Neurologische Klinik und Poliklinik
Refine
Has Fulltext
- yes (527)
Year of publication
Document Type
- Journal article (359)
- Doctoral Thesis (165)
- Report (2)
- Book (1)
Keywords
- ischemic stroke (27)
- multiple sclerosis (22)
- deep brain stimulation (20)
- Parkinson's disease (19)
- Parkinson’s disease (18)
- neuroinflammation (18)
- Fabry disease (17)
- Multiple Sklerose (17)
- stroke (17)
- Schlaganfall (16)
Institute
- Neurologische Klinik und Poliklinik (527)
- Institut für diagnostische und interventionelle Neuroradiologie (ehem. Abteilung für Neuroradiologie) (26)
- Graduate School of Life Sciences (19)
- Neurochirurgische Klinik und Poliklinik (18)
- Medizinische Klinik und Poliklinik I (17)
- Institut für Klinische Epidemiologie und Biometrie (16)
- Institut für Klinische Neurobiologie (16)
- Rudolf-Virchow-Zentrum (16)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (14)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (13)
Schriftenreihe
Sonstige beteiligte Institutionen
- Datenintegrationszentrum Würzburg (DIZ) (1)
- Institut für Musikphysiologie und Musiker-Medizin der Hochschule für Musik, Theater und Medien, Hannover (1)
- Interdisziplinäre Biomaterial- und Datenbank Würzburg (ibdw) (1)
- Interdisziplinäres Amyloidosezentrum Nordbayern (1)
- KfH Nierenzentrum (1)
- Klinische Studienzentrale (Universitätsklinikum) (1)
- Politecnico di Milano (1)
- Sahin Lab, F.M. Kirby Neurobiology Center Boston Children’s Hospital, Department of Neurology, Harvard Medical School (1)
- Wurzburg Fabry Center for Interdisciplinary Therapy (FAZIT), Wurzburg, Germany (1)
- Würzburg Fabry Center for Interdisciplinary Therapy (FAZIT), University of Würzburg, Würzburg, Germany (1)
Die Prognose einer lebensbedrohlichen Meningitis wird bestimmt durch möglichst erregergerechte und möglichst frühzeitige Therapie. Dabei spielt die Unterscheidung zwischen eitriger Meningitis durch typische oder schwer anzüchtbare Bakterien und abakterieller Meningitis eine Rolle, um die potentiellen Komplikationen unnötiger Polypragmasie zu vermeiden. Daher sind möglichst einfach und rasch zu bestimmende Laborparameter zur Untersuchung wünschenswert. Als relativ neuer Parameter zur Differenzierung bakterieller von nicht bakteriellen Infekten ist Procalcitonin (PCT) eingeführt, dessen Bestimmung jetzt auch am Krankenbett möglich ist. PCT hat bisher seine Nützlichkeit v. a. in der Sepsiserkennung und –therapie gezeigt. Erste Fragestellung dieser retrospektiven Analyse von Meningoencephalitispatienten war, ob bei Erwachsenen durch Messung des PCT-Spiegels eine Differenzierung zwischen bakterieller oder viraler Genese gelingt, und ob der Bedsidetest so zuverlässig ist wie der aufwändigere LUMItest®. Dazu wurden retrospektiv die Daten von 141 Patienten erhoben, die 1992-2001 an der Neurologischen Universitätsklinik Würzburg mit gesicherter Meningitis behandelt wurden, von denen sowohl Akten als auch Liquor- und Serumasservate vorlagen, in denen die PCT-Messungen durchgeführt wurden. In den Untersuchungen von Schwarz et al. [102], Gendrel et al. [100] und Jereb et al. [104] wurde bei einem PCT-Grenzwert von 0,5 ng/ml eine Spezifität von 100 % für die Differenzierung bakterielle verusus abakterielle Meninigitis gefunden. Dagegen wären bei gleicher Messmethodik im hier vorliegendem größeren Patientengut 35 % der gesicherten bakteriellen Meningitiden bei einem „cut-off“ von 0,5 ng/ml nicht als solche erkannt worden. 