TY - JOUR A1 - Gründahl, Marie A1 - Wacker, Beate A1 - Einsele, Hermann A1 - Heinz, Werner J. T1 - Invasive fungal diseases in patients with new diagnosed acute lymphoblastic leukaemia JF - Mycoses N2 - Background Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population. Methods In this retrospective single‐centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia. Results In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4%, 8.6%, and 17.2% likelihood, respectively. The incidence might be even higher, as nearly 40% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection. Conclusion Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated. KW - acute lymphoblastic leukaemia KW - fungal infection KW - galactomannan KW - incidence KW - mortality Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-217844 VL - 63 IS - 10 SP - 1101 EP - 1106 ER - TY - JOUR A1 - Pritchard, Rory A. A1 - Falk, Lovissa A1 - Larsson, Mathilda A1 - Leinders, Mathias A1 - Sorkin, Linda S. T1 - Different phosphoinositide 3-kinase isoforms mediate carrageenan nociception and inflammation JF - Pain N2 - Phosphoinositide 3-kinases (PI3Ks) participate in signal transduction cascades that can directly activate and sensitize nociceptors and enhance pain transmission. They also play essential roles in chemotaxis and immune cell infiltration leading to inflammation. We wished to determine which PI3K isoforms were involved in each of these processes. Lightly anesthetized rats (isoflurane) were injected subcutaneously with carrageenan in their hind paws. This was preceded by a local injection of 1% DMSO vehicle or an isoform-specific antagonist to PI3K-α (compound 15-e), -β (TGX221), -δ (Cal-101), or -γ (AS252424). We measured changes in the mechanical pain threshold and spinal c-Fos expression (4 hours after injection) as indices of nociception. Paw volume, plasma extravasation (Evans blue, 0.3 hours after injection), and neutrophil (myeloperoxidase; 1 hour after injection) and macrophage (CD11b+; 4 hour after injection) infiltration into paw tissue were the measured inflammation endpoints. Only PI3K-γ antagonist before treatment reduced the carrageenan-induced pain behavior and spinal expression of c-Fos (P <= 0.01). In contrast, pretreatment with PI3K-α, -δ, and -γ antagonists reduced early indices of inflammation. Plasma extravasation PI3K-α (P <= 0.05), -δ (P <= 0.05), and -γ (P <= 0.01), early (0-2 hour) edema -α (P <= 0.05), -δ (P <= 0.001), and -γ (P <= 0.05), and neutrophil infiltration (all P <= 0.001) were all reduced compared to vehicle pretreatment. Later (2-4 hour), edema and macrophage infiltration (P <= 0.05) were reduced by only the PI3K-δ and -γ isoform antagonists, with the PI3K-δ antagonist having a greater effect on edema. PI3K-β antagonism was ineffective in all paradigms. These data indicate that pain and clinical inflammation are pharmacologically separable and may help to explain clinical conditions in which inflammation naturally wanes or goes into remission, but pain continues unabated. KW - c-Fos KW - Edema KW - Macrophage KW - Neutrophil KW - Plasma extravasation KW - Pain KW - PI3K isoforms Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191312 VL - 157 IS - 1 ER - TY - JOUR A1 - Schmidbauer, Moritz L. A1 - Ferse, Caroline A1 - Salih, Farid A1 - Klingner, Carsten A1 - Musleh, Rita A1 - Kunst, Stefan A1 - Wittstock, Matthias A1 - Neumann, Bernhard A1 - Schebesch, Karl-Michael A1 - Bösel, Julian A1 - Godau, Jana A1 - Lochner, Piergiorgio A1 - Adam, Elisabeth H. A1 - Jahnke, Kolja A1 - Knier, Benjamin A1 - Schirotzek, Ingo A1 - Müllges, Wolfgang A1 - Notz, Quirin A1 - Dengl, Markus A1 - Güldner, Andreas A1 - Onur, Oezguer A. A1 - Garcia Borrega, Jorge A1 - Dimitriadis, Konstantinos A1 - Günther, Albrecht T1 - COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis JF - Journal of Clinical Medicine N2 - Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future. KW - COVID-19 KW - intracranial hemorrhage KW - prognosis KW - anticoagulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255236 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Gunreben, Ignaz A1 - Kleinschnitz, Christoph A1 - Kraft, Peter T1 - Immunohistochemical Analysis of Cerebral Thrombi Retrieved by Mechanical Thrombectomy from Patients with Acute Ischemic Stroke JF - International Journal of Molecular Sciences N2 - Mechanical thrombectomy is a novel treatment option for patients with acute ischemic stroke (AIS). Only a few studies have previously suggested strategies to categorize retrieved clots according to their histologic composition. However, these reports did not analyze potential biomarkers that are of importance in stroke-related inflammation. We therefore histopathologically investigated 37 intracerebral thrombi mechanically retrieved from patients with AIS, and focused on the composition of immune cells and platelets. We also conducted correlation analyses of distinctive morphologic patterns (erythrocytic, serpentine, layered, red, white, mixed appearance) with clinical parameters. Most T cells and monocytes were detected in erythrocytic and red clots, in which the distribution of these cells was random. In contrast, von Willebrand factor (vWF)-positive areas co-localized with regions of fibrin and collagen. While clots with huge amounts of vWF seem to be associated with a high National Institute of Health Stroke Scale score at admission, histologic findings could not predict the clinical outcome at discharge. In summary, we provide the first histologic description of mechanically retrieved intracerebral thrombi regarding biomarkers relevant for inflammation in ischemic stroke. KW - thrombus formation KW - immune cells KW - lymphocytes KW - mechanical thrombectomy KW - ischemic stroke KW - inflammation Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166206 VL - 17 IS - 3 ER - TY - JOUR A1 - Schischlevskij, Pavel A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Stendel, Claudia A1 - Müschen, Lars H. A1 - Osmanovic, Alma A1 - Binz, Camilla A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives JF - Brain Sciences N2 - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers' burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients' CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients' functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers' burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers' burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients' functional status (r\(_p\) = −0.555, p < 0.001, n = 242). It was influenced by the CGs' own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients' wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs' depression (r\(_p\) = 0.627, p < 0.001, n = 234), anxiety (r\(_p\) = 0.550, p < 0.001, n = 234), and poorer physical condition (r\(_p\) = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients' impairment in daily routine (r\(_s\) = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs' lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs' work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required. KW - amyotrophic lateral sclerosis (ALS) KW - informal caregiving KW - caregiver burden KW - functional status KW - decreasing autonomy KW - depression KW - anxiety KW - health-related quality of life KW - socioeconomic status KW - psychological support Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240981 SN - 2076-3425 VL - 11 IS - 6 ER - TY - JOUR A1 - Elhfnawy, Ahmed Mohamed A1 - Heuschmann, Peter U. A1 - Pham, Mirko A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Stenosis length and degree interact with the risk of cerebrovascular events related to internal carotid artery stenosis JF - Frontiers in Neurology N2 - Background and Purpose: Internal carotid artery stenosis (ICAS)≥70% is a leading cause of ischemic cerebrovascular events (ICVEs). However, a considerable percentage of stroke survivors with symptomatic ICAS (sICAS) have <70% stenosis with a vulnerable plaque. Whether the length of ICAS is associated with high risk of ICVEs is poorly investigated. Our main aim was to investigate the relation between the length of ICAS and the development of ICVEs. Methods: In a retrospective cross-sectional study, we identified 95 arteries with sICAS and another 64 with asymptomatic internal carotid artery stenosis (aICAS) among 121 patients with ICVEs. The degree and length of ICAS as well as plaque echolucency were assessed on ultrasound scans. Results: A statistically significant inverse correlation between the ultrasound-measured length and degree of ICAS was detected for sICAS≥70% (Spearman correlation coefficient ρ = –0.57, p < 0.001, n = 51) but neither for sICAS<70% (ρ = 0.15, p = 0.45, n = 27) nor for aICAS (ρ = 0.07, p = 0.64, n = 54). The median (IQR) length for sICAS<70% and ≥70% was 17 (15–20) and 15 (12–19) mm (p = 0.06), respectively, while that for sICAS<90% and sICAS 90% was 18 (15–21) and 13 (10–16) mm, respectively (p < 0.001). Among patients with ICAS <70%, a cut-off length of ≥16 mm was found for sICAS rather than aICAS with a sensitivity and specificity of 74.1% and 51.1%, respectively. Irrespective of the stenotic degree, plaques of the sICAS compared to aICAS were significantly more often echolucent (43.2 vs. 24.6%, p = 0.02). Conclusion: We found a statistically insignificant tendency for the ultrasound-measured length of sICAS<70% to be longer than that of sICAS≥70%. Moreover, the ultrasound-measured length of sICAS<90% was significantly longer than that of sICAS 90%. Among patients with sICAS≥70%, the degree and length of stenosis were inversely correlated. Larger studies are needed before a clinical implication can be drawn from these results. KW - ischemic stroke KW - carotid stenosis KW - carotid atherosclerosis KW - length of stenosis KW - degree of stenosis KW - carotid ultrasound KW - outcome Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196225 SN - 1664-2295 VL - 10 IS - 317 ER - TY - JOUR A1 - Pozzi, Nicoló G. A1 - Palmisano, Chiara A1 - Reich, Martin M. A1 - Capetian, Philip A1 - Pacchetti, Claudio A1 - Volkmann, Jens A1 - Isaias, Ioannis U. T1 - Troubleshooting gait disturbances in Parkinson’s disease with deep brain stimulation JF - Frontiers in Human Neuroscience N2 - Deep brain stimulation (DBS) of the subthalamic nucleus or the globus pallidus is an established treatment for Parkinson’s disease (PD) that yields a marked and lasting