TY - JOUR A1 - Isaias, Ioannis U. A1 - Trujillo, Paula A1 - Summers, Paul A1 - Marotta, Giorgio A1 - Mainardi, Luca A1 - Pezzoli, Gianni A1 - Zecca, Luigi A1 - Costa, Antonella T1 - Neuromelanin Imaging and Dopaminergic Loss in Parkinson's Disease JF - Frontiers in Aging Neuroscience N2 - Parkinson's disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the substantia nigra. Our main objective was to determine the correspondence between changes in the substantia nigra, evident in neuromelanin and iron sensitive magnetic resonance imaging (MRI), and dopaminergic striatal innervation loss in patients with PD. Eighteen patients and 18 healthy control subjects were included in the study. Using neuromelanin-MRI, we measured the volume of the substantia nigra and the contrast-to-noise-ratio between substantia nigra and a background region. The apparent transverse relaxation rate and magnetic susceptibility of the substantia nigra were calculated from dual-echo MRI. Striatal dopaminergic innervation was measured as density of dopamine transporter (DAT) by means of single-photon emission computed tomography and [123I] N-ω-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) tropane. Patients showed a reduced volume of the substantia nigra and contrast-to-noise-ratio and both positively correlated with the corresponding striatal DAT density. The apparent transverse relaxation rate and magnetic susceptibility values of the substantia nigra did not differ between patients and healthy controls. The best predictor of DAT reduction was the volume of the substantia nigra. Clinical and imaging correlations were also investigated for the locus coeruleus. Our results suggest that neuromelanin-MRI can be used for quantifying substantia nigra pathology in PD where it closely correlates with dopaminergic striatal innervation loss. Longitudinal studies should further explore the role of Neuromelanin-MRI as an imaging biomarker of PD, especially for subjects at risk of developing the disease. KW - MRI KW - neuromelanin KW - dopamine KW - Parkinson's disease KW - FP-CIT SPECT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164046 VL - 8 IS - 196 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 - JOUR A1 - Contarino, Maria Fiorella A1 - Smit, Marenka A1 - van den Dool, Joost A1 - Volkmann, Jens A1 - Tijssen, Marina A. J. T1 - Unmet Needs in the Management of Cervical Dystonia JF - Frontiers in Neurology N2 - Cervical dystonia (CD) is a movement disorder which affects daily living of many patients. In clinical practice, several unmet treatment needs remain open. This article focuses on the four main aspects of treatment. We describe existing and emerging treatment approaches for CD, including botulinum toxin injections, surgical therapy, management of non-motor symptoms, and rehabilitation strategies. The unsolved issues regarding each of these treatments are identified and discussed, and possible future approaches and research lines are proposed. KW - cervical dystonia KW - botulinum toxin KW - deep brain stimulation KW - physical therapy modalities KW - non-motor features Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165225 VL - 7 IS - 165 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Biko, Lydia A1 - Hose, Dorothea A1 - Hoffmann, Lukas A1 - Sommer, Claudia T1 - Comprehensive and differential long-term characterization of the alpha-galactosidase A deficient mouse model of Fabry disease focusing on the sensory system and pain development JF - Molecular Pain N2 - Fabry disease is an X-linked lysosomal storage disorder due to impaired activity of alpha-galactosidase A with intracellular accumulation of globotriaosylceramide. Associated small fiber pathology leads to characteristic pain in Fabry disease. We systematically assessed sensory system, physical activity, metabolic parameters, and morphology of male and female mice with alpha-galactosidase A deficiency (Fabry ko) from 2 to 27 months of age and compared results with those of age- and gender-matched wild-type littermates of C57Bl/6J background. Results From the age of two months, male and female Fabry mice showed mechanical hypersensitivity (p < 0.001 each) compared to wild-type littermates. Young Fabry ko mice of both genders were hypersensitive to heat stimulation (p < 0.01) and developed heat hyposensitivity with aging (p < 0.05), while cold hyposensitivity was present constantly in young (p < 0.01) and old (p < 0.05) Fabry ko mice compared to wild-type littermates. Stride angle increased only in male Fabry ko mice with aging (p < 0.01) in comparison to wild-type littermates. Except for young female mice, male (p < 0.05) and female (p < 0.01) Fabry ko mice had a higher body weight than wild-type littermates. Old male Fabry ko mice were physically less active than their wild-type littermates (p < 0.05), had lower chow intake (p < 0.001), and lost more weight (p < 0.001) in a one-week treadmill experiment than wild-type littermates. Also, Fabry ko mice showed spontaneous pain protective behavior and developed orofacial dysmorphism resembling patients with Fabry disease. Conclusions. Mice