@article{BaumToykaBlueheretal.2021, author = {Baum, Petra and Toyka, Klaus V. and Bl{\"u}her, Matthias and Kosacka, Joanna and Nowicki, Marcin}, title = {Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms221910835}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284556}, year = {2021}, abstract = {The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.}, language = {en} } @article{WieseDennstaedtHollmannetal.2021, author = {Wiese, Teresa and Dennst{\"a}dt, Fabio and Hollmann, Claudia and Stonawski, Saskia and Wurst, Catherina and Fink, Julian and Gorte, Erika and Mandasari, Putri and Domschke, Katharina and Hommers, Leif and Vanhove, Bernard and Schumacher, Fabian and Kleuser, Burkard and Seibel, J{\"u}rgen and Rohr, Jan and Buttmann, Mathias and Menke, Andreas and Schneider-Schaulies, J{\"u}rgen and Beyersdorf, Niklas}, title = {Inhibition of acid sphingomyelinase increases regulatory T cells in humans}, series = {Brain Communications}, volume = {3}, journal = {Brain Communications}, number = {2}, doi = {10.1093/braincomms/fcab020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259868}, year = {2021}, abstract = {Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3\(^+\) regulatory T-cell frequencies among CD4\(^+\) T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4\(^+\) Foxp3\(^+\) regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3\(^+\) regulatory T cell among human CD4\(^+\) T cells in vitro. In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4\(^+\) Foxp3\(^+\) regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA\(^-\) CD25\(^{high}\) effector CD4\(^+\) Foxp3\(^+\) regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4\(^+\) Foxp3\(^+\) regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3+ regulatory T cells among human CD4\(^+\) T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3+ regulatory T-cell frequencies among CD4\(^+\) T cells in humans both in vivo and in vitro.}, language = {en} } @article{FrankeBieberStolletal.2021, author = {Franke, Maximilian and Bieber, Michael and Stoll, Guido and Schuhmann, Michael Klaus}, title = {Validity and Efficacy of Methods to Define Blood Brain Barrier Integrity in Experimental Ischemic Strokes: A Comparison of Albumin Western Blot, IgG Western Blot and Albumin Immunofluorescence}, series = {Methods and Protocols}, volume = {4}, journal = {Methods and Protocols}, number = {1}, issn = {2409-9279}, doi = {10.3390/mps4010023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234214}, year = {2021}, abstract = {The clinical and preclinical research of ischemic strokes (IS) is becoming increasingly comprehensive, especially with the emerging evidence of complex thrombotic and inflammatory interactions. Within these, the blood brain barrier (BBB) plays an important role in regulating the cellular interactions at the vascular interface and is therefore the object of many IS-related questions. Consequently, valid, economic and responsible methods to define BBB integrity are necessary. Therefore, we compared the three ex-vivo setups albumin Western blot (WB), IgG WB and albumin intensity measurement (AIM) with regard to validity as well as temporal and economic efficacy. While the informative value of the three methods correlated significantly, the efficacy of the IgG WB dominated.}, language = {en} } @phdthesis{Andreska2021, author = {Andreska, Thomas}, title = {Effects of dopamine on BDNF / TrkB mediated signaling and plasticity on cortico-striatal synapses}, doi = {10.25972/OPUS-17431}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174317}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Progressive loss of voluntary movement control is the central symptom of Parkinson's disease (PD). Even today, we are not yet able to cure PD. This is mainly due to a lack of understanding the mechanisms of movement control, network activity and plasticity in motor circuits, in particular between the cerebral cortex and the striatum. Brain-derived neurotrophic factor (BDNF) has emerged as one of the most important factors for the development and survival of neurons, as well as for synaptic plasticity. It is thus an important target for the development of new therapeutic strategies against neurodegenerative diseases. Together with its receptor, the