5 % der nicht-bakteriellen Meningitiden wären mittels PCT-Messung als bakteriell eingestuft worden. Im hier untersuchten Patientenkollektiv hatte PCT als diagnostischer Parameter für diese Fragestellung bei einem Grenzwert von 0,5 ng/ml eine Sensitivität von 65 % und eine Spezifität von 96 %. Eine 100 % Spezifität wäre in unserer Untersuchung bei einem „cut-off“ von 1 ng/ml erreicht worden. Diese Grenze wird jedoch auf dem Schnelltest nicht angegeben. Es stellte sich hier heraus, dass der PCT®-Q Schnelltest im Bereich > 0,5 ng/ml bzw. <0,5 ng/ml dem LUMItest® vergleichbare Ergebnisse lieferte. Das bedeutet zwar, dass alle bakteriellen Meningitiden durch typische Erreger (Meningokokken und Pneumokokken) rasch und sicher bettseitig mittels PCT-Schnelltest hätten identifiziert werden können. Aber ein niedriger PCT-Wert schloss eine bakterielle Meningitis, insbesondere eine durch „atypische Erreger“ wie Listerien und Mycobakterien, nicht sicher aus. Denkbare Störgrößen für das vorliegende Ergebnis sind Antibiotikagabe und Immunschwäche. Ein statistisch auffallender Einfluss einer Antibiotikatherapie auf den PCT-Spiegel konnte in unserem Patientengut nicht festgestellt werden. Für die wenigen Fälle mit anzunehmender verminderter Immunleistung ließ sich keine Regel bezüglich der PCT-Reaktion ableiten. Damit erscheint der Schnelltest im klinischen Alltag für eine 100% spezifische, sichere Unterscheidung bakterielle vs. nicht-bakterielle Meniongoencephalitis nicht geeignet; das bisher größte untersuchte Kollektiv hat den in der Literatur angegebenen „cut-off“ von 0,5 ng/ml für eine sichere Differenzierung nicht bestätigen können. Die zweite Frage ist, ob die Messung des PCT den traditionellen Parametern Liquorzellzahl, Liquoreiweiß, Liquor/Serum-Glucosequotient, BSG, Serumleukozytenzahl oder CRP bezüglich Spezifität und Sensitivität in der Differentialdiagnose überlegen ist. Es zeigte sich, dass CRP bei einem Grenzwert von 5-6 mg/dl mit einer Sensitivität und Spezifität von 95 % und 98 % die sicherste Differenzierung zwischen bakterieller und abakterieller Meningitis bei diesem Patientenkollektiv leistete. Mithin kann die PCT-Bestimmung am Krankenbett in der Akutaufnahmesituation eines Patienten mit Meningoencephalitis bei Werten > 10 ng/ml zwar treffsicher die Diagnose einer Meningokokken- oder Pneumokokken-Infektion stützen. Für jede darüber hinaus gehende Schlussfolgerung erscheint die PCT-Messung aber entbehrlich wegen mangelhafter Spezifität und Sensitivität und v.a. der Unterlegenheit gegenüber traditionell herangezogenen Laborparametern, insbesondere CRP. Folglich erwies sich die Bestimmung des PCT bei akuter Meningoencephalitis als entbehrlich.