with alpha-galactosidase A deficiency show age-dependent and distinct deficits of the sensory system. alpha-galactosidase A-deficient mice seem to model human Fabry disease and may be helpful when studying the pathophysiology of Fabry-associated pain. KW - Fabry disease KW - alpha-galactosidase A KW - mouse model KW - pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147562 VL - 12 IS - 1744806916646370 ER - TY - JOUR A1 - Westermaier, Thomas A1 - Linsenmann, Thomas A1 - Homola, György A. A1 - Loehr, Mario A1 - Stetter, Christian A1 - Willner, Nadine A1 - Ernestus, Ralf-Ingo A1 - Soymosi, Laszlo A1 - Vince, Giles H. T1 - 3D rotational fluoroscopy for intraoperative clip control in patients with intracranial aneurysms – assessment of feasibility and image quality JF - BMC Medical Imaging N2 - Background Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. In this series, the image quality and value of intraoperative 3D fluoroscopy with intravenous contrast agent for the evaluation of aneurysm occlusion and vessel patency after clip placement was assessed in patients who underwent surgery for intracranial aneurysms. Materials and methods Twelve patients were included in this retrospective analysis. Prior to surgery, a 360° rotational fluoroscopy scan was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac® workstation, subtracted and reconstructed using OsiriX® free software. The procedure was repeated after clip placement. Both image sets were compared for assessment of aneurysm occlusion and vessel patency. Results Image acquisition and contrast administration caused no adverse effects. Image quality was sufficient to follow the patency of the vessels distal to the clip. Metal artifacts reduce the assessability of the immediate vicinity of the clip. Precise image subtraction and post-processing can reduce metal artifacts and make the clip-site assessable and depict larger neck-remnants. Conclusion This technique quickly supplies images at adequate quality to evaluate distal vessel patency after aneurysm clipping. Significant aneurysm remnants may be depicted as well. As it does not require visual control of all vessels that are supposed to be evaluated intraoperatively, this technique may be complementary to other intraoperative tools like indocyanine green videoangiography and micro-Doppler, especially for the assessment of larger aneurysms. At the momentary state of this technology, it cannot replace postoperative conventional angiography. However, 3D fluoroscopy and image post-processing are young technologies. Further technical developments are likely to result in improved image quality. KW - aneurysm surgery KW - clip control KW - angiography KW - 3D fluoroscopy KW - image quality KW - intraoperative KW - vessel patency KW - contrast KW - post-processing Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146381 VL - 16 IS - 30 ER - TY - JOUR A1 - Wolf, Karen A1 - Braun, Attila A1 - Haining, Elizabeth J. A1 - Tseng, Yu-Lun A1 - Kraft, Peter A1 - Schuhmann, Michael K. A1 - Gotru, Sanjeev K. A1 - Chen, Wenchun A1 - Hermanns, Heike M. A1 - Stoll, Guido A1 - Lesch, Klaus-Peter A1 - Nieswandt, Bernhard T1 - Partially Defective Store Operated Calcium Entry and Hem(ITAM) Signaling in Platelets of Serotonin Transporter Deficient Mice JF - PLoS One N2 - Background Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation. Objective To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke. Results In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice. Conclusion Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization. KW - platelets KW - serotonin KW - integrins KW - blood flow KW - collagens KW - platelet activation KW - platelet aggregation KW - ischemic stroke Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146399 VL - 11 IS - 1 ER - TY - JOUR A1 - Hopp, Sarah A1 - Albert-Weissenberger, Christiane A1 - Mencl, Stine A1 - Bieber, Michael A1 - Schuhmann, Michael K. A1 - Stetter, Christian A1 - Nieswandt, Bernhard A1 - Schmidt, Peter M. A1 - Monoranu, Camelia-Maria A1 - Alafuzoff, Irina A1 - Marklund, Niklas A1 - Nolte, Marc W. A1 - Sirén, Anna-Leena A1 - Kleinschnitz, Christoph T1 - Targeting coagulation factor XII as a novel therapeutic option in brain trauma JF - Annals of Neurology N2 - Objective: Traumatic brain injury is a major global public health problem for which specific therapeutic interventions are lacking. There is, therefore, a pressing need to identify innovative pathomechanism-based effective therapies for this condition. Thrombus formation in the cerebral microcirculation has been proposed to contribute to secondary brain damage by causing pericontusional ischemia, but previous studies have failed to harness this finding for therapeutic use. The aim of this study was to obtain preclinical evidence supporting the hypothesis that targeting factor XII prevents thrombus formation and has a beneficial effect on outcome after traumatic brain injury. Methods: We investigated the impact of genetic deficiency of factor XII and acute inhibition of activated factor XII with a single bolus injection