improvement of motor symptoms. Yet, DBS benefit on gait disturbances in PD is still debated and can be a source of dissatisfaction and poor quality of life. Gait disturbances in PD encompass a variety of clinical manifestations and rely on different pathophysiological bases. While gait disturbances arising years after DBS surgery can be related to disease progression, early impairment of gait may be secondary to treatable causes and benefits from DBS reprogramming. In this review, we tackle the issue of gait disturbances in PD patients with DBS by discussing their neurophysiological basis, providing a detailed clinical characterization, and proposing a pragmatic programming approach to support their management. KW - Parkinson’s disease KW - freezing of gait (FOG) KW - deep brain stimulation (DBS) KW - subthalamic nucleus (STN) KW - globus pallidus pars interna (GPi) KW - pedunculopontine nucleus (PPN) Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274007 SN - 1662-5161 VL - 16 ER - TY - JOUR A1 - Petzke, Frank A1 - Klose, Petra A1 - Welsch, Patrick A1 - Sommer, Claudia A1 - Häuser, Winfried T1 - Opioids for chronic low back pain: An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks of double‐blind duration JF - European Journal of Pain N2 - Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in non‐malignant chronic low back pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, MEDLINE and PsycINFO were searched from October 2013 to May 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks of double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences or standardized mean differences. We added nine new studies with 2,980 participants for a total of 21 studies with 7,650 participants. Study duration ranged between 4 and 15 weeks. Studies with a parallel and cross‐over design: Based on very low to low‐quality evidence, opioids provided no clinically relevant pain relief of 50% or greater, but a clinically relevant reduction of disability compared to placebo. Enriched enrolment randomized withdrawal (EERW) design: Based on very low to low‐quality evidence, opioids provided a clinically relevant pain relief of 50% or greater, but not a clinically relevant reduction of disability compared to placebo. There was no clinically relevant harm with regard to serious adverse events by opioids compared to placebo in studies with parallel/cross‐over and EERW design. There was a relevant harm with regard to drop out rates due to adverse events in studies with parallel/cross‐over, but not in studies with EERW design. Conclusions Opioids may provide a safe and clinically relevant pain relief for 4–15 weeks in highly selected patients. Significance Within the context of randomized controlled trials of 4–15 weeks, opioids provided a clinically relevant pain relief of 30% or greater and a clinically relevant reduction of disability compared to placebo in non‐malignant chronic low back pain. Number needed to treat for an additional drop out due to side effects was 11 (95% confidence interval: 6–33). Assessment of abuse and addiction was incomplete. The frequency of serious adverse events including deaths did not differ from placebo. KW - opioids KW - back pain KW - systematic review Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218498 VL - 24 IS - 3 SP - 497 EP - 517 ER - TY - JOUR A1 - Stengel, Helena A1 - Vural, Atay A1 - Brunder, Anna-Michelle A1 - Heinius, Annika A1 - Appeltshauser, Luise A1 - Fiebig, Bianca A1 - Giese, Florian A1 - Dresel, Christian A1 - Papagianni, Aikaterini A1 - Birklein, Frank A1 - Weis, Joachim A1 - Huchtemann, Tessa A1 - Schmidt, Christian A1 - Körtvelyessy, Peter A1 - Villmann, Carmen A1 - Meinl, Edgar A1 - Sommer, Claudia A1 - Leypoldt, Frank A1 - Doppler, Kathrin T1 - Anti–pan-neurofascin IgG3 as a marker of fulminant autoimmune neuropathy JF - Neurology: Neuroimmunology & Neuroinflammation N2 - Objective To identify and characterize patients with autoantibodies against different neurofascin (NF) isoforms. Methods Screening of a large cohort of patient sera for anti-NF autoantibodies by ELISA and further characterization by cell-based assays, epitope mapping, and complement binding assays. Results Two different clinical phenotypes became apparent in this study: The well-known clinical picture of subacute-onset severe sensorimotor neuropathy with tremor that is known to be associated with IgG4 autoantibodies against the paranodal isoform NF-155 was found in 2 patients. The second phenotype with a dramatic course of disease with tetraplegia and almost locked-in syndrome was associated with IgG3 autoantibodies against nodal and paranodal isoforms of NF in 3 patients. The epitope against which these autoantibodies were directed in this second phenotype was the common Ig domain found in all 3 NF isoforms. In contrast, anti–NF-155 IgG4 were directed against the NF-155–specific Fn3Fn4 domain. The description of a second phenotype of anti–NF-associated neuropathy is in line with some case reports of similar patients that were published in the last year. Conclusions Our results indicate that anti–pan-NF-associated neuropathy differs from anti–NF-155-associated neuropathy, and epitope and subclass play a major role in the pathogenesis and severity of anti–NF-associated neuropathy and should be determined to correctly classify patients, also in respect to possible differences in therapeutic response. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202462 VL - 6 IS - 5 ER - TY - JOUR A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Klitsch, Alexander A1 - Unterecker, Stefan A1 - Warrings, Bodo A1 - Serra, Jordi A1 - Papagianni, Aikaterini A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üceyler, Nurcan T1 - Reduction of skin innervation is associated with a severe fibromyalgia phenotype JF - Annals of Neurology N2 - Objective: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). Methods: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. Results: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MDP: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). Interpretation: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. KW - fibromyalgia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206168 VL - 86 IS - 4 ER - TY - JOUR A1 - Klitsch, Alexander A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Thomas, Dominique A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Sisignano, Marco A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome JF - Journal of the Peripheral Nervous System N2 - In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling. KW - corneal confocal microscopy KW - fibromyalgia syndrome KW - Langerhans cells KW - pain KW - small fiber neuropathy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214150 VL - 25 IS - 1 ER - TY - JOUR A1 - Wirsching, Isabelle A1 - Ort, Nora A1 - Üçeyler, Nurcan T1 - ALS or ALS mimic by neuroborreliosis — A case report JF - Clinical Case Reports N2 - Comprehensive investigation in motor neuron disease is vital not to miss a treatable differential diagnosis. Neuroborreliosis should be considered during an ALS work‐up. However, false‐positive CSF results do occur, and thus, results should be interpreted carefully in context of all clinical test results. KW - ALS mimic KW - El Escorial KW - motor neuron disease KW - muscle atrophy KW - neuroborreliosis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201308 VL - 8 ER - TY - JOUR A1 - Silwedel, Christine A1 - Speer, Christian P. A1 - Haarmann, Axel A1 - Fehrholz, Markus A1 - Claus, Heike A1 - Buttmann, Mathias A1 - Glaser, Kirsten T1 - Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells JF - Journal of Neuroinflammation N2 - Background: Atypical chemokine receptor 3 (ACKR3, synonym CXCR7) is increasingly considered relevant in neuroinflammatory conditions, in which its upregulation contributes to compromised endothelial barrier function and may ultimately allow inflammatory brain injury. While an impact of ACKR3 has been recognized in several neurological autoimmune diseases, neuroinflammation may also result from infectious agents, including Ureaplasma species (spp.). Although commonly regarded as commensals of the adult urogenital tract, Ureaplasma spp. may cause invasive infections in immunocompromised adults as well as in neonates and appear to be relevant pathogens in neonatal meningitis. Nonetheless, clinical and in vitro data on Ureaplasma-induced inflammation are scarce. Methods: We established a cell culture model of Ureaplasma meningitis, aiming to analyze ACKR3 variances as a possible pathomechanism in Ureaplasma-associated neuroinflammation. Non-immortalized human brain microvascular endothelial cells (HBMEC) were exposed to bacterial lipopolysaccharide (LPS) or tumor necrosis factor-α (TNF-α), and native as well as LPS-primed HBMEC were cultured with Ureaplasma urealyticum serovar 8 (Uu8) and U. parvum serovar 3 (Up3). ACKR3 responses were assessed via qRT-PCR, RNA sequencing, flow cytometry, and immunocytochemistry. Results: LPS, TNF-α, and Ureaplasma spp. influenced ACKR3 expression in HBMEC. LPS and TNF-α significantly induced ACKR3 mRNA expression (p < 0.001, vs. control), whereas Ureaplasma spp. enhanced ACKR3 protein expression in HBMEC (p < 0.01, vs. broth control). Co-stimulation with LPS and either Ureaplasma isolate intensified ACKR3 responses (p < 0.05, vs. LPS). Furthermore, stimulation wielded a differential influence on the receptor’s ligands. Conclusions: We introduce an in vitro model of Ureaplasma meningitis. We are able to demonstrate a pro-inflammatory capacity of Ureaplasma spp. in native and, even more so, in LPS-primed HBMEC, underlining their clinical relevance particularly in a setting of co-infection. Furthermore, our data may indicate a novel role for ACKR3, with an impact not limited to auto-inflammatory diseases, but extending to infection-related neuroinflammation as well. AKCR3-induced blood-brain barrier breakdown might constitute a potential common pathomechanism. KW - atypical chemokine receptor 3 KW - human brain microvascular endothelial cells KW - meningitis KW - neuroinflammation KW - Ureaplasma species Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175952 VL - 15 IS - 156 ER - TY - JOUR A1 - Hofmann, Lukas A1 - Karl, Franziska A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Affective and cognitive behavior in the alpha-galactosidase A deficient mouse model of Fabry