Tropomyosin receptor kinase B (TrkB), it is critically involved in development and function of the striatum. Nevertheless, little is known about the localization of BDNF within presynaptic terminals in the striatum, as well as the types of neurons that produce BDNF in the cerebral cortex. Furthermore, the influence of midbrain derived dopamine on the control of BDNF / TrkB interaction in striatal medium spiny neurons (MSNs) remains elusive so far. Dopamine, however, appears to play an important role, as its absence leads to drastic changes in striatal synaptic plasticity. This suggests that dopamine could regulate synaptic activity in the striatum via modulation of BDNF / TrkB function. To answer these questions, we have developed a sensitive and reliable protocol for the immunohistochemical detection of endogenous BDNF. We find that the majority of striatal BDNF is provided by glutamatergic, cortex derived afferents and not dopaminergic inputs from the midbrain. In fact, we found BDNF in cell bodies of neurons in layers II-III and V of the primary and secondary motor cortex as well as layer V of the somatosensory cortex. These are the brain areas that send dense projections to the dorsolateral striatum for control of voluntary movement. Furthermore, we could show that these projection neurons significantly downregulate the expression of BDNF during the juvenile development of mice between 3 and 12 weeks. In parallel, we found a modulatory effect of dopamine on the translocation of TrkB to the cell surface in postsynaptic striatal Medium Spiny Neurons (MSNs). In MSNs of the direct pathway (dMSNs), which express dopamine receptor 1 (DRD1), we observed the formation of TrkB aggregates in the 6-hydroxydopamine (6-OHDA) model of PD. This suggests that DRD1 activity controls TrkB surface expression in these neurons. In contrast, we found that DRD2 activation has opposite effects in MSNs of the indirect pathway (iMSNs). Activation of DRD2 promotes a rapid decrease in TrkB surface expression which was reversible and depended on cAMP. In parallel, stimulation of DRD2 led to induction of phospho-TrkB (pTrkB). This effect was significantly slower than the effect on TrkB surface expression and indicates that TrkB is transactivated by DRD2. Together, our data provide evidence that dopamine triggers dual modes of plasticity on striatal MSNs by acting on TrkB surface expression in DRD1 and DRD2 expressing MSNs. This surface expression of the receptor is crucial for the binding of BDNF, which is released from corticostriatal afferents. This leads to the induction of TrkB-mediated downstream signal transduction cascades and long-term potentiation (LTP). Therefore, the dopamine-mediated translocation of TrkB could be a mediator that modulates the balance between dopaminergic and glutamatergic signaling to allow synaptic plasticity in a spatiotemporal manner. This information and the fact that TrkB is segregated to persistent aggregates in PD could help to improve our understanding of voluntary movement control and to develop new therapeutic strategies beyond those focusing on dopaminergic supply.}, subject = {Brain-derived neurotrophic factor}, language = {en} } @article{SchischlevskijCordtsGuentheretal.2021, author = {Schischlevskij, Pavel and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and Stendel, Claudia and M{\"u}schen, Lars H. and Osmanovic, Alma and Binz, Camilla and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {Informal caregiving in amyotrophic lateral sclerosis (ALS): a high caregiver burden and drastic consequences on caregivers' lives}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {6}, issn = {2076-3425}, doi = {10.3390/brainsci11060748}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240981}, year = {2021}, abstract = {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.