of recombinant human albumin-fused infestin-4 (rHA-Infestin-4) on trauma-induced microvascular thrombus formation and the subsequent outcome in 2 mouse models of traumatic brain injury. Results: Our study showed that both genetic deficiency of factor XII and an inhibition of activated factor XII in mice minimize trauma-induced microvascular thrombus formation and improve outcome, as reflected by better motor function, reduced brain lesion volume, and diminished neurodegeneration. Administration of human factor XII in factor XII-deficient mice fully restored injury-induced microvascular thrombus formation and brain damage. Interpretation: The robust protective effect of rHA-Infestin-4 points to a novel treatment option that can decrease ischemic injury after traumatic brain injury without increasing bleeding tendencies. KW - Molecular-weight heparin KW - Thrombus formation KW - Cerebral-ischemia KW - in-vivo KW - Intravascular coagulation KW - Hemodynamic depression KW - Head-injury KW - Rats KW - Model KW - Mice Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188800 VL - 79 IS - 6 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Isaias, Ioannis U. A1 - Kusche-Tekin, Burak B. A1 - Klein, Dennis A1 - Groh, Janos A1 - O´Leary, Aet A1 - Knorr, Susanne A1 - Higuchi, Takahiro A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Toyka, Klaus V. A1 - Reif, Andreas A1 - Volkmann, Jens T1 - Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury JF - Acta Neuropathologica Communications N2 - Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia. KW - Dystonia KW - DYT1 KW - dopamine KW - peripheral injury KW - second hit Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147839 VL - 4 IS - 108 ER - TY - JOUR A1 - Korn, Thomas A1 - Kleinschnitz, Christoph A1 - Magnus, Tim A1 - Meuth, Sven G. A1 - Linker, Ralf A. T1 - Report on the 7th scientific meeting of the Association for the Advancement of Young Academics in Neurology (NEUROWIND e.V.) held in Motzen, Germany, October 30–November 1, 2015 JF - Experimental and Translational Stroke Medicine N2 - From October 30–November 1, 2015, the 7th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Seventy doctoral students and postdocs from over 25 different groups working in German and Swiss University Hospitals or Research Institutes attended the meeting to discuss their latest experiments and findings in the fields of neuroimmunology, neurodegeneration and neurovascular research. This meeting report summarizes the many diverse presentations and the new preclinical to clinical neurology research data that were shared by the participants at the meeting. KW - NEUROWIND Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146595 VL - 8 IS - 3 ER - TY - JOUR A1 - Israel, Ina A1 - Ohsiek, Andrea A1 - Al-Momani, Ehab A1 - Albert-Weissenberger, Christiane A1 - Stetter, Christian A1 - Mencl, Stine A1 - Buck, Andreas K. A1 - Kleinschnitz, Christoph A1 - Samnick, Samuel A1 - Sirén, Anna-Leena T1 - Combined [\(^{18}\)F]DPA-714 micro-positron emission tomography and autoradiography imaging of microglia activation after closed head injury in mice JF - Journal of Neuroinflammation N2 - Background Traumatic brain injury (TBI) is a major cause of death and disability. Neuroinflammation contributes to acute damage after TBI and modulates long-term evolution of degenerative and regenerative responses to injury. The aim of the present study was to evaluate the relationship of microglia activation to trauma severity, brain energy metabolism, and cellular reactions to injury in a mouse closed head injury model using combined in vivo PET imaging, ex vivo autoradiography, and immunohistochemistry. Methods A weight-drop closed head injury model was used to produce a mixed diffuse and focal TBI or a purely diffuse mild TBI (mTBI) in C57BL6 mice. Lesion severity was determined by evaluating histological damage and functional outcome using a standardized neuroscore (NSS), gliosis, and axonal injury by immunohistochemistry. Repeated intra-individual in vivo μPET imaging with the specific 18-kDa translocator protein (TSPO) radioligand [\(^{18}\)F]DPA-714 was performed on day 1, 7, and 16 and [\(^{18}\)F]FDG-μPET imaging for energy metabolism on days 2–5 after trauma using freshly synthesized radiotracers. Immediately after [\(^{18}\)F]DPA-714-μPET imaging on days 7 and 16, cellular identity of the [\(^{18}\)F]DPA-714 uptake was confirmed by exposing freshly cut cryosections to film autoradiography and successive immunostaining with antibodies against the microglia/macrophage marker IBA-1. Results Functional outcome correlated with focal brain lesions, gliosis, and axonal injury. [\(^{18}\)F]DPA-714-μPET showed increased radiotracer uptake in focal brain lesions on days 7 and 16 after TBI and correlated with reduced cerebral [\(^{18}\)F]FDG uptake on days 2–5, with functional outcome and number of IBA-1 positive cells on day 7. In autoradiography, [\(^{18}\)F]DPA-714 uptake co-localized with areas of IBA1-positive staining and correlated strongly with both NSS and the number of IBA1-positive cells, gliosis, and axonal