsible for the commonly observed, flu-like side effects of IFN-&#946;. The results raise the question of whether the observed induction of chemokines is also relevant for the therapeutic effect of IFN-&#946;. Whether chemokines can be used as biomarkers to predict therapeutic success is currently being explored in ongoing work built upon this study.
KW  - Multiple Sklerose
KW  - Interferon <beta->
KW  - Chemokine
KW  - CCL2
KW  - CXCL10
KW  - CCL2
KW  - CXCL10
Y1  - 2008
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-35828
ER  - 
TY  - THES
A1  - Nehen, Mathias Julius
T1  - Modulation der Schrankenfunktion primärer humaner zerebraler Endothelzellen durch Fumarsäureester unter inflammatorischen und nicht-inflammatorischen Bedingungen
T1  - Fumaracids modulation on the barrier of primary human cerebral endothelia cells in inflammatory and non-imflammatory conditions
N2  - Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbemühungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament für die schubförmige Multiple Sklerose zugelassen. Die Wirkungen von Fumarsäureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht.
Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumarsäureestern auf die Adhäsion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine Übertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres möglich. Daher galt es potentielle Effekte von Fumarsäureestern auf primäre humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu überprüfen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS Läsionen zu finden ist. In Leukozyten-Adhäsionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adhäsion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adhäsionsmoleküls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazelluläre Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumarsäureester ebenso wenig beeinflusst. 
Diese in sich konsistenten Ergebnisse führen zu der Schlussfolgerung, dass im Gegensatz zu anderen Gefäßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken.
N2  - Dimethyl fumarate (DMF) is approved for disease-modifying treatment of patients with relapsing-remitting multiple sclerosis. Animal experiments suggested that part of its therapeutic effect is due to a reduction of T-cell infiltration of the central nervous system (CNS) by uncertain mechanisms. Here we evaluated whether DMF and its primary metabolite monomethyl fumarate (MMF) modulate pro-inflammatory intracellular signaling and T-cell adhesiveness of nonimmortalized single donor human brain microvascular endothelial cells at low passages. Neither DMF nor MMF at concentrations of 10 or 50 μM blocked the IL-1β-induced nuclear translocation of NF-κB/p65, whereas the higher concentration of DMF inhibited the nuclear entry of p65 in human umbilical vein endothelium cultured in parallel. DMF and MMF also did not alter the IL-1β-stimulated activation of p38 MAPK in brain endothelium. Furthermore, neither DMF nor MMF reduced the basal or IL-1β-inducible expression of ICAM-1. In accordance, both fumaric acid esters did not reduce the adhesion of activated Jurkat T cells to brain endothelium under basal or inflammatory conditions. Therefore, brain endothelial cells probably do not directly mediate a potential blocking effect of fumaric acid esters on the inflammatory infiltration of the CNS by T cells.
KW  - Multiple Sklerose
KW  - Blut-Hirn-Schranke
KW  - Dimethylfumarat
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240925
ER  - 
TY  - JOUR
A1  - Kress, Michaela
A1  - Hüttenhofer, Alexander
A1  - Landry, Marc
A1  - Kuner, Rohini
A1  - Favereaux, Alexandre
A1  - Greenberg, David
A1  - Bednarik, Josef
A1  - Heppenstall, Paul
A1  - Kronenberg, Florian
A1  - Malcangio, Marzia
A1  - Rittner, Heike
A1  - Üçeyler, Nurcan
A1  - Trajanoski, Zlatko
A1  - Mouritzen, Peter
A1  - Birklein, Frank
A1  - Sommer, Claudia
A1  - Soreq, Hermona
T1  - microRNAs in nociceptive circuits as predictors of future clinical applications
JF  - Frontiers in Molecular Neuroscience
N2  - Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs – and microRNAs (miRNAs) in particular – regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.