}, language = {en} } @phdthesis{Braun2021, author = {Braun, Alexandra}, title = {Psychosocial and somatic resilience factors of patients with fibromyalgia syndrome (FMS)}, doi = {10.25972/OPUS-24280}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242809}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Background: In recent years, health care has increasingly become the focus of public interest, politics, health insurance companies, and research. This includes the development of therapeutic concepts that can respond individually to patients' resources in order to improve coping with chronic diseases. Research into psychosocial and biological resilience factors is very important and the basic objective of the present work. I studied patients with fibromyalgia syndrome (FMS), who suffer among others from chronic pain, fatigue, sleep and gastrointestinal problems. This patient cohort is characterized by a pronounced heterogeneity in terms of clinical outcome, degree in disability and coping. FMS has a prevalence of 3 - 8 \% in the Western population and has a significant socio-economic impact. Validated psychosocial resilience factors include optimism, humor, coherence, self-efficacy, awareness with one's own resources and the ability to apply them profitably (coping), and a healthy social environment with positive relationships. Studies in patients with cancer revealed religiosity as positive and negative factor on the health outcome, but there is little data on religious aspects of pain resilience. Various genetic polymorphisms and anti-inflammatory cytokines are known as biological resilience factors. Various microRNA (miRNA) were detected to contribute to resilience in the context of stress and psychiatric disorders. Objective: The underlying research question of this work is to understand the factors that make some FMS patients resilient and others not, even though they suffer from the same disease. The long-term aim was to understand mechanisms and influencing factors of resilience to design preventive and resource-oriented therapies for FMS patients. Material and Methods: Three studies examined religious, physiological, biological, and psychosocial factors which may contribute to resilience in FMS patients. Study one combined data of questionnaires, a psychosocial interview, and regression analyses to investigate the relevance of religiosity for coping and resilience. Study two examined variance explaining factors and defined clusters among FMS patients by their differences in coping, pain phenotype and disability. The factor analysis used variables derived from questionnaires and qPCR of cytokines in white blood samples (WBC) of patients and healthy controls. Study three assessed cluster-wise miRNA signatures which may underly differences in behaviour, emotional and physiological disability, and resilience among patient clusters. A cluster-specific speculative model of a miRNA-mediated regulatory cycle was proposed and its potential targets verified by an online tool. Results: The data from the first study revealed a not very religious patient cohort, which was rather ambivalent towards the institution church, but described itself as a believer. The degree of religiosity played a role in the choice of coping strategy but had no effect on psychological parameters or health outcomes. The coping strategy "reinterpretation", which is closely related iv to the religious coping "reappraisal", had the highest influence on FMS related disability. Cognitive active coping strategies such as reappraisal which belongs to religious coping had the highest effect on FMS related disability (resilience) and could be trained by a therapist. Results from the second study showed high variances of all measured cytokines within the patient group and no difference between patient and control group. The high dispersion indicated cluster among patients. Factor analysis extracted four variance-explaining factors named as affective load, coping, pain, and pro-inflammatory cytokines. Psychological factors such as depression were the most decisive factors of everyday stress in life and represented the greatest influence on the variance of the data. Study two identified four clusters with respective differences in the factors and characterized them as poorly adapted (maladaptive), well adapted (adaptive), vulnerable and resilient. Their naming was based on characteristics of both resilience concepts, indicated by patients who were less stress-sensitive and impaired as a personal characteristic and by patients who emerged as more resilient from a learning and adaptive process. The data from the variance analysis suggests that problem- and emotion-focused coping strategies and