injury. After mTBI, numbers of IBA-1 positive cells with microglial morphology increased in both brain hemispheres; however, uptake of [\(^{18}\)F]DPA-714 was not increased in autoradiography or in μPET imaging. Conclusions [\(^{18}\)F]DPA-714 uptake in μPET/autoradiography correlates with trauma severity, brain metabolic deficits, and microglia activation after closed head TBI. KW - neuroinflammation KW - TBI KW - immunohistochemistry KW - weight drop KW - PET KW - diffuse KW - focal KW - TSPO KW - autoradiography KW - IBA-1 Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146606 VL - 13 IS - 140 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 - TY - THES A1 - Hopp-Krämer, Sarah T1 - Untersuchungen zur Pathophysiologie und therapeutischer Relevanz des Blutgerinnungsfaktors XII nach experimentellem Schädel-Hirn-Trauma T1 - Studies on the pathophysiology and therapeutic relevance of the coagulation factor XII following experimental traumatic brain injury N2 - Das Schädel-Hirn-Trauma (SHT) entsteht durch äußere Gewalteinwirkung auf den Kopf und verursacht mechanisch eine Schädigung des Hirngewebes. Zusätzlich tragen sekundäre Pathomechanismen, wie Entzündungsprozesse und die Schädigung der Blut-Hirn-Schranke (BHS), dazu bei, dass sich das initial geschädigte Läsionsareal im Laufe der Zeit vergrößert. Vor allem bei jungen Erwachsenen ist das SHT eine der häufigsten Ursachen für bleibende Behinderungen und Todesfälle. Aufgrund der schweren Auswirkungen des SHT und der bislang fehlenden Therapieoptionen ist die Identifizierung neuer Zielstrukturen für eine kausale Therapie von größter Bedeutung. Ausgehend von tierexperimentellen Studien ist das Kallikrein-Kinin-System (KKS) ein besonders erfolgversprechender Angriffspunkt zur Behandlung des SHT. Die Aktivierung des KKS über den Gerinnungsfaktor XII (FXII) und die darauf folgende Bildung von Bradykinin sind mit dem Entstehen von Hirnödemen und Entzündungsreaktionen assoziiert. Vorangegangene Studien haben weiterhin die Frage aufgeworfen, ob und in welchem Maße thrombotische Prozesse einen Einfluss auf die Pathophysiologie und die sekundären Hirnschädigungen nach SHT haben. Da FXII sowohl das KKS als auch die intrinsische plasmatische Gerinnungskaskade initiiert und somit zur Fibrinbildung beiträgt, stand FXII im Mittelpunkt der Untersuchungen dieser Dissertation. Die vorliegende Arbeit beschäftigt sich mit den Fragen, (I) inwiefern FXII eine Rolle bei der sekundären Hirnschädigung nach Trauma spielt und (II) ob thrombotische Prozesse ein pathophysiologisches Merkmal nach Trauma darstellen. In zwei unterschiedlichen Trauma-Modellen wurden FXII-defiziente Tiere und mit einem spezifischen Inhibitor des aktivierten FXII (FXIIa) behandelte Tiere gegen Kontrolltiere nach SHT verglichen. Die Analyse der funktionellen Ausfallerscheinungen und des Ausmaßes an neuronaler Degeneration zeigte, dass FXII-Defizienz und FXIIa-Inhibition vor den Auswirkungen eines SHT schützen. Als zugrundeliegende Mechanismen wurden die Reduktion von thrombotisch verschlossenen Gefäßen in der Mikrovaskulatur des Gehirns sowie der Schutz vor BHS-Störungen und verringerte inflammatorische Prozesse identifiziert. Weiterhin wurde festgestellt, dass eine Blockade der intrinsischen Gerinnungskaskade über FXII keine intrazerebralen Blutungen auslöst. In Gewebeproben von Patienten mit SHT wurde gezeigt, dass Thrombozytenaggregate auch im klinischen Verlauf auftreten und sich somit die tierexperimentellen Befunde auf die humane Situation übertragen lassen. Insgesamt tragen die Ergebnisse dazu bei, die komplexen und vielfältigen Pathomechanismen nach SHT besser zu verstehen und vor allem die Relevanz thrombo-inflammatorischer Prozesse nach SHT aufzuzeigen. Die gezielte Blockade des FXII(a) könnte als therapeutisches Prinzip zur Abschwächung der Sekundärschaden nach SHT geeignet sein. N2 - Traumatic brain injury (TBI) is the result of an outside force causing mechanical disruption of the brain tissue. In addition, delayed pathogenic events, like inflammatory processes and blood-brain barrier damage occur, which collectively exacerbate the injury. In young adults, TBI is one of the main reasons for permanent disability and death. Because of its severe consequences and the lack of causal treatment, the identification of novel therapeutic options is of utmost importance. Based on animal studies, the kallikrein-kinin-system (KKS) is a very promising target to treat secondary injury processes following TBI. The activation of the KKS via coagulation factor XII (FXII) and the subsequent formation of bradykinin are tightly associated with the development of brain edema and inflammation. Recent studies have raised the question to what extent thrombotic processes might influence the pathophysiology and secondary injury processes following TBI. As FXII is not only the starting point of the KKS, but also the initiator of the intrinsic coagulation cascade which leads to fibrin formation, FXII was the center of interest for this dissertation. The work presented here deals with the issue, (I) whether FXII plays a role in the development