Diabetic peripheral neuropathy (DPN) is a common complication of diabetes with potential severe consequences. Its pathogenesis involves hyperglycemia-linked mechanisms, which may include changes in the expression of neurotrophic growth factors. We analyzed the expression of 29 factors potentially related to nerve degeneration and regeneration in skin biopsies from 13 type 1 diabetic pancreas and kidney recipients with severe DPN including severe depletion of intraepidermal nerve fibers (IENF) in lower limb skin biopsies (group Tx1 1st examination). The investigation was repeated after a median 28-month period of normoglycemia achieved by pancreas transplantation (group Tx1 2nd examination). The same tests were performed in 13 stable normoglycemic pancreas and kidney recipients 6-12 years posttransplantation (group Tx2), in 12 matched healthy controls (group HC), and in 12 type 1 diabetic subjects without severe DPN (group DM). Compared to DM and HC groups, we found a significantly higher (p < 0.05-0.001) expression of NGF (nerve growth factor), NGFR (NGF receptor), NTRK1 (neurotrophic receptor tyrosine kinase 1), GDNF (glial cell-derived neurotrophic factor), GFRA1 (GDNF family receptor alpha 1), and GFAP (glial fibrillary acidic protein) in both transplant groups (Tx1 and Tx2). Enhanced expression of these factors was not normalized following the median 28-month period of normoglycemia (Tx1 2nd examination) and negatively correlated with IENF density and with electrophysiological indices of DPN (vibration perception threshold, electromyography, and autonomic tests). In contrast to our expectation, the expression of most of 29 selected factors related to neural regeneration was comparable in subjects with severe peripheral nerve fiber depletion and healthy controls and the expression of six factors was significantly upregulated. These findings may be important for better understanding the pathophysiology of nerve regeneration and for the development of intervention strategies.
Cortex-basal ganglia circuits participate in motor timing and temporal perception, and are important for the dynamic configuration of sensorimotor networks in response to exogenous demands. In Parkinson's disease (PD) patients, rhythmic auditory stimulation (RAS) induces motor performance benefits. Hitherto, little is known concerning contributions of the basal ganglia to sensory facilitation and cortical responses to RAS in PD. Therefore, we conducted an EEG study in 12 PD patients before and after surgery for subthalamic nucleus deep brain stimulation (STN-DBS) and in 12 age-matched controls. Here we investigated the effects of levodopa and STN-DBS on resting-state EEG and on the cortical-response profile to slow and fast RAS in a passive-listening paradigm focusing on beta-band oscillations, which are important for auditory–motor coupling. The beta-modulation profile to RAS in healthy participants was characterized by local peaks preceding and following auditory stimuli. In PD patients RAS failed to induce pre-stimulus beta increases. The absence of pre-stimulus beta-band modulation may contribute to impaired rhythm perception in PD. Moreover, post-stimulus beta-band responses were highly abnormal during fast RAS in PD patients. Treatment with levodopa and STN-DBS reinstated a post-stimulus beta-modulation profile similar to controls, while STN-DBS reduced beta-band power in the resting-state. The treatment-sensitivity of beta oscillations suggests that STN-DBS may specifically improve timekeeping functions of cortical beta oscillations during fast auditory pacing.
Controlling posture, i.e., governing the ensemble of involuntary muscular activities that manage body equilibrium, represents a demanding function in which the cerebellum plays a key role. Postural activities are particularly important during gait initiation when passing from quiet standing to locomotion. Indeed, several studies used such motor task for evaluating pathological conditions, including cerebellar disorders. The linkage between cerebellum maturation and the development of postural control has received less attention. Therefore, we evaluated postural control during quiet standing and gait initiation in children affected by a slow progressive generalized cerebellar atrophy (SlowP) or non-progressive vermian hypoplasia (Joubert syndrome, NonP), compared to that of healthy children (H). Despite the similar clinical evaluation of motor impairments in NonP and SlowP, only SlowP showed a less stable quiet standing and a shorter and slower first step than H. Moreover, a descriptive analysis of lower limb and back muscle activities suggested a more severe timing disruption in SlowP. Such differences might stem from the extent of cerebellar damage. However, literature reports that during childhood, neural plasticity of intact brain areas could compensate for cerebellar agenesis. We thus proposed that the difference might stem from disease progression, which contrasts the consolidation of compensatory strategies.
Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
Charcot-Marie-Tooth disease (CMT) is a cohort of human hereditary disorders of the peripheral nervous system (PNS) which exhibit symptoms like sensory dysfunction, muscle weakness and gait disturbances. Different mutations are described as causation for this neuropathy, such as a duplication of chromosome 17 comprising the gene for the peripheral myelin protein-22 (PMP22). Based on different animal models former studies identified immune cells, i.e. macrophages and T-lymphocytes, as crucial mediators of pathology in these neuropathies. In this study, PMP22-overexpressing mice (PMP22tg, C61), serving as a model for a specific type of CMT – CMT1A – were crossbred with immune-deficient mutant mice to examine the impact of the immune system on nerve pathology. Crossbreeding of PMP22tg mice with recombination activating gene-1 (RAG-1) deficient mice, lacking mature T- and B-lymphocytes, caused no striking alterations of pathogenesis in peripheral nerves of mutant mice. In contrast, crossbreeding of PMP22tg myelin mutants with mice deficient in the chemokine monocyte chemoattractant protein-1 (MCP-1, CCL2) caused an amelioration of the demyelinating phenotype of peripheral nerves when MCP-1 was either reduced or completely absent. Furthermore, functional investigations, i.e. neurographic recordings and examinations of the grip strength of the extremities, revealed an amelioration in PMP22tg/MCP-1-/- mice in regard to a symptomatic improvement in the compound action muscle potential (CMAP) and stronger grip strength of the hindlimbs. Interestingly, peripheral nerves of PMP22tg mice showed an irregular distribution of potassium channels in presence of MCP-1, whereas the absence of MCP-1 in the myelin mutants rescued the ion channel distribution and resulted in a more wild type-like phenotype. Having shown the impact of MCP-1 as an important mediator of nerve pathology in PMP22/MCP-1 double mutants, the regulation of this chemokine became an important target for potential treatment strategies. We found that the signaling cascade MEK1/2/ERK1/2 was more strongly activated in peripheral nerves of PMP22tg mice compared to nerves of wild type mice. This activation corresponded to an increase in MCP-1 mRNA expression in peripheral nerves at the same age. Furthermore, a MEK1/2-inhibitor was used in vivo to confirm the regulation of MCP-1 by the MEK1/2/ERK1/2 pathway. After a treatment period of three weeks, a clear reduction of ERK1/2-phosphorylation as well as a reduction of MCP-1 mRNA expression was observed, accompanied by a decline in macrophage number in peripheral nerves of PMP22tg mice. These observations suggest that the expression of MCP-1 is crucial for the neuropathological progression in a mouse model for CMT1A. Therefore, this chemokine could provide a basis for a putative treatment strategy of inherited neuropathies.
Autophagy-mediated degradation of synaptic components maintains synaptic homeostasis but also constitutes a mechanism of neurodegeneration. It is unclear how autophagy of synaptic vesicles and components of presynaptic active zones is regulated. Here, we show that Pleckstrin homology containing family member 5 (Plekhg5) modulates autophagy of synaptic vesicles in axon terminals of motoneurons via its function as a guanine exchange factor for Rab26, a small GTPase that specifically directs synaptic vesicles to preautophagosomal structures. Plekhg5 gene inactivation in mice results in a late-onset motoneuron disease, characterized by degeneration of axon terminals. Plekhg5-depleted cultured motoneurons show defective axon growth and impaired autophagy of synaptic vesicles, which can be rescued by constitutively active Rab26. These findings define a mechanism for regulating autophagy in neurons that specifically targets synaptic vesicles. Disruption of this mechanism may contribute to the pathophysiology of several forms of motoneuron disease.