disease JF - PLoS ONE N2 - Fabry disease is an X-linked inherited lysosomal storage disorder with intracellular accumulation of globotriaosylceramide (Gb3) due to α-galactosidase A (α-Gal A) deficiency. Fabry patients frequently report of anxiety, depression, and impaired cognitive function. We characterized affective and cognitive phenotype of male mice with α-Gal A deficiency (Fabry KO) and compared results with those of age-matched male wildtype (WT) littermates. Young (3 months) and old (≥ 18 months) mice were tested in the naïve state and after i.pl. injection of complete Freund`s adjuvant (CFA) as an inflammatory pain model. We used the elevated plus maze (EPM), the light-dark box (LDB) and the open field test (OF) to investigate anxiety-like behavior. The forced swim test (FST) and Morris water maze (MWM) were applied to assess depressive-like and learning behavior. The EPM test revealed no intergroup difference for anxiety-like behavior in naïve young and old Fabry KO mice compared to WT littermates, except for longer time spent in open arms of the EPM for young WT mice compared to young Fabry KO mice (p<0.05). After CFA injection, young Fabry KO mice showed increased anxiety-like behavior compared to young WT littermates (p<0.05) and naïve young Fabry KO mice (p<0.05) in the EPM as reflected by shorter time spent in EPM open arms. There were no relevant differences in the LDB and the OF test, except for longer time spent in the center zone of the OF by young WT mice compared to young Fabry KO mice (p<0.05). Complementary to this, depression-like and learning behavior were not different between genotypes and age-groups, except for the expectedly lower memory performance in older age-groups compared to young mice. Our results indicate that genetic influences on affective and cognitive symptoms in FD may be of subordinate relevance, drawing attention to potential influences of environmental and epigenetic factors. KW - cognitive impairment KW - mouse models KW - depression KW - swimming KW - learning KW - Fabry disease KW - genetics Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170745 VL - 12 IS - 6 ER - TY - JOUR A1 - Piro, Inken A1 - Eckes, Anna-Lena A1 - Kasaragod, Vikram Babu A1 - Sommer, Claudia A1 - Harvey, Robert J. A1 - Schaefer, Natascha A1 - Villmann, Carmen T1 - Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease JF - Frontiers in Molecular Neuroscience N2 - Startle disease is a rare disorder associated with mutations in GLRA1 and GLRB, encoding glycine receptor (GlyR) α1 and β subunits, which enable fast synaptic inhibitory transmission in the spinal cord and brainstem. The GlyR β subunit is important for synaptic localization via interactions with gephyrin and contributes to agonist binding and ion channel conductance. Here, we have studied three GLRB missense mutations, Y252S, S321F, and A455P, identified in startle disease patients. For Y252S in M1 a disrupted stacking interaction with surrounding aromatic residues in M3 and M4 is suggested which is accompanied by an increased EC\(_{50}\) value. By contrast, S321F in M3 might stabilize stacking interactions with aromatic residues in M1 and M4. No significant differences in glycine potency or efficacy were observed for S321F. The A455P variant was not predicted to impact on subunit folding but surprisingly displayed increased maximal currents which were not accompanied by enhanced surface expression, suggesting that A455P is a gain-of-function mutation. All three GlyR β variants are trafficked effectively with the α1 subunit through intracellular compartments and inserted into the cellular membrane. In vivo, the GlyR β subunit is transported together with α1 and the scaffolding protein gephyrin to synaptic sites. The interaction of these proteins was studied using eGFP-gephyrin, forming cytosolic aggregates in non-neuronal cells. eGFP-gephyrin and β subunit co-expression resulted in the recruitment of both wild-type and mutant GlyR β subunits to gephyrin aggregates. However, a significantly lower number of GlyR β aggregates was observed for Y252S, while for mutants S321F and A455P, the area and the perimeter of GlyR β subunit aggregates was increased in comparison to wild-type β. Transfection of hippocampal neurons confirmed differences in GlyR-gephyrin clustering with Y252S and A455P, leading to a significant reduction in GlyR β-positive synapses. Although none of the mutations studied is directly located within the gephyrin-binding motif in the GlyR β M3-M4 loop, we suggest that structural changes within the GlyR β subunit result in differences in GlyR β-gephyrin interactions. Hence, we conclude that loss- or gain-of-function, or alterations in synaptic GlyR clustering may underlie disease pathology in startle disease patients carrying GLRB mutations. KW - glycine receptor KW - hyperekplexia KW - startle disease KW - gephyrin Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246676 SN - 1662-5099 VL - 14 ER - TY - JOUR A1 - Wagenhäuser, Laura A1 - Rickert, Vanessa A1 - Sommer, Claudia A1 - Wanner, Christoph A1 - Nordbeck, Peter A1 - Rost, Simone A1 - Üçeyler, Nurcan T1 - X-chromosomal inactivation patterns in women with Fabry disease JF - Molecular Genetics & Genomic Medicine N2 - Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25% distribution) in 6/87 (7%) mouth epithelial cell samples, 31/88 (35%) blood samples, and 9/27 (33%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns. KW - Fabry disease KW - Fabry genotype KW - Fabry phenotype KW - female Fabry patients KW - X-chromosomal inactivation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312795 VL - 10 IS - 9 ER - TY - JOUR A1 - Spitzel, Marlene A1 - Wagner, Elise A1 - Breyer, Maximilian A1 - Henniger, Dorothea A1 - Bayin, Mehtap A1 - Hofmann, Lukas A1 - Mauceri, Daniela A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Dysregulation of immune response mediators and pain-related ion channels is associated with pain-like behavior in the GLA KO mouse model of Fabry disease JF - Cells N2 - Fabry disease (FD) is a rare life-threatening disorder caused by deficiency of the alpha-galactosidase A (GLA) enzyme with a characteristic pain phenotype. Impaired GLA production or function leads to the accumulation of the cell membrane compound globotriaosylceramide (Gb3) in the neurons of the dorsal root ganglia (DRG) of FD patients. Applying immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT PCR) analysis on DRG tissue of the GLA knockout (KO) mouse model of FD, we address the question of how Gb3 accumulation may contribute to FD pain and focus on the immune system and pain-associated ion channel gene expression. We show a higher Gb3 load in the DRG of young (<6 months) (p < 0.01) and old (≥12 months) (p < 0.001) GLA KO mice compared to old wildtype (WT) littermates, and an overall suppressed immune response in the DRG of old GLA KO mice, represented by a reduced number of CD206\(^+\) macrophages (p < 0.01) and lower gene expression levels of the inflammation-associated targets interleukin(IL)1b (p < 0.05), IL10 (p < 0.001), glial fibrillary acidic protein (GFAP) (p < 0.05), and leucine rich alpha-2-glycoprotein 1 (LRG1) (p < 0.01) in the DRG of old GLA KO mice compared to old WT. Dysregulation of immune-related genes may be linked to lower gene expression levels of the pain-associated ion channels calcium-activated potassium channel 3.1 (KCa3.1) and transient receptor potential ankyrin 1 channel (TRPA1). Ion channel expression might further be disturbed by impaired sphingolipid recruitment mediated via the lipid raft marker flotillin-1 (FLOT1). This impairment is represented by an increased number of FLOT1\(^+\) DRG neurons with a membranous expression pattern in old GLA KO mice compared to young GLA KO, young WT, and old WT mice (p < 0.001 each). Further, we provide evidence for aberrant behavior of GLA KO mice, which might be linked to dysregulated ion channel gene expression levels and disturbed FLOT1 distribution patterns. Behavioral testing revealed mechanical hypersensitivity in young (p < 0.01) and old (p < 0.001) GLA KO mice compared to WT, heat hypersensitivity in young GLA KO mice (p < 0.001) compared to WT, age-dependent heat hyposensitivity in old GLA KO mice (p < 0.001) compared to young GLA KO mice, and cold hyposensitivity in young (p < 0.001) and old (p < 0.001) GLA KO mice compared to WT, which well reflects the clinical phenotype observed in FD patients. KW - Fabry disease KW - globotriaosylceramide KW - inflammation KW - macrophages KW - cytokines KW - ion channels KW - flotillin-1 lipid rafts KW - pain-associated behavior KW - mouse model Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275186 SN - 2073-4409 VL - 11 IS - 11 ER - TY - JOUR A1 - Krämer, Stefanie D. A1 - Schuhmann, Michael K. A1 - Volkmann, Jens A1 - Fluri, Felix T1 - Deep brain stimulation in the subthalamic nucleus can improve skilled Forelimb movements and retune dynamics of striatal networks in a rat stroke model JF - International Journal of Molecular Sciences N2 - Recovery of upper limb (UL) impairment after stroke is limited in stroke survivors. Since stroke can be considered as a network disorder, neuromodulation may be an approach to improve UL motor dysfunction. Here, we evaluated the effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) in rats on forelimb grasping using the single-pellet reaching (SPR) test after stroke and determined costimulated brain regions during STN-HFS using 2-[\(^{18}\)F]Fluoro-2-deoxyglucose-([\(^{18}\)F]FDG)-positron emission tomography (PET). After a 4-week training of SPR, photothrombotic stroke was induced in the sensorimotor cortex of the dominant hemisphere. Thereafter, an electrode was implanted in the STN ipsilateral to the infarction, followed by a continuous STN-HFS or sham stimulation for 7 days. On postinterventional day 2 and 7, an SPR test was performed during STN-HFS. Success rate of grasping was compared between these two time points. [\(^{18}\)F]FDG-PET was conducted on day 2 and 3 after stroke, without and with STN-HFS, respectively. STN-HFS resulted in a significant improvement of SPR compared to sham stimulation. During STN-HFS, a significantly higher [\(^{18}\)F]FDG-uptake was observed in the corticosubthalamic/pallidosubthalamic circuit, particularly ipsilateral to the stimulated side. Additionally, STN-HFS led to an increased glucose metabolism within the brainstem. These data