a more anti-inflammatory cytokine pattern are associated with low impairment and contribute to resilience. Additional favorable factors include low anxiety, acceptance, and persistence. Some cluster-specific intervention proposals were created that combine existing concepts of behavioral and mindfulness therapies with alternative therapies such as vitamin D supplementation and a healthy intestinal flora. The results of the third study revealed lower relative gene expression of miR103a-3p, miR107, and miR130a-3p in the FMS cohort compared to the healthy controls with a large effect size. The adaptive cluster had the highest gene expression of miR103a-3p and tendentially of miR107, which was correlated with the subscale score "physical abuse" of the trauma questionnaire. Further correlations were found in particular with pain catastrophizing and FMS-related disability. MiR103a-3p and miR107 form a miRNA-family. Based on this, we proposed a miR103a/107 regulated model of an adaptive process to stress, inflammation and pain by targeting genetic factors which are included in different anti-inflammatory and stress-regulating pathways. Conclusion: All three studies provide new insights into resilience in FMS patients. Cognitive coping (reappraisal/reinterpretation) plays a central role and thus offers therapeutic targets (reframing in the context of behavioral therapy). Religosity as a resilience factor was only partially valid for our patient cohort. Basically, the use of resource-oriented therapy in large institutions still requires research and interdisciplinary cooperation to create a consensus between the humanities, natural sciences and humanism.}, subject = {Resilienz}, language = {en} } @phdthesis{Rost2021, author = {Rost, Anna-Lena}, title = {Akute erregerbedingte Meningoenzephalitiden am Universit{\"a}tsklinikum W{\"u}rzburg von 2006-2015}, doi = {10.25972/OPUS-24084}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240846}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Am Universit{\"a}tsklinikum W{\"u}rzburg wurden zwischen 2006-2015 447 F{\"a}lle einer akuten erregerbedingten Meningoenzephalitis in den Kliniken der Neurologie, Kinderklinik, Neurochirurgie und Psychiatrie behandelt. Es konnten sowohl F{\"a}lle durch Bakterien als auch F{\"a}lle durch Viren, Parasiten und Pilze gesichert werden. Diese Arbeit beschreibt die lokale Epidemiologie akuter erregerbedingter Meningoenzephalitiden.}, subject = {Meningoenzephalitis}, language = {de} } @article{PiroEckesKasaragodetal.2021, author = {Piro, Inken and Eckes, Anna-Lena and Kasaragod, Vikram Babu and Sommer, Claudia and Harvey, Robert J. and Schaefer, Natascha and Villmann, Carmen}, title = {Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease}, series = {Frontiers in Molecular Neuroscience}, volume = {14}, journal = {Frontiers in Molecular Neuroscience}, issn = {1662-5099}, doi = {10.3389/fnmol.2021.745275}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246676}, year = {2021}, abstract = {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.}, language = {en} } @article{GoebVollZimmermannetal.2021, author = {G{\"o}b, Vanessa and Voll, Maximilian G. and Zimmermann, Lena and Hemmen, Katharina and Stoll, Guido and Nieswandt, Bernhard and Schuhmann, Michael K. and Heinze, Katrin G. and Stegner, David}, title = {Infarct growth precedes cerebral thrombosis following experimental stroke in mice}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-02360-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265791}, year = {2021}, abstract = {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.}, language = {en} } @phdthesis{Nguyen2021, author = {Nguyen, Ngoc Bich}, title = {Vitamin D bei Patienten mit idiopathischen Parkinson-Syndrom}, doi = {10.25972/OPUS-22302}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223026}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {In einer Vielzahl von epidemiologischen Studien zeigten Patienten, die an einem idiopathischen Parkinson-Syndrom (IPS) erkrankt waren, erniedrigte Vitamin D-Serumspiegel (25-(OH)-Vit D). Die Rolle von Vitamin D im Knochenstoffwechsel ist weitgehend bekannt, allerdings konnten Assoziationen zwischen Vitamin D und chronischen Erkrankungen, die das Nervensystem sowie das kardiovaskul{\"a}re