and aggravation of secondary injury processes after trauma and (II) if thrombotic processes display a pathophysiological feature in TBI. In two different models of brain trauma, FXII-deficient mice and mice treated with a specific inhibitor of activated FXII (FXIIa) were compared to their respective control groups after trauma induction. The analyses of the functional outcome and the amount of neurodegenerative processes showed a distinct amelioration in favor of the genetically modified and treated animals. As underlying mechanisms, the reduction of thrombotic vessels in the brain microvasculature and additionally, protection from blood-brain barrier damages and less inflammation were identified. Moreover, it was observed that interference with the intrinsic coagulation cascade via FXII does not lead to the formation of intracerebral bleedings. The evaluation of human brain tissue surgically obtained following TBI demonstrated that platelet aggregates occur regularly in the course of brain trauma and that they seem to contribute to the secondary injury processes and the ischemia-like injury pattern. Taken together, the results contribute to the understanding of the highly complex and heterogeneous pathomechanisms following TBI, especially concerning thrombo-inflammatory processes. The targeted pharmacological blocking of FXII(a) could be a useful therapeutic principle in the treatment of TBI-associated pathologic processes. KW - Schädel-Hirn-Trauma KW - Blutgerinnungsfaktor XII KW - Pathophysiologie KW - Kallikrein-Kinin-System KW - Intrinsische Gerinnungskaskade Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144421 ER - TY - THES A1 - Reymann, Stephan Andreas T1 - Pathophysiologische Rolle und therapeutische Relevanz von Plasmakallikrein beim experimentellen Schlaganfall T1 - Pathophysiological role and therapeutic relevance of plasma kallikrein in experimental stroke N2 - Die Rolle thromboinflammatorischer Vorgänge in der Pathogenese des ischämischen Schlaganfalls ist in den letzten Jahren immer mehr in den wissenschaftlichen Fokus gerückt. Plasmakallikrein (PK) spaltet von hochmolekularem Kininogen (KNG) Bradykinin (BK) ab und ist dadurch Ausgangspunkt des proinflammatorischen Kallikrein-Kinin-Systems (KKS). Zum anderen kann es den Gerinnungsfaktor XII (FXII) aktivieren, den Ausgangspunkt der intrinsischen Gerinnungskaskade. Es initiiert also sowohl inflammatorische als auch thrombotische Vorgänge. Daher wurde in dieser Arbeit der Effekt einer Blockade PKs in einem Mausmodell der fokalen zerebralen Ischämie untersucht – und zwar sowohl durch genetische Depletion als auch durch pharmakologische Blockade. Beide Ansätze brachten einen nachhaltigen protektiven Effekt in Bezug auf Infarktgrößen und funktionelles Outcome, ohne die Blutungsgefahr zu erhöhen. N2 - Recent scientific evidence raises the question whether ischemic stroke is a thromboinflammatory disease. Plasma kallikrein (PK) cleaves high–molecular-weight kininogen to release bradykinin (BK) and is a key constituent of the proinflammatory contact-kinin system. In addition, PK can activate coagulation factor XII, the origin of the intrinsic coagulation cascade. Thus, PK triggers 2 important pathological pathways of stroke formation, thrombosis and inflammation. Therefore we investigated the consequences of both genetic and pharmacological PK inhibition in a model of ischemic stroke and found out that PK-inhibition leads to significantly smaller brain infarctions and less severe neurological deficits compared with controls without an increase in infarct-associated hemorrhage. KW - Plasmakallikrein KW - Schlaganfall KW - Plasmakallikrein ischämischer Schlaganfall Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135834 ER - TY - THES A1 - Hullin, Marcus T1 - Zusammenhang zwischen Raumwahrnehmung, Körperselbstgefühl und Puppenhandillusion bei gesunden Älteren und Patienten mit kortikobasalem Syndrom T1 - Relationship between spatial attention, the feeling of bodily self and the rubber hand illusion in the healthy elderly and patients with corticobasal syndrome N2 - Das Körperselbstgefühl (KSG) bezeichnet das Gefühl, einen bestimmten Kör-perteil als dem eigenen Körper zugehörig zu empfinden. Es erscheint stabil und nicht störbar, lässt sich jedoch bei den meisten Menschen experimentell beein-flussen. Ein Beispiel hierfür ist die Puppenhandillusion (PHI), bei der die nicht sichtbare eigene Hand des Probanden und eine sichtbare Plastikhand in glei-cher Stellung an den gleichen Fingerstellen synchron mit zwei Pinseln bestri-chen wird, wodurch die Wahrnehmung entsteht, die Plastikhand sei die eigene. Veränderungen des KSG können jedoch auch im Rahmen neurodegenerativer Erkrankungen vorkommen. So nimmt beim kortikobasalen Syndrom (CBS) etwa die Hälfte der Patienten im Krankheitsverlauf einen Arm und seine Bewegungen als fremd war ("Alien-limb“-Phänomen). Das CBS beginnt oft einseitig und ist durch eine rasch fortschreitende, akinetisch-rigide Parkinson-Symptomatik, aber auch durch kortikale Funktionsstörungen gekennzeichnet, so dass es ne-ben einer Störung des KSG auch zu