demonstrate that STN-HFS supports rehabilitation of skilled forelimb movements, probably by retuning dysfunctional motor centers within the cerebral network. KW - photothrombosis KW - experimental stroke KW - subthalamic nucleus KW - invasive electric stimulation KW - skilled forelimb movements KW - neuronal network KW - [18F]FDG positron emission tomography Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312828 VL - 23 IS - 24 ER - TY - JOUR A1 - Odorfer, Thorsten M. A1 - Wind, Teresa A1 - Zeller, Daniel T1 - Temporal discrimination thresholds and proprioceptive performance: impact of age and nerve conduction JF - Frontiers in Neuroscience N2 - Background Increasing attention is payed to the contribution of somatosensory processing in motor control. In particular, temporal somatosensory discrimination has been found to be altered differentially in common movement disorders. To date, there have only been speculations as to how impaired temporal discrimination and clinical motor signs may relate to each other. Prior to disentangling this relationship, potential confounders of temporal discrimination, in particular age and peripheral nerve conduction, should be assessed, and a quantifiable measure of proprioceptive performance should be established. ObjectiveTo assess the influence of age and polyneuropathy (PNP) on somatosensory temporal discrimination threshold (STDT), temporal discrimination movement threshold (TDMT), and behavioral measures of proprioception of upper and lower limbs. Methods STDT and TDMT were assessed in 79 subjects (54 healthy, 25 with PNP; age 30–79 years). STDT was tested with surface electrodes over the thenar or dorsal foot region. TDMT was probed with needle electrodes in flexor carpi radialis (FCR) and tibialis anterior (TA) muscle. Goniometer-based devices were used to assess limb proprioception during (i) active pointing to LED markers, (ii) active movements in response to variable visual cues, and (iii) estimation of limb position following passive movements. Pointing (or estimation) error was taken as a measure of proprioceptive performance. Results In healthy subjects, higher age was associated with higher STDT and TDMT at upper and lower extremities, while age did not correlate with proprioceptive performance. Patients with PNP showed higher STDT and TDMT values and decreased proprioceptive performance in active pointing tasks compared to matched healthy subjects. As an additional finding, there was a significant correlation between performance in active pointing tasks and temporal discrimination thresholds. Conclusion Given their notable impact on measures of temporal discrimination, age and peripheral nerve conduction need to be accounted for if STDT and TDMT are applied in patients with movement disorders. As a side observation, the correlation between measures of proprioception and temporal discrimination may prompt further studies on the presumptive link between these two domains. KW - pointing task KW - position estimation KW - aging KW - kinesthesia KW - somatosensory temporal discrimination KW - TDMT KW - temporal discrimination threshold Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-195648 SN - 1662-453X VL - 13 IS - 1241 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Kraft, Peter A1 - Bieber, Michael A1 - Kollikowski, Alexander M. A1 - Schulze, Harald A1 - Nieswandt, Bernhard A1 - Pham, Mirko A1 - Stegner, David A1 - Stoll, Guido T1 - Targeting platelet GPVI plus rt-PA administration but not α2β1-mediated collagen binding protects against ischemic brain damage in mice JF - International Journal of Molecular Science N2 - Platelet collagen interactions at sites of vascular injuries predominantly involve glycoprotein VI (GPVI) and the integrin α2β1. Both proteins are primarily expressed on platelets and megakaryocytes whereas GPVI expression is also shown on endothelial and integrin α2β1 expression on epithelial cells. We recently showed that depletion of GPVI improves stroke outcome without increasing the risk of cerebral hemorrhage. Genetic variants associated with higher platelet surface integrin α2 (ITGA2) receptor levels have frequently been found to correlate with an increased risk of ischemic stroke in patients. However until now, no preclinical stroke study has addressed whether platelet integrin α2β1 contributes to the pathophysiology of ischemia/reperfusion (I/R) injury. Focal cerebral ischemia was induced in C57BL/6 and Itga2\(^{−/−}\) mice by a 60 min transient middle cerebral artery occlusion (tMCAO). Additionally, wild-type animals were pretreated with anti-GPVI antibody (JAQ1) or Fab fragments of a function blocking antibody against integrin α2β1 (LEN/B). In anti-GPVI treated animals, intravenous (IV) recombinant tissue plasminogen activator (rt-PA) treatment was applied immediately prior to reperfusion. Stroke outcome, including infarct size and neurological scoring was determined on day 1 after tMCAO. We demonstrate that targeting the integrin α2β1 (pharmacologic; genetic) did neither reduce stroke size nor improve functional outcome on day 1 after tMCAO. In contrast, depletion of platelet GPVI prior to stroke was safe and effective, even when combined with rt-PA treatment. Our results underscore that GPVI, but not ITGA2, is a promising and safe target in the setting of ischemic stroke. KW - ischemic stroke KW - integrin α2 KW - glycoprotein VI KW - recombinant tissue-type plasminogen activator KW - intracranial bleeding KW - transient middle cerebral artery occlusion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201700 SN - 1422-0067 VL - 20 IS - 8 ER - TY - JOUR A1 - Karl, Franziska A1 - Wußmann, Maximiliane A1 - Kreß, Luisa A1 - Malzacher, Tobias A1 - Fey, Phillip A1 - Groeber‐Becker, Florian A1 - Üçeyler, Nurcan T1 - Patient‐derived in vitro skin models for investigation of small fiber pathology JF - Annals of Clinical and Translational Neurology N2 - Objective To establish individually expandable primary fibroblast and keratinocyte cultures from 3‐mm skin punch biopsies for patient‐derived in vitro skin models to investigate of small fiber pathology. Methods We obtained 6‐mm skin punch biopsies from the calf of two patients with small fiber neuropathy (SFN) and two healthy controls. One half (3 mm) was used for diagnostic intraepidermal nerve fiber density (IENFD). From the second half, we isolated and cultured fibroblasts and keratinocytes. Cells were used to generate patient‐derived full‐thickness three‐dimensional (3D) skin models containing a dermal and epidermal component. Cells and skin models were characterized morphologically, immunocyto‐ and ‐histochemically (vimentin, cytokeratin (CK)‐10, CK 14, ki67, collagen1, and procollagen), and by electrical impedance. Results Distal IENFD was reduced in the SFN patients (2 fibers/mm each), while IENFD was normal in the controls (8 fibers/mm, 7 fibers/mm). Two‐dimensional (2D) cultured skin cells showed normal morphology, adequate viability, and proliferation, and expressed cell‐specific markers without relevant difference between SFN patient and healthy control. Using 2D cultured fibroblasts and keratinocytes, we obtained subject‐derived 3D skin models. Morphology of the 3D model was analogous to the respective skin biopsy specimens. Both, the dermal and the epidermal layer carried cell‐specific markers and showed a homogenous expression of extracellular matrix proteins. Interpretation Our protocol allows the generation of disease‐specific 2D and 3D skin models, which can be used to investigate the cross‐talk between skin cells and sensory neurons in small fiber pathology. KW - neurology Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201649 VL - 6 IS - 9 ER - TY - JOUR A1 - Kollikowski, Alexander M. A1 - Schuhmann, Michael K. A1 - Nieswandt, Bernhard A1 - Müllges, Wolfgang A1 - Stoll, Guido A1 - Pham, Mirko T1 - Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke JF - Annals of Neurology N2 - Objective Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization. Methods We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines. Results Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T‐cell chemoattractant CXCL‐11. Finally, we found evidence that short‐term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation. Interpretation We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466–479 KW - neurology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212168 VL - 87 IS - 3 ER - TY - JOUR A1 - Göb, Vanessa A1 - Voll, Maximilian G. A1 - Zimmermann, Lena A1 - Hemmen, Katharina A1 - Stoll, Guido A1 - Nieswandt, Bernhard A1 - Schuhmann, Michael K. A1 - Heinze, Katrin G. A1 - Stegner, David T1 - Infarct growth precedes cerebral thrombosis following experimental stroke in mice JF - Scientific Reports N2 - Ischemic stroke is among the leading causes of disability and death worldwide. In acute ischemic stroke, successful recanalization of occluded vessels is the primary therapeutic aim, but even if it is achieved, not all patients benefit. Although blockade of platelet aggregation did not prevent infarct progression, cerebral thrombosis as cause of secondary infarct growth has remained a matter of debate. As cerebral thrombi are frequently observed after experimental stroke, a thrombus-induced impairment of the brain microcirculation is considered to contribute to tissue damage. Here, we combine the model of transient middle cerebral artery occlusion (tMCAO) with light sheet fluorescence microscopy and immunohistochemistry of brain slices to investigate the kinetics of thrombus formation and infarct progression. Our data reveal that tissue damage already peaks after 8 h of reperfusion following 60 min MCAO, while cerebral thrombi are only observed at later time points. Thus, cerebral thrombosis is not causative for secondary infarct growth during ischemic stroke. KW - cerebrovascular disorders KW - thrombosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265791 VL - 11 IS - 1 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Guthmann, Josua A1 - Stoll, Guido A1 - Nieswandt, Bernhard A1 - Kraft, Peter A1 - Kleinschnitz, Christoph T1 - Blocking of platelet glycoprotein receptor Ib reduces “thrombo-inflammation” in mice with acute ischemic stroke JF - Journal of Neuroinflammation N2 - Background: Ischemic stroke causes a strong inflammatory response that includes T cells, monocytes/macrophages, and neutrophils. Interaction of these immune cells with platelets and endothelial cells facilitates microvascular dysfunction and leads to secondary infarct growth. We recently showed that blocking of platelet glycoprotein (GP) receptor Ib improves stroke outcome without increasing the risk of intracerebral hemorrhage. Until now, it has been unclear whether GPIb only mediates thrombus formation or also contributes to the pathophysiology of local inflammation. Methods: Focal cerebral ischemia was induced in C57BL/6 mice by a 60-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab). Rat immunoglobulin G (IgG) Fab was used as control treatment. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 1 after tMCAO. Results: Blocking of GPIb reduced stroke size and improved functional outcome on day 1 after tMCAO without increasing the risk of intracerebral hemorrhage. As expected, disruption of GPIb-mediated pathways in platelets significantly reduced thrombus burden in the cerebral microvasculature. In addition, inhibition of GPIb limited the local inflammatory response in the ischemic brain as indicated by lower numbers of infiltrating T cells and macrophages and lower expression levels of inflammatory cytokines compared with rat IgG Fab-treated controls. Conclusion: In acute ischemic stroke, thrombus formation and inflammation are closely intertwined (“thrombo-inflammation”). Blocking of platelet GPIb can ameliorate thrombo-inflammation. KW - ischemic stroke KW - occlusion KW - transient middle cerebral artery KW - glycoprotein receptor Ib KW - thrombo-inflammation Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157582 VL - 14 IS - 18 ER - TY - JOUR A1 - Bellut, Maximilian A1 - Bieber, Michael A1 - Kraft, Peter A1 - Weber, Alexander N. R. A1 - Stoll, Guido A1 - Schuhmann, Michael K. T1 - Delayed NLRP3 inflammasome inhibition ameliorates subacute stroke progression in mice JF - Journal of Neuroinflammation N2 - Background Ischemic stroke immediately evokes a strong neuro-inflammatory response within the vascular compartment, which contributes to primary infarct development under vessel occlusion as well as further infarct growth despite recanalization, referred to as ischemia/reperfusion injury. Later, in the subacute phase of stroke (beyond day 1 after recanalization), further inflammatory processes within the brain parenchyma follow. Whether this second wave of parenchymal inflammation contributes to an additional/secondary increase in infarct volumes and bears the potential to be pharmacologically targeted remains elusive. We addressed the role of the NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome in the subacute phase of ischemic stroke. Methods Focal cerebral ischemia was induced in C57Bl/6 mice by a 30-min transient middle cerebral artery occlusion (tMCAO). Animals were treated with the NLRP3 inhibitor MCC950 therapeutically 24 h after or prophylactically before tMCAO. Stroke outcome, including infarct size and functional deficits as well as the local inflammatory response, was assessed on day 7 after tMCAO. Results Infarct sizes on day 7 after tMCAO decreased about 35% after delayed and about 60% after prophylactic NLRP3 inhibition compared to vehicle. Functionally, pharmacological inhibition of NLRP3 mitigated the local inflammatory response in the ischemic brain as indicated by reduction of infiltrating immune cells and reactive astrogliosis. Conclusions Our results demonstrate that the NLRP3 inflammasome continues to drive neuroinflammation within the subacute stroke phase. NLRP3 inflammasome inhibition leads to a better long-term outcome—even when administered with a delay of 1 day after stroke induction, indicating ongoing inflammation-driven infarct progression. These findings may pave the way for eagerly awaited delayed treatment options in ischemic stroke. KW - ischemic stroke KW - secondary infarct growth KW - neuroinflammation KW - middle cerebral artery occlusion KW - NLRP3 KW - inflammasome Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300599 VL - 20 IS - 1 ER - TY - JOUR A1 - Schuhmann, Michael K. A1 - Bieber, Michael A1 - Franke, Maximilian A1 - Kollikowski, Alexander M. A1 - Stegner, David A1 - Heinze, Katrin G. A1 - Nieswandt, Bernhard A1 - Pham, Mirko A1 - Stoll, Guido T1 - Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice JF - Journal of Neuroinflammation N2 - Background In acute ischemic stroke, cessation of blood flow causes immediate tissue necrosis within the center of the ischemic brain region accompanied by functional failure in the surrounding brain tissue designated the penumbra. The penumbra can be salvaged by timely thrombolysis/thrombectomy, the only available acute stroke treatment to date, but is progressively destroyed by the expansion of infarction. The underlying mechanisms of progressive infarction are not fully understood. Methods To address mechanisms, mice underwent filament occlusion of the middle cerebral artery (MCAO) for up to 4 h. Infarct development was compared between mice treated with antigen-binding fragments (Fab) against the platelet surface molecules GPIb (p0p/B Fab) or rat immunoglobulin G (IgG) Fab as control treatment. Moreover, Rag1\(^{−/−}\) mice lacking T-cells underwent the same procedures. Infarct volumes as well as the local inflammatory response were determined during vessel occlusion. Results We show that blocking of the platelet adhesion receptor, glycoprotein (GP) Ibα in mice, delays cerebral infarct progression already during occlusion and thus before recanalization/reperfusion. This therapeutic effect was accompanied by decreased T-cell infiltration, particularly at the infarct border zone, which during occlusion is supplied by collateral blood flow. Accordingly, mice lacking T-cells were likewise protected from infarct progression under occlusion. Conclusions Progressive brain infarction can be delayed by blocking detrimental lymphocyte/platelet responses already during occlusion paving the way for ultra-early treatment strategies in hyper-acute stroke before recanalization. KW - ischemic penumbra KW - glycoprotein receptor Ib KW - T-cells KW - ischemic stroke KW - thrombo-inflammation KW - middle cerebral artery occlusion Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259172 VL - 18 IS - 1 ER - TY - JOUR A1 - Piroth, Tobias A1 - Boelmans, Kai A1 - Amtage, Florian A1 - Rijntjes, Michel A1 - Wierciochin, Anna A1 - Musacchio, Thomas A1 - Weiller, Cornelius A1 - Volkmann, Jens A1 - Klebe, Stephan T1 - Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult JF - Frontiers in Neurology N2 - Niemann–Pick type C disease (NP-C) presents with heterogeneous neurological and psychiatric symptoms. Adult onset is rare and possibly underdiagnosed due to frequent lack of specific and obvious key symptoms. For both early and adolescent/adult onset, the available data from studies and case reports describe a positive effect of Miglustat (symptom relief or stabilization). However, due to the low frequency of NP-C, experience with this therapy is still limited. We describe two adult-onset cases of NP-C. In both cases, vertical supranuclear gaze palsy was not recognized at symptom onset. Correct diagnosis was delayed from onset of symptoms by more than 10 years. The video demonstrates the broad spectrum of symptoms in later stages of the disease. Compared with published data, the treatment outcome observed in our cases after delayed initiation of Miglustat therapy was disappointing, with continuing disease progression in both cases. Thus, early treatment initiation could be necessary to achieve a good symptomatic effect. Hence, early biochemical testing for NP-C should be considered in patients suffering from atypical neurological/neuropsychological and psychiatric symptoms, even in cases of uncertainty. KW - Niemann–Pick disease type C KW - adult-onset KW - NPC1 gene KW - NPC2 gene KW - plasma oxysterols Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171001 VL - 8 IS - 108 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Schließer, Mira A1 - Evdokimov, Dimitar A1 - Radziwon, Jakub A1 - Feulner, Betty A1 - Unterecker, Stefan A1 - Rimmele, Florian A1 - Walter, Uwe T1 - Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome JF - PloS One N2 - Objectives The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS. Methods Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis. Results Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms. Conclusion We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression. KW - midbrain KW - fibromyalgia KW - depression KW - pain KW - ultrasound imaging KW - neuropathic pain KW - diagnostic medicine KW - migraine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300639 VL - 17 IS - 11 ER - TY - JOUR A1 - Sommer, Claudia A1 - Carroll, Antonia S. A1 - Koike, Haruki A1 - Katsuno, Masahisa A1 - Ort, Nora A1 - Sobue, Gen A1 - Vucic, Steve A1 - Spies, Judith M. A1 - Doppler, Kathrin A1 - Kiernan, Matthew C. T1 - Nerve biopsy in acquired neuropathies JF - Journal of the Peripheral Nervous System N2 - A diagnosis of neuropathy can typically be determined through clinical assessment and focused investigation. With technological advances, including significant progress in genomics, the role of nerve biopsy has receded over recent years. However, making a specific and, in some cases, tissue-based diagnosis is essential across a wide array of potentially treatable acquired peripheral neuropathies. When laboratory investigations do not suggest a definitive diagnosis, nerve biopsy remains the final step to ascertain the etiology of the disease. The present review highlights the utility of nerve biopsy in confirming a diagnosis, while further illustrating the importance of a tissue-based diagnosis in relation to treatment strategies, particularly when linked to long-term immunosuppressive therapies, KW - inflammatory neuropathy KW - nerve biopsy KW - nerve tumor KW - neuroleukemiosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259555 VL - 26 IS - S2 ER - TY - JOUR A1 - Karikari, Akua A. A1 - McFleder, Rhonda L. A1 - Ribechini, Eliana A1 - Blum, Robert A1 - Bruttel, Valentin A1 - Knorr, Susanne A1 - Gehmeyr, Mona A1 - Volkmann, Jens A1 - Brotchie, Jonathan M. A1 - Ahsan, Fadhil A1 - Haack, Beatrice A1 - Monoranu, Camelia-Maria A1 - Keber, Ursula A1 - Yeghiazaryan, Rima A1 - Pagenstecher, Axel A1 - Heckel, Tobias A1 - Bischler, Thorsten A1 - Wischhusen, Jörg A1 - Koprich, James