KW  - chronic pain
KW  - biomarker
KW  - polymorphism
KW  - miRNA-based diagnostics
KW  - miRNA expression patterns
KW  - miRNA polymorphisms
KW  - antagomir
KW  - miRNA-based analgesic
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154597
VL  - 6
IS  - 33
ER  - 
TY  - THES
A1  - Leinders, Mathias
T1  - microRNAs in chronic pain
T1  - microRNAs bei chronischen Schmerzen
N2  - Chronic pain is a common problem in clinical practice, not well understood clinically, and frequently tough to satisfactorily diagnose. Because the pathophysiology is so complex, finding effective treatments for people with chronic pain has been overall less than successful and typically reduced to an unsatisfactory trial-and-error process, all of which translates into a significant burden to society. Knowledge of the mechanisms underlying the development of chronic pain, and moreover why some patients experience pain and others not, may aid in developing specific treatment regimens. Although nerve injuries are major contributors to pain chronification, they cannot explain the entire phenomenon. Considerable research has underscored the importance of the immune system for the development and maintenance of chronic pain, albeit the exact factors regulating inflammatory reactions remain unclear. Understanding the putative molecular and cellular regulator switches of inflammatory reactions will open novel opportunities for immune modulatory analgesics with putatively higher specificity and less adverse effects. It has become clear that small, non- coding RNA molecules known as microRNAs are in fact potent regulators of many thousands of genes and possibly cross-communicate between cellular pathways in multiple systems acting as so-called “master-switches”. Aberrant expression of miRNAs is now implicated in numerous disorders, including nerve injuries as well as in inflammatory processes. Moreover, compelling evidence supports the idea that miRNAs also regulate pain, and in analogy to the oncology field aid in the differential diagnosis of disease subtypes. In fact, first reports describing characteristic miRNA expression profiles in blood or cerebrospinal fluid of patients with distinct pain conditions are starting to emerge, however evidence linking specific miRNA expression profiles to specific pain disorders is still insufficient. The present thesis aimed at first, identifying specific miRNA signatures in two distinct chronic pain conditions, namely peripheral neuropathies of different etiologies and fibromyalgia syndrome. Second, it aimed at identifying miRNA profiles to better understand potential factors that differentiate painful from painless neuropathies and third, study the mechanistic role of miRNAs in the pathophysiology of pain, to pave the way for new druggable targets.
Three studies were conducted in order to identify miRNA expression signatures that are characteristic for the given chronic pain disorder. The first study measured expression of miR-21, miR-146a and miR-155 in white blood cells, skin and nerve biopsies of patients with peripheral neuropathies. It shows that peripheral neuropathies of different etiologies are associated with increased peripheral miR-21 and miR-146a, but decreased miR-155 expression. More importantly, it was shown that painful neuropathies have increased sural nerve miR-21 and miR-155 expression, but reduced miR-146a and miR-155 expression in distal skin of painful neuropathies. These results point towards the potential use of miRNAs profiles to stratify painful neuropathies. The seconds study extends these findings and first analyzed the role of miR-132-3p in patients and subsequently in an animal model of neuropathic pain. Interestingly, miR-132-3p was upregulated in white blood cells and sural nerve biopsies of patients with painful neuropathies and in animals after spared nerve injury. Pharmacologically modulating the expression of miR-132-3p dose-dependently reversed pain behavior and pain aversion, indicating the pro-nociceptive effect of miR-132-3p in chronic pain. This study thus demonstrates the potential analgesic impact by modulating miRNA expression. Fibromyalgia is associated with chronic widespread pain and, at least in a subgroup, impairment in small nerve fiber morphology and function. Interestingly, the disease probably comprises subgroups with different underlying pathomechanisms. In accordance with this notion, the third study shows that fibromyalgia is associated with both aberrant white blood cell and cutaneous miRNA expression. Being the first of its kind, this study identified miR-let-7d and its downstream target IGF-1R as potential culprit for impaired small nerve fiber homeostasis in a subset of patients with decreased intra-epidermal nerve fiber density. The work presented in this thesis is a substantial contribution towards the goal of better characterizing chronic pain based on miRNA expression signatures and thus pave the way for new druggable targets.
N2  - Chronische Schmerzen sind in der klinischen Praxis ein häufiges Problem, die
Ätiologie und Pathogenese jedoch oftmals unklar. Aufgrund der Komplexität des pathophysiologischen 
Ursprunges chronischer Schmerzen, ist bei einem Teil der Patienten Schmerzfreiheit oder 
Schmerzreduktion mit gängigen Analgetika nur insuffizient zu erreichen. Dies führt zu einer enormen 
sozio-ökonomischen Belastung für die Gesellschaft. Daher können Kenntnisse über  die Mechanismen, 
die der Entwicklung von chronischen Schmerzen zugrunde liegen, und darüber hinaus, warum einige 
Patienten Schmerzen entwickeln und andere nicht, bei der Entwicklung spezifischer und individueller 
Behandlungsschemata helfen. Eine Vielzahl an Studien belegen die Bedeutung des Immunsystems für die 
Entwicklung und Aufrechterhaltung chronischer Schmerzen, wenngleich die genauen Faktoren, die 
entzündliche Reaktionen regulieren, noch unklar bleiben. Rezente Entdeckungen der 
hochkonservierten, nicht-kodierenden RNA-Moleküle, sogenannten microRNAs, lassen in der Tat darauf 
schließen, dass diese eine wichtige Rolle im Netzwerk der Genregulation spielen. microRNAs 
regulieren die hochspezifische „cross-communication“ mehrerer simultaner 
Signaltransduktionsvorgänge zellulärer Prozesse, und werden daher auch "master-switches" genannt. 