und immunologische System betreffen, nachgewiesen werden. In Tiermodellen konnten anti-oxidative Effekte von Vitamin D im Nervensystem gezeigt werden. In den letzten Jahren h{\"a}uften sich allerdings Studien, die gegen einen direkten Zusammenhang zwischen IPS und Vitamin D sprechen. Demnach stellt sich die Frage, ob dem geh{\"a}uften Auftreten eines Vitamin D-Mangels bei IPS-Patienten eine krankheitsspezifische Ursache zugrunde liegt oder ob diese lediglich ein unspezifisches krankheitsbegleitendes Ph{\"a}nomen darstellt. In der vorliegenden Arbeit wurden in einer retrospektiven Analyse Parkinson-Patienten aus der neurogerontopsychiatrischen Tagesklinik sowie der neurogeriatrischen Fr{\"u}hrehastation der Neurologischen Klinik der Universit{\"a}tsklinik W{\"u}rzburg hinsichtlich ihres 25-(OH)-Vit D-Serumspiegel mit zwei Kontrollgruppen bestehend aus Patienten mit psychiatrischer bzw. anderweitig neurologischer Erkrankung, die keiner Parkinson-Erkrankung entsprach, verglichen. Im Anschluss wurde auf m{\"o}gliche Konfounder sowie der Zusammenhang zwischen IPS-Risiko bzw. Krankheitsschwere und 25-(OH)-Vit D-Serumspiegel untersucht. Der mittlere 25-(OH)-Vit D-Serumspiegel der Neurologie-Gruppe war im Vergleich zur Psychiatrie-Gruppe signifikant niedriger. Der Unterschied zwischen IPS-Gruppe und Psychiatrie- bzw. Neurologie-Gruppe war nicht signifikant. Bei Hinzunahme von weiteren rekrutierten Parametern (Body-Mass-Index, Frailty, Sturzanamnese, Gehhilfe, CHA2DS2-VASc-Score, C-reaktives Protein, H{\"a}moglobin) konnte kein signifikanter Unterschied zwischen der Neurologie- und Psychiatrie-Gruppe mehr gefunden werden. Das Risiko sowie die Krankheitsschwere einer Parkinson-Erkrankung, gemessen am Hoehn-Yahr-Stadium und den erreichten Werten im MDS UPDRS III, korrelierten mit dem Vitamin D-Serumspiegel. Allerdings war auch hier nach Hinzunahme von Kovariaten wie Alter, Geschlecht und Krankheitsdauer der Effekt nicht mehr signifikant. Die Ergebnisse unterst{\"u}tzen die Annahme, dass die vorgefundenen niedrigen 25-(OH)-Vit D-Serumspiegel bei Parkinson-Patienten ein krankheitsbegleitendes Ph{\"a}nomen ist, das wom{\"o}glich durch die eingeschr{\"a}nkten motorischen F{\"a}higkeiten mit resultierend niedriger Sonnenexposition bedingt ist und durch zunehmende Kranheitsdauer und damit Krankheitsschwere verst{\"a}rkt wird. Da es sich jedoch beim IPS um eine Krankheit handelt, die zum Einen mit motorischen Einschr{\"a}nkungen und resultierend erh{\"o}htem Sturzrisiko einhergeht und zum Anderen vorwiegend Menschen h{\"o}heren Alters betrifft, besteht ein erh{\"o}htes Osteoporose- und sturzbedingtes Frakturrisiko, sodass ein Monitoring des Vitamin D-Serumspiegels sowie eine gegebenenfalls notwendige Vitamin D-Supplementierung weiterhin eine Rolle in der Behandlung von Parkinson-Patienten spielen.}, subject = {Vitamin D-Mangel}, language = {de} } @article{SchuhmannBieberFrankeetal.2021, author = {Schuhmann, Michael K. and Bieber, Michael and Franke, Maximilian and Kollikowski, Alexander M. and Stegner, David and Heinze, Katrin G. and Nieswandt, Bernhard and Pham, Mirko and Stoll, Guido}, title = {Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice}, series = {Journal of Neuroinflammation}, volume = {18}, journal = {Journal of Neuroinflammation}, number = {1}, doi = {10.1186/s12974-021-02095-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259172}, pages = {46}, year = {2021}, abstract = {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.}, language = {en} } @article{SommerCarrollKoikeetal.2021, author = {Sommer, Claudia and Carroll, Antonia S. and Koike, Haruki and Katsuno, Masahisa and Ort, Nora and Sobue, Gen and Vucic, Steve and Spies, Judith M. and Doppler, Kathrin and Kiernan, Matthew C.