B. A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson’s disease mice JF - Brain, Behavior, and Immunity N2 - Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson’s disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68–78) and surrounding the pathogenically relevant S129 (120–134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology. KW - Parkinson’s disease KW - α-synuclein-specific T cells KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300600 VL - 101 SP - 194 EP - 210 ER - TY - JOUR A1 - Peseschkian, Tara A1 - Cordts, Isabell A1 - Günther, René A1 - Stolte, Benjamin A1 - Zeller, Daniel A1 - Schröter, Carsten A1 - Weyen, Ute A1 - Regensburger, Martin A1 - Wolf, Joachim A1 - Schneider, Ilka A1 - Hermann, Andreas A1 - Metelmann, Moritz A1 - Kohl, Zacharias A1 - Linker, Ralf A. A1 - Koch, Jan Christoph A1 - Büchner, Boriana A1 - Weiland, Ulrike A1 - Schönfelder, Erik A1 - Heinrich, Felix A1 - Osmanovic, Alma A1 - Klopstock, Thomas A1 - Dorst, Johannes A1 - Ludolph, Albert C. A1 - Boentert, Matthias A1 - Hagenacker, Tim A1 - Deschauer, Marcus A1 - Lingor, Paul A1 - Petri, Susanne A1 - Schreiber-Katz, Olivia T1 - A nation-wide, multi-center study on the quality of life of ALS patients in Germany JF - Brain Sciences N2 - Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care. KW - Amyotrophic Lateral Sclerosis (ALS) KW - Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) KW - ALS treatment KW - “bulbar-onset” ALS (bALS) KW - “limb-onset” ALS (lALS) KW - EuroQol Five Dimension Five Level Scale (EQ-5D-5L) KW - health-related quality of life (HRQoL) KW - quality of life (QoL) KW - symptom-specific treatment KW - assistive devices Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234147 SN - 2076-3425 VL - 11 IS - 3 ER - TY - JOUR A1 - Kremer, Naomi I. A1 - Pauwels, Rik W. J. A1 - Pozzi, Nicolò G. A1 - Lange, Florian A1 - Roothans, Jonas A1 - Volkmann, Jens A1 - Reich, Martin M. T1 - Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions JF - Journal of Clinical Medicine N2 - Deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus is one of the main advanced neurosurgical treatments for drug-resistant tremor. However, not every patient may be eligible for this procedure. Nowadays, various other functional neurosurgical procedures are available. In particular cases, radiofrequency thalamotomy, focused ultrasound and radiosurgery are proven alternatives to DBS. Besides, other DBS targets, such as the posterior subthalamic area (PSA) or the dentato-rubro-thalamic tract (DRT), may be appraised as well. In this review, the clinical characteristics and pathophysiology of tremor syndromes, as well as long-term outcomes of DBS in different targets, will be summarized. The effectiveness and safety of lesioning procedures will be discussed, and an evidence-based clinical treatment approach for patients with drug-resistant tremor will be presented. Lastly, the future directions in the treatment of severe tremor syndromes will be elaborated. KW - deep brain stimulation KW - tremor KW - essential tremor KW - Parkinson’s disease KW - outcomes KW - clinical approach KW - target considerations KW - future directions Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244982 SN - 2077-0383 VL - 10 IS - 16 ER - TY - JOUR A1 - Samper Agrelo, Iria A1 - Schira-Heinen, Jessica A1 - Beyer, Felix A1 - Groh, Janos A1 - Bütermann, Christine A1 - Estrada, Veronica A1 - Poschmann, Gereon A1 - Bribian, Ana A1 - Jadasz, Janusz J. A1 - Lopez-Mascaraque, Laura A1 - Kremer, David A1 - Martini, Rudolf A1 - Müller, Hans Werner A1 - Hartung, Hans Peter A1 - Adjaye, James A1 - Stühler, Kai A1 - Küry, Patrick T1 - Secretome analysis of mesenchymal stem cell factors fostering oligodendroglial differentiation of neural stem cells in vivo JF - International Journal of Molecular Sciences N2 - Mesenchymal stem cell (MSC)-secreted factors have been shown to significantly promote oligodendrogenesis from cultured primary adult neural stem cells (aNSCs) and oligodendroglial precursor cells (OPCs). Revealing underlying mechanisms of how aNSCs can be fostered to differentiate into a specific cell lineage could provide important insights for the establishment of novel neuroregenerative treatment approaches aiming at myelin repair. However, the nature of MSC-derived differentiation and maturation factors acting on the oligodendroglial lineage has not been identified thus far. In addition to missing information on active ingredients, the degree to which MSC-dependent lineage instruction is functional in vivo also remains to be established. We here demonstrate that MSC-derived factors can indeed stimulate oligodendrogenesis and myelin sheath generation of aNSCs transplanted into different rodent central nervous system (CNS) regions, and furthermore, we provide insights into the underlying mechanism on the basis of a comparative mass spectrometry secretome analysis. We identified a number of secreted proteins known to act on oligodendroglia lineage differentiation. Among them, the tissue inhibitor of metalloproteinase type 1 (TIMP-1) was revealed to be an active component of the MSC-conditioned medium, thus validating our chosen secretome approach. KW - neural stem cells KW - mesenchymal stem cells KW - transplantation KW - oligodendroglia KW - glial fate modulation KW - myelin KW - spinal cord KW - secretome KW - TIMP-1 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285465 SN - 1422-0067 VL - 21 IS - 12 ER - TY - JOUR A1 - Peterka, Manuel A1 - Odorfer, Thorsten A1 - Schwab, Michael A1 - Volkmann, Jens A1 - Zeller, Daniel T1 - LSVT-BIG therapy in Parkinson's disease: physiological evidence for proprioceptive recalibration JF - BMC Neurology N2 - Background There is growing evidence for proprioceptive dysfunction in patients with Parkinson's disease (PD). The Lee Silvermann Voice Treatment-BIG therapy (LSVT-BIG), a special training program aiming at an increase of movement amplitudes in persons with PD (PwPD), has shown to be effective on motor symptoms. LSVT-BIG is conceptionally based on improving bradykinesia, in particular the decrement of repetitive movements, by proprioceptive recalibration. Objective To assess proprioceptive impairment in PwPD as compared to matched controls and to probe potential recalibration effects of the LSVT-BIG therapy on proprioception. Methods Proprioceptive performance and fine motor skills were assessed in 30 PwPD and 15 matched controls. Measurements with significant impairment in PwPD were chosen as outcome parameters for a standardized 4 weeks amplitude-based training intervention (LSVT-BIG) in 11 PwPD. Proprioceptive performance served as primary outcome measure. Secondary outcome measures included the motor part of the MDS-UPDRS, the nine-hole-peg test, and a questionnaire on quality of life. Post-interventional assessments were conducted at weeks 4 and 8. Results Compared to the control group, PwPD showed significantly larger pointing errors. After 4 weeks of LSVT-BIG therapy and even more so after an additional 4 weeks of continued training, proprioceptive performance improved significantly. In addition, quality of life improved as indicated by a questionnaire. Conclusion LSVT-BIG training may achieve a recalibration of proprioceptive processing in PwPD. Our data indicates a probable physiological mechanism of a symptom-specific, amplitude-based behavioral intervention in PwPD. KW - Proprioception KW - Amplitude KW - Training KW - Pointing error KW - LSVT-big therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230084 VL - 20 ER - TY - JOUR A1 - Schulte, Annemarie A1 - Blum, Robert T1 - Shaped by leaky ER: Homeostatic Ca\(^{2+}\) fluxes JF - Frontiers in Physiology N2 - At any moment in time, cells coordinate and balance their calcium ion (Ca\(^{2+}\)) fluxes. The term ‘Ca\(^{2+}\) homeostasis’ suggests that balancing resting Ca2+ levels is a rather static process. However, direct ER Ca\(^{2+}\) imaging shows that resting Ca\(^{2+}\) levels are maintained by surprisingly dynamic Ca\(^{2+}\) fluxes between the ER Ca\(^{2+}\) store, the cytosol, and the extracellular space. The data show that the ER Ca\(^{2+}\) leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca\(^{2+}\) dynamics. Based on simplistic Ca\(^{2+}\) toolkit models, we discuss how the ER Ca\(^{2+}\) leak could contribute to evolutionarily conserved Ca\(^{2+}\) phenomena such as Ca\(^{2+}\) entry, ER Ca\(^{2+}\) release, and Ca\(^{2+}\) oscillations. KW - Ca2+ homeostasis KW - Ca2+ ion analysis KW - ER Ca2+ store KW - ER Ca2+ imaging KW - SERCA KW - store-operated Ca2+ entry KW - Ca2+ leak KW - Ca2+ oscillation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287102 SN - 1664-042X VL - 13 ER - TY - JOUR A1 - Sommer, Claudia A1 - Klose, Petra A1 - Welsch, Patrick A1 - Petzke, Frank A1 - Häuser, Winfried T1 - Opioids for chronic non‐cancer neuropathic pain. An updated systematic review and meta‐analysis of efficacy, tolerability and safety in randomized placebo‐controlled studies of at least 4 weeks duration JF - European Journal of Pain N2 - Background and Objective This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non‐cancer neuropathic pain. Databases and Data Treatment Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross‐over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo. Conclusions Some opioids provided a short‐term substantial pain relief in highly selected patients in some neuropathic pain syndromes. Significance Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4–12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care. Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218487 VL - 24 IS - 1 SP - 3 EP - 18 ER - TY - JOUR A1 - Deeb, Wissam A1 - Giordano, James J. A1 - Rossi, Peter J. A1 - Mogilner, Alon Y. A1 - Gunduz, Aysegul A1 - Judy, Jack W. A1 - Klassen, Bryan T. A1 - Butson, Christopher R. A1 - Van Horne, Craig A1 - Deny, Damiaan A1 - Dougherty, Darin D. A1 - Rowell, David A1 - Gerhardt, Greg A. A1 - Smith, Gwenn S. A1 - Ponce, Francisco A. A1 - Walker, Harrison C. A1 - Bronte-Stewart, Helen M. A1 - Mayberg, Helen S. A1 - Chizeck, Howard J. A1 - Langevin, Jean-Philippe A1 - Volkmann, Jens A1 - Ostrem, Jill L. A1 - Shute, Jonathan B. A1 - Jimenez-Shahed, Joohi A1 - Foote, Kelly D. A1 - Wagle Shukla, Aparna A1 - Rossi, Marvin A. A1 - Oh, Michael A1 - Pourfar, Michael A1 - Rosenberg, Paul B. A1 - Silburn, Peter A. A1 - de Hemptine, Coralie A1 - Starr, Philip A. A1 - Denison, Timothy A1 - Akbar, Umer A1 - Grill, Warren M. A1 - Okun, Michael S. T1 - Proceedings of the Fourth Annual Deep Brain Stimulation Think Tank: A Review of Emerging Issues and Technologies JF - Frontiers in Integrative Neuroscience N2 - This paper provides an overview of current progress in the technological advances and the use of deep brain stimulation (DBS) to treat neurological and neuropsychiatric disorders, as presented by participants of the Fourth Annual DBS Think Tank, which was convened in March 2016 in conjunction with the Center for Movement Disorders and Neurorestoration at the University of Florida, Gainesveille FL, USA. The Think Tank discussions first focused on policy and advocacy in DBS research and clinical practice, formation of registries, and issues involving the use of DBS in the treatment of Tourette Syndrome. Next, advances in the use of neuroimaging and electrochemical markers to enhance DBS specificity were addressed. Updates on ongoing use and developments of DBS for the treatment of Parkinson's disease, essential tremor, Alzheimer's disease, depression, post-traumatic stress disorder, obesity, addiction were presented, and progress toward innovation(s) in closed-loop applications were discussed. Each section of these proceedings provides updates and highlights of new information as presented at this year's international Think Tank, with a view toward current and near future advancement of the field. KW - deep brain stimulation KW - Parkinson’s disease KW - Alzheimer’s disease KW - closed-loop KW - depression KW - post-traumatic stress disorder KW - Tourette syndrome KW - DARPA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168493 VL - 10 IS - 38 ER - TY - JOUR A1 - Friedrich, Maximilian A1 - Hartig, Johannes A1 - Prüss, Harald A1 - Ip, Wang Chi A1 - Volkmann, Jens T1 - Rapidly progressive dementia: Extending the spectrum of GFAP-astrocytopathies? JF - Annals of Clinical and Translational Neurology N2 - Autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A) is a steroid-responsive meningoencephalomyelitis, sometimes presenting with atypical clinical signs such as movement disorders or psychiatric and autonomic features. Beyond clinical presentation and imaging, diagnosis relies on detection of GFAP-antibodies (AB) in CSF. Using quantitative behavioral, serologic, and immunohistochemical analyses, we characterize two patients longitudinally over 18–24 months who presented with rapidly progressive neurocognitive deterioration in the context of GFAP-AB in CSF and unremarkable cranial MRI studies. Intensified immunotherapy was associated with clinical stabilization. The value of GFAP-AB screening in selected cases of rapidly progressive dementias is discussed. KW - GFAP-astrocytopathies KW - dementia Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312957 VL - 9 IS - 3 ER - TY - JOUR A1 - Braun, Alexandra A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Pauli, Paul A1 - Wabel, Thomas A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Relevance of Religiosity for Coping Strategies and Disability in Patients with Fibromyalgia Syndrome JF - Journal of Religion and Health N2 - Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome. KW - Fibromyalgia syndrome KW - religiosity KW - coping KW - disability Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269135 SN - 1573-6571 VL - 61 IS - 1 ER - TY - JOUR A1 - Odorfer, Thorsten M. A1 - Volkmann, Jens T1 - Deep brain stimulation for focal or segmental craniocervical dystonia in patients who have failed botulinum neurotoxin therapy - a narrative review of the literature JF - Toxins N2 - (1) Background: The first-line treatment for patients with focal or segmental dystonia with a craniocervical distribution is still the intramuscular injection of botulinum neurotoxin (BoNT). However, some patients experience primary or secondary treatment failure from this potential immunogenic therapy. Deep brain stimulation (DBS) may then be used as a backup strategy in this situation. (2) Methods: Here, we reviewed the current study literature to answer a specific question regarding the efficacy and safety of the use of DBS, particularly for cervical dystonia (CD) and Meige syndrome (MS) in patients with documented treatment failure under BoNT. (3) Results: There are only two studies with the highest level of evidence in this area. Despite this clear limitation, in the context of the narrowly defined research question of this paper, it is possible to report 161 patients with CD or MS who were included in studies that were able to show a statistically significant reduction in dystonic symptoms using DBS. Safety and tolerability data appeared adequate. However, much of the information is based on retrospective observations. (4) Conclusions: The evidence base in this area is in need of further scientific investigation. Most importantly, more randomized, controlled and double-blind trials are needed, possibly including a head-to-head comparison of DBS and BoNT. KW - cervical dystonia KW - Meige syndrome KW - deep brain stimulation KW - internal globus pallidus KW - subthalamic nucleus KW - botulinum neurotoxin KW - medication therapy failure KW - symptom control KW - safety and tolerability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357707 SN - 2072-6651 VL - 15 IS - 10 ER - TY - JOUR A1 - Hiew, Shawn A1 - Eibeck, Leila A1 - Nguemeni, Carine A1 - Zeller, Daniel T1 - The influence of age and physical activity on locomotor adaptation JF - Brain Sciences N2 - Background: Aging increases individual susceptibility to falls and injuries, suggesting poorer adaptation of balance responses to perturbation during locomotion, which can be measured with the locomotor adaptation task (LAT). However, it is unclear how aging and lifestyle factors affect these responses during walking. Hence, the present study investigates the relationship between balance and lifestyle factors during the LAT in healthy individuals across the adult lifespan using a correlational design. Methods: Thirty participants aged 20–78 years performed an LAT on a split-belt treadmill (SBT). We evaluated the magnitude and rate of adaptation and deadaptation during the LAT. Participants reported their lifelong physical and cognitive activity. Results: Age positively correlated with gait-line length asymmetry at the late post-adaptation phase (p = 0.007). These age-related effects were mediated by recent physical activity levels (p = 0.040). Conclusion: Our results confirm that locomotor adaptive responses are preserved in aging, but the ability to deadapt newly learnt balance responses is compromised with age. Physical activity mediates these age-related effects. Therefore, gait symmetry post-adaptation could effectively measure the risk of falling, and maintaining physical activity could protect against declines in balance. KW - locomotor adaptation KW - walking KW - physical activity KW - exercise KW - aging KW - balance Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-362478 SN - 2076-3425 VL - 13 IS - 9 ER - TY - JOUR A1 - Bohmann, Ferdinand O. A1 - Kurka, Natalia A1 - du Mesnil de Rochemont, Richard A1 - Gruber, Katharina A1 - Guenther, Joachim A1 - Rostek, Peter A1 - Rai, Heike A1 - Zickler, Philipp A1 - Ertl, Michael A1 - Berlis, Ansgar A1 - Poli, Sven A1 - Mengel, Annerose A1 - Ringleb, Peter A1 - Nagel, Simon A1 - Pfaff, Johannes A1 - Wollenweber, Frank A. A1 - Kellert, Lars A1 - Herzberg, Moriz A1 - Koehler, Luzie A1 - Haeusler, Karl Georg A1 - Alegiani, Anna A1 - Schubert, Charlotte A1 - Brekenfeld, Caspar A1 - Doppler, Christopher E. J. A1 - Onur, Oezguer A. A1 - Kabbasch, Christoph A1 - Manser, Tanja A1 - Pfeilschifter, Waltraud T1 - Simulation-based training of the rapid evaluation and management of acute stroke (STREAM) — a prospective single-arm multicenter trial JF - Frontiers in Neurology N2 - Introduction: Acute stroke care delivered by interdisciplinary teams is time-sensitive. Simulation-based team training is a promising tool to improve team performance in medical operations. It has the potential to improve process times, team communication, patient safety, and staff satisfaction. We aim to assess whether a multi-level approach consisting of a stringent workflow revision based on peer-to-peer review and 2–3 one-day in situ simulation trainings can improve acute stroke care processing times in high volume neurocenters within a 6 months period. Methods and Analysis: The trial is being carried out in a pre-test-post-test design at 7 tertiary care university hospital neurocenters in Germany. The intervention is directed at the interdisciplinary multiprofessional stroke teams. Before and after the intervention, process times of all direct-to-center stroke patients receiving IV thrombolysis (IVT) and/or endovascular therapy (EVT) will be recorded. The primary outcome measure will be the “door-to-needle” time of all consecutive stroke patients directly admitted to the neurocenters who receive IVT. Secondary outcome measures will be intervention-related process times of the fraction of patients undergoing EVT and effects on team communication, perceived patient safety, and staff satisfaction via a staff questionnaire. Interventions: We are applying a multi-level intervention in cooperation with three “STREAM multipliers” from each center. First step is a central meeting of the multipliers at the sponsor's institution with the purposes of algorithm review in a peer-to-peer process that is recorded in a protocol and an introduction to the principles of simulation training and debriefing as well as crew resource management and team communication. Thereafter, the multipliers cooperate with the stroke team trainers from the sponsor's institution to plan and execute 2–3 one-day simulation courses in situ in the emergency department and CT room of the trial centers whereupon they receive teaching materials to perpetuate the trainings. Clinical Trial Registration: STREAM is a registered trial at https://clinicaltrials.gov/ct2/show/NCT03228251. KW - CRM KW - thrombolysis (tPA) KW - stroke KW - emergency care KW - simulation training Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369239 SN - 1664-2295 VL - 10 ER - TY - JOUR A1 - Bolzoni, Francesco A1 - Esposti, Roberto A1 - Marchese, Silvia M. A1 - Pozzi, Nicoló G. A1 - Ramirez-Pasos, Uri E. A1 - Isaias, Ioannis U. A1 - Cavallari, Paolo T1 - Disrupt of intra-limb APA pattern in parkinsonian