einer Störung der räumlichen Aufmerk-samkeit (Hemineglect) kommt. Bislang wurde der Zusammenhang zwischen Raumwahrnehmung, KSG und PHI bei gesunden älteren Menschen noch nicht systematisch untersucht. Ebenso wenig war bisher bekannt, inwieweit das KSG bei CBS-Patienten durch die PHI modulierbar ist. Wir untersuchten 65 gesunde ältere Probanden (60 - 90 Jahre) ohne neurologi-sche Vorerkrankungen sowie zehn Patienten zwischen 59 und 77 Jahren mit wahrscheinlichem oder möglichem CBS. Den kognitiven und orientierend seeli-schen Zustand eruierten wir mit Hilfe des PANDA- und des Uhrentests, die Raumwahrnehmung testeten wir mittels des Milner-Landmark-Tests sowie des Letter-Cancellation-Tests, das spontane Körperselbstgefühl wurde mittels eines Fragebogens erfasst. Der PHI-Versuch wurde mit synchroner sowie asynchro-ner taktiler Stimulation durchgeführt, das Auftreten eines Selbstgefühls für die Plastikhand wurde subjektiv über spontane Äußerungen und einen etablierten Fragebogen, objektiv über den sog. propriozeptiven Drift der stimulierten Hand erfasst. Unter den Kontrollprobanden fanden sich 12% mit einer wahrscheinlichen De-menz, wohingegen dies bei 80% der CBS-Patienten der Fall war. Im Milner-Landmark-Test zeigte sich bei den Kontrollprobanden eine Überschätzung des rechten Segmentes einer mittig geteilten Linie, entsprechend einem milden Hemineglect, bei den CBS-Patienten konnte keine einheitliche Tendenz festge-stellt werden. Das spontane Körperselbstgefühl stellte sich bei nahezu allen Probanden als intakt dar, während sich bei vier Patienten mit CBS Hinweise auf aktuelle oder intermittierende Störungen desselben ergaben. Die Puppenhandil-lusion war in der Gruppe gesunder Älterer bei synchroner Stimulation auslös-bar, nicht jedoch bei asynchroner Stimulation. Eine Lateralisierungstendenz zeigte sich nicht. Darüber hinaus konnte bei den Probanden eine positive Korre-lation zwischen dem propriozeptiven Drift der linken Hand nach synchroner Stimulation und dem Hemineglect nach links gefunden werden. Bei den CBS-Patienten fand sich unabhängig von der Stimulationsart (synchron oder asyn-chron) eine erhöhte Bereitschaft, die linke Puppenhand ins eigene Körperbild zu integrieren. Das Auftreten der PHI bei gesunden älteren Probanden ist vergleichbar mit den Daten jüngerer Probandengruppen. Hinweise auf eine hemisphärische Laterali-sierungstendenz der PHI ergaben sich nicht, jedoch scheint der in dieser Grup-pe festgestellte leichtgradige Hemineglect nach links den multisensorischen Prozess zu beeinflussen, eine künstliche Hand in das eigene Körperschema zu integrieren. Bei den CBS-Patienten war die PHI unabhängig vom Stimulations-modus links besser auslösbar als rechts, was mit vorwiegend rechtshemisphä-rischen krankheitsbedingten Veränderungen des multisensorischen Integrati-onsprozesses vereinbar ist. N2 - The feeling of bodily self describes the perception of a particular body part as belonging to the own body. While it appears stable and nearly undisturbable to us, it can be easily modulated experimentally in most people. During the “rubber hand illusion” (RHI) paradigm, a well-known example for such an experimental manipulation, synchronous brushstrokes are applied to a subject´s hidden real hand and an aligned plastic hand. This results in the perception that the plastic hand is one´s own hand. An impairment of the feeling of bodily self can also occur spontaneously in the course of neurodegenerative diseases. About half of the patients with corticobasal syndrome (CBS) perceive one arm, including its movements, as strange ("alien-limb" phenomenon). CBS usually starts unilaterally and is characterized by progressive akinetic-rigid symptoms as well as cortical dysfunction. This may result in an impairment of the feeling of bodily self and of spatial attention (hemineglect). So far, the relationship between spatial attention, the feeling of bodily self and the rubber hand illusion in the healthy elderly has not been assessed systematically. Moreover, it was unknown whether the RHI may be used to modulate the feeling of bodily self in CBS patients. Sixty-five elderly subjects (age 60 to 90 years) without neurological history and ten patients aged between 59 and 77 years with a diagnosis of probable or possible CBS were assessed in this study. We used the PANDA and the clock-drawing test to assess the cognitive condition. The PANDA also includes a rough assessment for depressive symptoms. Spatial attention was assessed by the Milner landmark task as well as by the letter cancellation test; the spontaneous feeling of limb ownership was inquired by a questionnaire. The RHI experiment was conducted with synchronous and asynchronous tactile stimlation, respectively. The appearance of the illusion was assessed both subjectively by spontaneous statements and by a well established questionnaire, and objectively by the so-called proprioceptive drift of the stimulated hand. We found probable dementia in 12% of healthy controls, but in 80% of CBS-patients. The Milner's landmark test showed an asymmetry of spatial attention in the control group, with