}, title = {Nerve biopsy in acquired neuropathies}, series = {Journal of the Peripheral Nervous System}, volume = {26}, journal = {Journal of the Peripheral Nervous System}, number = {S2}, doi = {10.1111/jns.12464}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259555}, pages = {S21-S41}, year = {2021}, abstract = {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,}, language = {en} } @article{PeseschkianCordtsGuentheretal.2021, author = {Peseschkian, Tara and Cordts, Isabell and G{\"u}nther, Ren{\´e} and Stolte, Benjamin and Zeller, Daniel and Schr{\"o}ter, Carsten and Weyen, Ute and Regensburger, Martin and Wolf, Joachim and Schneider, Ilka and Hermann, Andreas and Metelmann, Moritz and Kohl, Zacharias and Linker, Ralf A. and Koch, Jan Christoph and B{\"u}chner, Boriana and Weiland, Ulrike and Sch{\"o}nfelder, Erik and Heinrich, Felix and Osmanovic, Alma and Klopstock, Thomas and Dorst, Johannes and Ludolph, Albert C. and Boentert, Matthias and Hagenacker, Tim and Deschauer, Marcus and Lingor, Paul and Petri, Susanne and Schreiber-Katz, Olivia}, title = {A nation-wide, multi-center study on the quality of life of ALS patients in Germany}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {3}, issn = {2076-3425}, doi = {10.3390/brainsci11030372}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234147}, year = {2021}, abstract = {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.}, language = {en} } @article{KremerPauwelsPozzietal.2021, author = {Kremer, Naomi I. and Pauwels, Rik W. J. and Pozzi, Nicol{\`o} G. and Lange, Florian and Roothans, Jonas and Volkmann, Jens and Reich, Martin M.}, title = {Deep Brain Stimulation for Tremor: Update on Long-Term Outcomes, Target Considerations and Future Directions}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {16}, issn = {2077-0383}, doi = {10.3390/jcm10163468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244982}, year = {2021}, abstract = {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.}, language = {en} } @phdthesis{Nehen2021, author = {Nehen, Mathias Julius}, title = {Modulation der Schrankenfunktion prim{\"a}rer humaner zerebraler Endothelzellen durch Fumars{\"a}ureester unter inflammatorischen und nicht-inflammatorischen Bedingungen}, doi = {10.25972/OPUS-24092}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240925}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Multiple Sklerose ist eine bisher nicht heilbare, chronisch-inflammatorische demyelinisierende Erkrankung des zentralen Nervensystems. Trotz intensiver Forschungsbem{\"u}hungen ist der exakte Pathomechanismus nicht vollkommen verstanden. Klar ist jedoch, dass der Blut-Hirn-Schranke eine entscheidende Rolle bei der Pathogenese zukommt. Seit Februar 2014 ist mit Dimethylfumarat ein neues orales Medikament f{\"u}r die schubf{\"o}rmige Multiple Sklerose zugelassen. Die Wirkungen von Fumars{\"a}ureestern auf humane zerebrale Endothelzellen als Grundsteine der Blut-Hirn-Schranke sind allerdings nur unzureichend untersucht. Mehrere Forschungsgruppen demonstrierten an humanem Nabelschnurvenenendothel einen hemmenden Effekt von Fumars{\"a}ureestern auf die Adh{\"a}sion von Leukozyten und beschrieben eine Inhibition der Aktivierung des proinflammatorischen Transkriptionsfaktors NFB in den Endothelzellen. Aufgrund der charakteristischen Eigenschaften zerebralen Endothels ist eine {\"U}bertragung dieser Beobachtungen auf die Blut-Hirn-Schranke allerdings nicht ohne weiteres m{\"o}glich. Daher galt es potentielle Effekte von Fumars{\"a}ureestern auf prim{\"a}re humane zerebrale Endothelzellen als in vitro Modell der Blut-Hirn-Schranke zu {\"u}berpr{\"u}fen. Dabei wurden die Zellen nicht nur unter ruhenden Bedingungen, sondern auch unter inflammatorischer Stimulation mit TNF-α, IL-1 und IFN untersucht, einem Milieu, wie es in inflammatorischen MS L{\"a}sionen zu finden ist. In Leukozyten-Adh{\"a}sionsassays konnte durch Inkubation mit Monomethylfumarat und Dimethylfumarat keine funktionale Beeinflussung der Adh{\"a}sion von T-Lymphozyten an den verwendeten zerebralen Endothelzellen verzeichnet werden. Kongruent dazu fand sich in durchflusszytometrischen Analysen keine Hemmung der inflammatorisch vermittelten Expression des Adh{\"a}sionsmolek{\"u}ls ICAM-1, welches eine tragende Rolle bei der Leukozytenmigration spielt. Inflammatorische intrazellul{\"a}re Signalwege, wie die NFB-Kerntranslokation oder die Phosphorylierung von p38 wurden in HECE im Gegensatz zu HUVEC durch Fumars{\"a}ureester ebenso wenig beeinflusst. Diese in sich konsistenten Ergebnisse f{\"u}hren zu der Schlussfolgerung, dass im Gegensatz zu anderen Gef{\"a}ßbetten weder Dimethylfumarat noch Monomethylfumarat direkt am zerebralen Endothel anti-inflammatorisch wirken.