Ischemia-reperfusion injury (I/R injury) is a common complication in ischemic stroke (IS) treatment, which is characterized by a paradoxical perpetuation of tissue damage despite the successful re-establishment of vascular perfusion. This phenomenon is known to be facilitated by the detrimental interplay of platelets and inflammatory cells at the vascular interface. However, the spatio-temporal and molecular mechanisms underlying these cellular interactions and their contribution to infarct progression are still incompletely understood. Therefore, this study intended to clarify the temporal mechanisms of infarct growth after cerebral vessel recanalization. The data presented here could show that infarct progression is driven by early blood-brain-barrier perturbation and is independent of secondary thrombus formation. Since previous studies unravelled the secretion of platelet granules as a molecular mechanism of how platelets contribute to I/R injury, special emphasis was placed on the role of platelet granule secretion in the process of barrier dysfunction. By combining an in vitro approach with a murine IS model, it could be shown that platelet α-granules exerted endothelial-damaging properties, whereas their absence (NBEAL2-deficiency) translated into improved microvascular integrity. Hence, targeting platelet α-granules might serve as a novel treatment option to reduce vascular integrity loss and diminish infarct growth despite recanalization.
Recent evidence revealed that pathomechanisms underlying I/R injury are already instrumental during large vessel occlusion. This indicates that penumbral tissue loss under occlusion and I/R injury during reperfusion share an intertwined relationship. In accordance with this notion, human observational data disclosed the presence of a neutrophil dominated immune response and local platelet activation and secretion, by the detection of the main components of platelet α-granules, within the secluded vasculature of IS patients. These initial observations of immune cells and platelets could be further expanded within this thesis by flow cytometric analysis of local ischemic blood samples. Phenotyping of immune cells disclosed a yet unknown shift in the lymphocyte population towards CD4+ T cells and additionally corroborated the concept of an immediate intravascular immune response that is dominated by granulocytes. Furthermore, this thesis provides first-time evidence for the increased appearance of platelet-leukocyte-aggregates within the secluded human vasculature. Thus, interfering with immune cells and/or platelets already under occlusion might serve as a potential strategy to diminish infarct expansion and ameliorate clinical outcome after IS.
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.
Experimental evidence has emerged that local platelet activation contributes to inflammation and infarct formation in acute ischemic stroke (AIS) which awaits confirmation in human studies. We conducted a prospective observational study on 258 consecutive patients undergoing mechanical thrombectomy (MT) due to large-vessel-occlusion stroke of the anterior circulation (08/2018-05/2020). Intraprocedural microcatheter aspiration of 1 ml of local (occlusion condition) and systemic arterial blood samples (self-control) was performed according to a prespecified protocol. The samples were analyzed for differential leukocyte counts, platelet counts, and plasma levels of the platelet-derived neutrophil-activating chemokine C-X-C-motif ligand (CXCL) 4 (PF-4), the neutrophil attractant CXCL7 (NAP-2), and myeloperoxidase (MPO). The clinical-biological relevance of these variables was corroborated by specific associations with molecular-cellular, structural-radiological, hemodynamic, and clinical-functional parameters. Seventy consecutive patients fulfilling all predefined criteria entered analysis. Mean local CXCL4 (+ 39%: 571 vs 410 ng/ml, P = .0095) and CXCL7 (+ 9%: 693 vs 636 ng/ml, P = .013) concentrations were higher compared with self-controls. Local platelet counts were lower (- 10%: 347,582 vs 383,284/µl, P = .0052), whereas neutrophil counts were elevated (+ 10%: 6022 vs 5485/µl, P = 0.0027). Correlation analyses revealed associations between local platelet and neutrophil counts (r = 0.27, P = .034), and between CXCL7 and MPO (r = 0.24, P = .048). Local CXCL4 was associated with the angiographic degree of reperfusion following recanalization (r = - 0.2523, P = .0479). Functional outcome at discharge correlated with local MPO concentrations (r = 0.3832, P = .0014) and platelet counts (r = 0.288, P = .0181). This study provides human evidence of cerebral platelet activation and platelet-neutrophil interactions during AIS and points to the relevance of per-ischemic thrombo-inflammatory mechanisms to impaired reperfusion and worse functional outcome following recanalization.