overestimation of the right segment of the mid-bisected line, according to a mild hemineglect, whereas there was no clear trend in CBS patients. In all healthy subjects except for one, the spontaneous feeling of limb-ownership was unimpaired, whereas we found evidence of an impairment in most CBS patients. In the control group, subjective responses indicated an experience of the RHI during synchronous, but not asynchronous stimulation, without lateralization. The proprioceptive drift towards the plastic hand following synchronous stroking was comparable between sides. With the left hand, however, the proprioceptive drift correlated with the rightward bias of spatial attention. In CBS patients, we found an increased disposition to integrate the left rubber hand into their body schema irrespective of the kind of stimulation (synchronous or asynchronous). The occurrence of the RHI in healthy, elderly subjects is comparable with data of younger subject groups. Neither subjective nor objective measures of the RHI were lateralized on group level. However, asymmetric spatial attention may influence the multisensory process of embodiment of an artificial hand into one's body schema. In CBS patients, the RHI was perceived stronger with left hand stimulation, which is in line with a pronounced right-hemispheric dysfunction of multisensory integration caused by CBS pathology. KW - Raumwahrnehmung KW - Körperwahrnehmung KW - Raumwahrnehmung KW - Körperselbstgefühl KW - Puppenhandillusion KW - Ältere KW - Kortikobasales Syndrom KW - spatial attention KW - feeling of bodily self KW - rubber hand illusion KW - elderly KW - corticobasal syndrome Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134291 ER - TY - JOUR A1 - Oder, Daniel A1 - Üceyler, Nurcan A1 - Liu, Dan A1 - Hu, Kai A1 - Petritsch, Bernhard A1 - Sommer, Claudia A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Organ manifestations and long-term outcome of Fabry disease in patients with the GLA haplotype D313Y JF - BMJ Open N2 - Objectives: The severity of Fabry disease is dependent on the type of mutation in the α-galactosidase A (AgalA) encoding gene (GLA). This study focused on the impact of the GLA haplotype D313Y on long-term organ involvement and function. Setting and participants: In this monocentric study, all participants presenting with the D313Y haplotype between 2001 and 2015 were comprehensively clinically investigated at baseline and during a 4-year follow-up if available. Five females and one male were included. Primary and secondary outcome measures: Cardiac, nephrological, neurological, laboratory and quality of life data. Results: AgalA enzyme activity in leucocytes (0.3±0.9 nmol/min/mg protein (mean±SD)) and serum lyso-Gb3 (0.6±0.3 ng/mL at baseline) were in normal range in all patients. Cardiac morphology and function were normal (left-ventricular (LV) ejection fraction 66±8%; interventricular septum 7.7±1.4 mm; LV posterior wall 7.5±1.4 mm; normalised LV mass in MRI 52±9 g/m2; LV global longitudinal strain −21.6±1.9%) and there were no signs of myocardial fibrosis in cardiac MRI. Cardiospecific biomarkers were also in normal range. Renal function was not impaired (estimated glomerular filtration rate MDRD 103±15 mL/min; serum-creatinine 0.75±0.07 mg/dL; cystatin-c 0.71±0.12 mg/L). One female patient (also carrying a Factor V Leiden mutation) had a transitory ischaemic attack. One patient showed white matter lesions in brain MRI, but none had Fabry-associated pain attacks, pain crises, evoked pain or permanent pain. Health-related quality of life analysis revealed a reduction in individual well-being. At long-term follow-up after 4 years, no significant change was seen in any parameter. Conclusions: The results of the current study suggest that the D313Y genotype does not lead to severe organ manifestations as seen in genotypes known to be causal for classical FD." KW - inherited metabolic disorders KW - Anderson-Fabry Disease KW - D313Y genotype KW - Fabry cardiomyopathy KW - Fabry nephropathy KW - Fabry-associated pain Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161210 VL - 6 ER - TY - JOUR A1 - Steigerwald, Frank A1 - Müller, Lorenz A1 - Johannes, Silvia A1 - Matthies, Cordula A1 - Volkmann, Jens T1 - Directional deep brain stimulation of the subthalamic nucleus: a pilot study using a novel neurostimulation device JF - Movement Disorders N2 - Introduction A novel neurostimulation system allows steering current in horizontal directions by combining segmented leads and multiple independent current control. The aim of this study was to evaluate directional DBS effects on parkinsonian motor features and adverse effects of subthalamic neurostimulation. Methods Seven PD patients implanted with the novel directional DBS system for bilateral subthalamic DBS underwent an extended monopolar review session during the first postoperative week, in which current thresholds were determined for rigidity control and stimulation-induced adverse effects using either directional or ring-mode settings. Results Effect or adverse effect thresholds were modified by