}, subject = {Multiple Sklerose}, language = {de} } @phdthesis{Soda2021, author = {Soda, Hassan}, title = {Interdisziplin{\"a}res Schlaganfallmanagement anhand des Stroke Manager Programms - Studiendaten und Perspektiven f{\"u}r die Schlaganfallversorgung}, doi = {10.25972/OPUS-24206}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242061}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Die Schlaganfallnachsorge in Deutschland wird von verschiedenen Leistungserbringern gepr{\"a}gt, die teilweise komplement{\"a}re und komplexe Dienstleistungen erbringen und sektoren{\"u}bergreifend arbeiten. In Bad Neustadt wurde in Kooperation mit der Universit{\"a}t W{\"u}rzburg und dem Zentrum f{\"u}r Telemedizin Bad Kissingen das Stroke Manager Programm entwickelt und evaluiert. Das strukturierte Nachsorgeprogramm Stroke Manager basiert auf einer standardisierten Informations- und Software Unterst{\"u}tzung von der Akutversorgung bis drei Monate nach Entlassung aus der station{\"a}ren Versorgung. Anhand der Ergebnisse des Stroke Manager Programms konnte eine vergleichsweise hohe Persistenz bzgl. der station{\"a}r verordneten medikament{\"o}sen Sekund{\"a}rpr{\"a}vention {\"u}ber einen Zeitraum von drei Monaten festgestellt werden, ebenso konnten wir nachweisen, dass sich das Programm positiv auf die Versorgungsqualit{\"a}t sowie die Patientenzufriedenheit nach Schlaganfall auswirken kann. Die im Stroke Manager-Programm betreuten Schlaganfallpatienten wiesen im Vergleich signifikante Unterschiede bei den Faktoren Rauchverhalten, Schlaganfallschweregrad und subjektive, globale Lebensqualit{\"a}t auf.}, subject = {Stroke Manager}, language = {de} } @phdthesis{Leinweber2022, author = {Leinweber, Jonas}, title = {Untersuchung zur pathophysiologischen Rolle und therapeutischen Relevanz der neuen Inhibitoren der plasmatischen Blutgerinnung Agaphelin und Ixolaris im experimentellen Schlaganfallmodell der Maus}, doi = {10.25972/OPUS-25292}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252921}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Beim isch{\"a}mischen Schlaganfall f{\"u}hrt ein thrombotischer Verschluss von gehirnversorgenden Arterien zu einer akuten Durchblutungsst{\"o}rung, mit der Folge von neurologischen Defiziten. Prim{\"a}res Therapieziel ist es, diese Blutgerinnsel aufzul{\"o}sen, um die Sauerstoffversorgung des Gehirns wiederherzustellen und den isch{\"a}mischen Hirnschaden zu begrenzen. Dazu stehen die intraven{\"o}sen Thrombolyse mit rt-PA (rekombinanter Gewebe-Plasminogen-Aktivator) sowie die endovaskul{\"a}re mechanische Thrombektomie zur Verf{\"u}gung. H{\"a}ufig kann ein Schlaganfall, trotz erfolgreicher Rekanalisation der Gef{\"a}ße, zu einer weiteren Gr{\"o}ßenzunahme des Infarktes und neurologischen Defiziten bei den Patienten f{\"u}hren. Diese Gr{\"o}ßenzunahme beruht zum einen auf einem sich entwickelnden Hirn{\"o}dem und zum anderen auf entz{\"u}ndlichen Prozessen. Zahlreiche Hinweise deuten darauf hin, dass der Schlaganfall ein Zusammenspiel aus thrombotischen und entz{\"u}ndlichen Ereignissen ist, ein Ph{\"a}nomen, das als Thromboinflammation bezeichnet wird. Aufgrund der begrenzten Behandlungsm{\"o}glichkeiten ist die Entwicklung neuer Therapieans{\"a}tze f{\"u}r den isch{\"a}mischen Schlaganfall besonders wichtig. Agaphelin und Ixolaris sind Proteine aus den Speicheldr{\"u}sen von H{\"a}matophagen, f{\"u}r welche in fr{\"u}heren Studien eine starke antithrombotische Wirkung bei gleichzeitig geringem Blutungsrisiko nachgewiesen wurde. Diese m{\"o}glichen antithrombotischen Effekte wurden in dieser Studie im Hinblick auf ihre Wirksamkeit und Sicherheit im Mausmodell der zerebralen Isch{\"a}mie untersucht. Die Behandlung der M{\"a}use mit Agaphelin 1 Stunde nach transienter Okklusion der Arteria cerebri media (tMCAO) f{\"u}hrte zu kleineren Schlaganfallvolumina und geringeren neurologischen Defiziten an Tag 1 nach dem Schlaganfall. Die Mortalit{\"a}t der M{\"a}use war bis Tag 7 deutlich gesunken. Aus klinischer Sicht ist ebenfalls relevant, dass der starke antithrombotische Effekt von Agaphelin im Mausmodell nicht mit einem erh{\"o}hten Risiko f{\"u}r intrazerebrale Blutungen einherging. Diesem protektiven Effekt von Agaphelin lagen eine verminderte intrazerebrale Thrombusbildung, eine abgeschw{\"a}chte Entz{\"u}ndungsantwort und eine Stabilisierung der Blut-Hirn-Schranke sowie eine Reduzierung der