Interessanterweise, wurden aberrante Expressionen spezifischer miRNAs in zahlreichen Krankheiten, 
einschließlich Nervenverletzungen, sowie in entzündlichen Prozessen nachgewiesen. Darüber hinaus 
belegen stichhaltige Beweise nicht nur die Idee, dass miRNAs auch bei der Regulierung von Schmerzen 
eine wichtige Rolle spielen, sondern auch hilfreich bei der Differentialdiagnose von Krankheits- 
Subtypen sein können. Dies wurde bei rezenten onkologischen Studien deutlich. Tatsächlich weisen 
erste Berichte auf ein charakteristisches miRNA- Expressionsprofil   in   Blut   oder   
Zerebrospinalflüssigkeit   von   Patienten   mit verschiedenen  Schmerztypen  hin.  Jedoch  ist  die  Assoziation  spezifischer
miRNA-Expressionsprofile mit spezifischen Schmerzstörungen noch unzureichend. Die Zielvorgabe der 
vorliegenden Arbeit war daher zunächst, spezifische miRNA-Signaturen in zwei verschiedenen 
chronischen Schmerzzuständen zu identifizieren, nämlich peripheren Neuropathien verschiedener 
Ätiologien und dem Fibromyalgie-Syndrom. Zweitens wurden die erarbeiteten Ergebnisse dazu 
verwendet, bestimmte miRNA-Profile zu identifizieren, die schmerzhafte von schmerzlosen 
Neuropathien unterscheiden lassen und einen Hinweis auf die Pathologie der kleinkalibrigen Fasern 
bei der Fibromyalgie geben. Darüber hinaus wurde die mechanistische Rolle von miRNAs in der 
Pathophysiologie von Schmerzen Tierexperimentell untersucht, um künftig neuartige Therapien 
entwickeln zu können.
Die erste Studie untersuchte die Expression von miR-21, miR-146a und miR-155 in weißen 
Blutkörperchen, Haut- und Nervenbiopsien bei Patienten mit peripheren Neuropathien. Sie zeigt, dass 
periphere Neuropathien verschiedener Ätiologien mit erhöhten peripheren miR-21 und miR-146a und 
verminderter miR-
155 Expression assoziiert sind. Wichtiger jedoch, dass Patienten mit schmerzhaften Neuropathien 
erhöhte miR-21 und miR-155-Expression im Suralis und verminderte miR-146a- und miR-155-Expression 
in distalen im Vergleich zu proximalen Hautbiopsien aufweisen. Diese Ergebnisse weisen auf die 
potenzielle Verwendung von miRNA-Profilen zur Stratifizierung schmerzhafter Neuropathien hin. Die 
zweite Studie baut dieses Ergebnis aus und untersuchte zunächst die Rolle von miR-132-3p im humanen 
und anschließend bei tierexperimentellen neuropathischen Schmerzen. Interessanterweise war 
miR-132-3p sowohl in weißen Blutkörperchen und Suralis-Nervenbiopsien von Patienten mit 
schmerzhaften Neuropathien als auch bei Tieren nach Läsion eines peripheren Nervens hochreguliert. 
Nach pharmakologischer Intervention gab es eine dosisabhängige Schmerzreduktion und 
Schmerzaversion, was somit auf den pro- nozizeptiven Effekt von miR-132-3p hinweist. Diese Studie 
zeigt somit die potenzielle analgetische Wirksamkeit microRNA-gerichteter pharmakologischer
Interventionen. Das Fibromyalgie Syndrome ist  eine chronische Erkrankung, die von  einem  multilokulären  Schmerzbild  und  Beeinträchtigungen  in  kleinen
Nervenfasern dominiert wird. Es wird angenommen, dass die Erkrankung wahrscheinlich aus Subgruppen 
mit unterschiedlichen zugrunde liegenden Pathomechanismen besteht. Die hierzu durchgeführte Studie 
zeigt, dass Fibromyalgie-Patienten veränderte microRNA Expression sowohl in weißen Blutkörperchen 
als auch in der Haut aufweisen. Erstmals identifiziert diese Studie miR-let-7d und ihr 
„downstream-target“ IGF-1R als potentiellen Schädigungsmechanismus kleiner Nervenfaserfunktionen, 
in einer Subgruppe von Patienten mit verminderter intra-epidermalen Nervenfaserdichte. Die 
Ergebnisse, die in dieser Arbeit vorgestellt werden, liefern einen wesentlichen Beitrag,  die  
Pathophysiologie  chronischer  Schmerzen,  aufgrund  von  miRNA-Expressions-Signaturen zu charakterisieren.
KW  - chronic pain
KW  - microRNA
KW  - miRNS
KW  - Chronischer Schmerz
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144395
ER  -