directional settings for each of the 14 STN leads. Magnitude of change varied markedly between leads, as did orientation of optimal horizontal current steering. Conclusion Directional current steering through chronically implanted segmented electrodes is feasible, alters adverse effect and efficacy thresholds in a highly individual manner, and expands the therapeutic window in a monopolar review as compared to ring-mode DBS. KW - deep brain stimulation KW - Parkinson's disease Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187683 VL - 31 IS - 8 ER - TY - JOUR A1 - Canessa, Andrea A1 - Pozzi, Nicolò G. A1 - Arnulfo, Gabriele A1 - Brumberg, Joachim A1 - Reich, Martin M. A1 - Pezzoli, Gianni A1 - Ghilardi, Maria F. A1 - Matthies, Cordula A1 - Steigerwald, Frank A1 - Volkmann, Jens A1 - Isaias, Ioannis U. T1 - Striatal Dopaminergic Innervation Regulates Subthalamic Beta-Oscillations and Cortical-Subcortical Coupling during Movements: Preliminary Evidence in Subjects with Parkinson's Disease JF - Frontiers in Human Neuroscience N2 - Activation of the basal ganglia has been shown during the preparation and execution of movement. However, the functional interaction of cortical and subcortical brain areas during movement and the relative contribution of dopaminergic striatal innervation remains unclear. We recorded local field potential (LFP) activity from the subthalamic nucleus (STN) and high-density electroencephalography (EEG) signals in four patients with Parkinson’s disease (PD) off dopaminergic medication during a multi-joint motor task performed with their dominant and non-dominant hand. Recordings were performed by means of a fully-implantable deep brain stimulation (DBS) device at 4 months after surgery. Three patients also performed a single-photon computed tomography (SPECT) with [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (FP-CIT) to assess striatal dopaminergic innervation. Unilateral movement execution led to event-related desynchronization (ERD) followed by a rebound after movement termination event-related synchronization (ERS) of oscillatory beta activity in the STN and primary sensorimotor cortex of both hemispheres. Dopamine deficiency directly influenced movement-related beta-modulation, with greater beta-suppression in the most dopamine-depleted hemisphere for both ipsi- and contralateral hand movements. Cortical-subcortical, but not interhemispheric subcortical coherencies were modulated by movement and influenced by striatal dopaminergic innervation, being stronger in the most dopamine-depleted hemisphere. The data are consistent with a role of dopamine in shielding subcortical structures from an excessive cortical entrapment and cross-hemispheric coupling, thus allowing fine-tuning of movement. KW - beta oscillations KW - Parkinson’s disease KW - motor control KW - movement disorders KW - imaging KW - subthalamic nucleus KW - coherence analysis Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164061 VL - 10 IS - 611 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 - Krupka, Jennifer A1 - May, Frauke A1 - Weimer, Thomas A1 - Pragst, Ingo A1 - Kleinschnitz, Christoph A1 - Stoll, Guido A1 - Panousis, Con A1 - Dickneite, Gerhard A1 - Nolte, Marc W. T1 - The Coagulation Factor XIIa Inhibitor rHA-Infestin-4 Improves Outcome after Cerebral Ischemia/Reperfusion Injury in Rats JF - PLoS ONE N2 - Background and Purpose Ischemic stroke provokes severe brain damage and remains a predominant disease in industrialized countries. The coagulation factor XII (FXII)-driven contact activation system plays a central, but not yet fully defined pathogenic role in stroke development. Here, we investigated the efficacy of the FXIIa inhibitor rHA-Infestin-4 in a rat model of ischemic stroke using both a prophylactic and a therapeutic approach. Methods For prophylactic treatment, animals were treated intravenously with 100 mg/kg rHA-Infestin-4 or an equal volume of saline 15 min prior to transient middle cerebral artery occlusion (tMCAO) of 90 min. For therapeutic treatment, 100 mg/kg rHA-Infestin-4, or an equal volume of saline, was administered directly after the start of reperfusion. At 24 h after tMCAO, rats were tested for neurological deficits and blood was drawn for coagulation assays. Finally, brains were removed and analyzed for infarct area and edema formation. Results Within prophylactic rHA-Infestin-4 treatment, infarct areas and brain edema formation were reduced accompanied by better neurological scores and survival compared to controls. Following therapeutic treatment, neurological outcome and survival were still improved although overall effects were less pronounced compared to prophylaxis. Conclusions With regard to the central role of the FXII-driven contact activation system in ischemic stroke, inhibition of FXIIa may represent a new and promising treatment approach to prevent cerebral ischemia/reperfusion injury. KW - coagulation factor XIIa KW - ischemic stroke KW - contact activation system KW - FXIIa inhibitor rHA-Infestin Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167370 VL - 11 IS - 1 ER -