patients performing index-finger flexion JF - Frontiers in Physiology N2 - Voluntary movements induce postural perturbations which are counteracted by anticipatory postural adjustments (APAs). These actions are known to build up long fixation chains toward available support points (inter-limb APAs), so as to grant whole body equilibrium. Moreover, recent studies highlighted that APAs also build-up short fixation chains, within the same limb where a distal segment is moved (intra-limb APAs), aimed at stabilizing the proximal segments. The neural structures generating intra-limb APAs still need investigations; the present study aims to compare focal movement kinematics and intra-limb APA latencies and pattern between healthy subjects and parkinsonian patients, assuming the latter as a model of basal ganglia dysfunction. Intra-limb APAs that stabilize the arm when the index-finger is briskly flexed were recorded in 13 parkinsonian patients and in 10 age-matched healthy subjects. Index-finger movement was smaller in parkinsonian patients vs. healthy subjects (p = 0.01) and more delayed with respect to the onset of the prime mover flexor digitorum superficialis (FDS, p < 0.0001). In agreement with the literature, in all healthy subjects the FDS activation was preceded by an inhibitory intra-limb APA in biceps brachii (BB) and anterior deltoid (AD), and almost simultaneous to an excitatory intra-limb APA in triceps brachii (TB). In parkinsonian patients, no significant differences were found for TB and AD intra-limb APA timings, however only four patients showed an inhibitory intra-limb APA in BB, while other four did not show any BB intra-limb APAs and five actually developed a BB excitation. The frequency of occurrence of normal sign, lacking, and inverted BB APAs was different in healthy vs. parkinsonian participants (p = 0.0016). The observed alterations in index-finger kinematics and intra-limb APA pattern in parkinsonian patients suggest that basal ganglia, in addition to shaping the focal movement, may also contribute to intra-limb APA control. KW - intra-limb anticipatory postural adjustments KW - Parkinson disease KW - basal ganglia KW - motor control KW - human Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369245 SN - 1664-042X VL - 9 ER - TY - JOUR A1 - Doppler, Kathrin A1 - Brockmann, Kathrin A1 - Sedghi, Annahita A1 - Wurster, Isabel A1 - Volkmann, Jens A1 - Oertel, Wolfgang H. A1 - Sommer, Claudia T1 - Dermal phospho-alpha-synuclein deposition in patients with Parkinson's disease and mutation of the glucocerebrosidase gene JF - Frontiers in Neurology N2 - Heterozygous mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson's disease (PD) and are histopathologically associated with a widespread load of alpha-synuclein in the brain. Therefore, PD patients with GBA1 mutations are a cohort of high interest for clinical trials on disease-modifying therapies targeting alpha-synuclein. There is evidence that detection of phospho-alpha-synuclein (p-syn) in dermal nerve fibers might be a biomarker for the histopathological identification of PD patients even at premotor or very early stages of disease. It is so far unknown whether dermal p-syn deposition can also be found in PD patients with GBA1 mutations and may serve as a biomarker for PD in these patients. Skin biopsies of 10 PD patients with different GBA1 mutations (six N3705, three E326K, one L444P) were analyzed by double-immunofluorescence labeling with anti-p-syn and anti-protein gene product 9.5 (PGP9.5, axonal marker) to detect intraaxonal p-syn deposition. Four biopsy sites (distal, proximal leg, paravertebral Th10, and C7) per patient were studied. P-syn was found in six patients (three N370S, three E326K). P-syn deposition was mainly detected in autonomic nerve fibers, but also in somatosensory fibers and was not restricted to a certain GBA1 mutation. In summary, dermal p-syn in PD patients with GBA1 mutations seems to offer a similar distribution and frequency as observed in patients without a known mutation. Skin biopsy may be suitable to study p-syn deposition in these patients or even to identify premotor patients with GBA1 mutations. KW - Parkinson's disease KW - glucocerebrosidase mutation KW - alpha-synuclein KW - skin biopsy KW - biomarker Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222828 VL - 9 ER - TY - JOUR A1 - Odin, Per A1 - Chaudhuri, K. Ray A1 - Volkmann, Jens A1 - Antonini, Angelo A1 - Storch, Alexander A1 - Dietrichs, Espen A1 - Pirtošek, Zvezdan A1 - Henriksen, Tove A1 - Horne, Malcolm A1 - Devos, David A1 - Bergquist, Filip T1 - Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson’s disease JF - npj Parkinson's Disease N2 - Motor aspects of Parkinson’s disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of “wearable” technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson’s disease (PD) is defining cutoff values that separate “controlled” from “uncontrolled” symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base. KW - Parkinson's disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234435 VL - 4 ER - TY - JOUR A1 - Langhauser, Friederike A1 - Casas, Ana I. A1 - Dao, Vu-Thao-Vi A1 - Guney, Emre A1 - Menche, Jörg A1 - Geuss, Eva A1 - Kleikers, Pamela W. M. A1 - López, Manuela G. A1 - Barabási, Albert-L. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection JF - npj Systems Biology and Applications N2 - Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy. KW - neurology KW - pharmacology KW - systems biology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236381 VL - 4 ER - TY - JOUR A1 - Sulzer, David A1 - Cassidy, Clifford A1 - Horga, Guillermo A1 - Kang, Un Jung A1 - Fahn, Stanley A1 - Casella, Luigi A1 - Pezzoli, Gianni A1 - Langley, Jason A1 - Hu, Xiaoping P. A1 - Zucca, Fabio A. A1 - Isaias, Ioannis U. A1 - Zecca, Luigi T1 - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease JF - npj Parkinson's Disease N2 - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207 VL - 4 ER - TY - JOUR A1 - Ullrich, M A1 - Weber, M A1 - Post, A M A1 - Popp, S A1 - Grein, J A1 - Zechner, M A1 - González, H Guerrero A1 - Kreis, A A1 - Schmitt, A G A1 - Üҫeyler, N A1 - Lesch, K-P A1 - Schuh, K T1 - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency JF - Molecular Psychiatry N2 - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD. KW - molecular biology KW - neuroscience KW - physiology KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096 VL - 23 ER - TY - JOUR A1 - Geran, Rohat A1 - Uecker, Florian C. A1 - Prüss, Harald A1 - Haeusler, Karl Georg A1 - Paul, Friedemann A1 - Ruprecht, Klemens A1 - Harms, Lutz A1 - Schmidt, Felix A. T1 - Olfactory and Gustatory Dysfunction in Patients With Autoimmune Encephalitis JF - Frontiers in Neurology N2 - Objective: To test the hypothesis that olfactory (OF) and gustatory function (GF) is disturbed in patients with autoimmune encephalitides (AE). Methods: The orthonasal OF was tested in 32 patients with AE and 32 age- and sex-matched healthy controls (HC) with the standardized Threshold Discrimination Identification (TDI) score. This validated olfactory testing method yields individual scores for olfactory threshold (T), odor discrimination (D), and identification (I), along with a composite TDI score. The GF was determined by the Taste Strip Test (TST). Results: Overall, 24/32 (75%) of patients with AE, but none of 32 HC (p < 0.001) had olfactory dysfunction in TDI testing. The results of the threshold, discrimination and identification subtests were significantly reduced in patients with AE compared to HC (all p < 0.001). Assessed by TST, 5/19 (26.3%) of patients with AE, but none of 19 HC presented a significant limitation in GF (p < 0.001). The TDI score was correlated with the subjective estimation of the olfactory capacity on a visual analog scale (VAS; rs = 0.475, p = 0.008). Neither age, sex, modified Rankin Scale nor disease duration were associated with the composite TDI score. Conclusions: This is the first study investigating OF and GF in AE patients. According to unblinded assessment, patients with AE have a reduced olfactory and gustatory capacity compared to HC, suggesting that olfactory and gustatory dysfunction are hitherto unrecognized symptoms in AE. Further studies with larger number of AE patients would be of interest to verify our results. KW - autoimmune encephalitis KW - olfactory dysfunction KW - gustatory dysfunction KW - olfactory testing KW - threshold discrimination identification test Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232921 VL - 10 ER - TY - JOUR A1 - Vural, Atay A1 - Doppler, Kathrin A1 - Meinl, Edgar T1 - Autoantibodies Against the Node of Ranvier in Seropositive Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic, Pathogenic, and Therapeutic Relevance JF - Frontiers in Immunology N2 - Discovery of disease-associated autoantibodies has transformed the clinical management of a variety of neurological disorders. Detection of autoantibodies aids diagnosis and allows patient stratification resulting in treatment optimization. In the last years, a set of autoantibodies against proteins located at the node of Ranvier has been identified in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). These antibodies target neurofascin, contactin1, or contactin-associated protein 1, and we propose to name CIDP patients with these antibodies collectively as seropositive. They have unique clinical characteristics that differ from seronegative CIDP. Moreover, there is compelling evidence that autoantibodies are relevant for the pathogenesis. In this article, we review the current knowledge on the characteristics of autoantibodies against the node of Ranvier proteins and their clinical relevance in CIDP. We start with a description of the structure of the node of Ranvier followed by a summary of assays used to identify seropositive patients; and then, we describe clinical features and characteristics linked to seropositivity. We review knowledge on the role of these autoantibodies for the pathogenesis with relevance for the emerging concept of nodopathy/paranodopathy and summarize the treatment implications. KW - autoantibody KW - seropositive KW - chronic inflammatory demyelinating polyneuropathy KW - node of Ranvier KW - paranode KW - neurofascin KW - contactin KW - contactin-associated protein 1 Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233279 VL - 9 ER -