Apoptose zugrunde. Nach der Gabe von Ixolaris 1 Stunde nach tMCAO waren zwar signifikant geringere Infarktgr{\"o}ßen messbar, diese f{\"u}hrten allerdings nicht zu einer Verbesserung der neurologischen Defizite. Zudem verursachte die Gabe von Ixolaris schon 24 Stunden nach tMCAO erhebliche intrazerebrale Blutungen und auch die Mortalit{\"a}t der M{\"a}use war zu diesem Zeitpunkt bereits erh{\"o}ht. Aufgrund dieser massiven Nebenwirkungen scheint Ixolaris kein geeigneter Kandidat f{\"u}r eine humane Anwendung zu sein. Bei Agaphelin hingegen k{\"o}nnte es sich um einen vielversprechenden Kandidaten f{\"u}r die Behandlung des isch{\"a}mischen Schlaganfalls handeln. Vor einer m{\"o}glichen Testung von Agaphelin in klinischen Studien, sind weitere translationale Untersuchungen notwendig, um ein noch pr{\"a}ziseres Verst{\"a}ndnis f{\"u}r die Wirksamkeit und Sicherheit von Agaphelin zu gewinnen. Insgesamt stellt die Hemmung thromboinflammatorischer Prozesse, ohne eine Erh{\"o}hung der Blutungskomplikationen, eine vielversprechende Option zur Behandlung des isch{\"a}mischen Schlaganfalls dar.}, subject = {Schlaganfall}, language = {de} } @phdthesis{Nakchbandi2022, author = {Nakchbandi, Luis}, title = {Adaptives motorisches Lernen und seine Konsolidierung bei Multipler Sklerose}, doi = {10.25972/OPUS-25246}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252465}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Der Verlauf der Multiplen Sklerose ist heterogener Natur; die F{\"a}higkeit zu einem intakten adaptiven motorischen Lernen und einer intakten Konsolidierung k{\"o}nnten einen milden Krankheitsverlauf beg{\"u}nstigen. In der vorliegenden Arbeit wurden das adaptive motorische Lernen und seine Konsolidierung bei MS-Patienten im Vergleich zu neurologisch gesunden Kontrollprobanden untersucht; außerdem wurde das Verh{\"a}ltnis dieser Formen des Lernens zu klinischen und apparativen Parametern des Krankheitsprogresses untersucht. Dazu f{\"u}hrten 20 MS-Patienten und 20 Kontrollprobanden eine visuoadaptive Lernaufgabe durch. Hierzu sollten mittels Computerbildschirm und Computermaus geradlinige Zielbewegungen zwischen einem Startpunkt und einem Zielpunkt wechselnder Lokalisation durchgef{\"u}hrt werden, wobei in einem Rotationsmodus eine externe Ablenkung der Zielbewegung im Uhrzeigersinn eingef{\"u}hrt wurde, welche auszugleichen war. Die {\"U}bungssitzung wurde nach 24 Stunden und nach 72 Stunden wiederholt. Analysiert wurden die Richtungsfehler der Zielbewegungen, die Adaptationsrate an die Ablenkung und die Retention der erlernten Adaptation bis zur Folgesitzung. Motorische Einschr{\"a}nkung wurde durch den EDSS-Score und den 9-Loch-Stecktest quantifiziert, zentralnerv{\"o}se L{\"a}sionslast wurde mittels cMRT und MEP ermittelt. Die Adaptation und Lernf{\"a}higkeit innerhalb einer {\"U}bungssitzung waren in der Patienten- und der Kontrollgruppe vergleichbar; jedoch zeigte sich eine signifikant verminderte Retentionsrate in der Patientengruppe an den Folgeuntersuchungstagen im Vergleich zur Kontrollgruppe. In den Korrelationsanalysen und Subgruppenvergleichen innerhalb der Patientengruppe nach Stratifizierung aufgrund von EDSS-Score, 9-Lochstecktest und zentralnerv{\"o}ser L{\"a}sionslast im MRT konnte kein eindeutiger Zusammenhang zwischen klinischer Beeintr{\"a}chtigung bzw. zentralnerv{\"o}ser L{\"a}sionslast auf der einen Seite und Adaptation bzw. Konsolidierung auf der anderen Seite identifiziert werden. Jedoch zeigte sich in der Patientengruppe f{\"u}r den ersten Nachuntersuchungstag eine signifikant h{\"o}here Retentionsrate in der Subgruppe mit geringerer Leistung im 9-Lochsteck-Test. Insgesamt deuten die vorliegenden Daten auf eine erhaltene F{\"a}higkeit zu adaptivem motorischen Lernen und somit auf eine erhaltene rasch einsetzende Neuroplastizit{\"a}t bei leicht bis mittelgradig betroffenen MS-Patienten hin; jedoch sprechen die Daten f{\"u}r eine eingeschr{\"a}nkte Konsolidierungsf{\"a}higkeit. Zentralnerv{\"o}se L{\"a}sionslast scheint Motoradaptation und Konsolidierung nicht zu verhindern. Das genaue Verh{\"a}ltnis der Motoradapation und Konsolidierung zum klinischen Funktionserhalt konnte nicht genauer aufgekl{\"a}rt werden. Um die genaue Beziehung zwischen Motoradaptation und Konsolidierung und klinischer Beeintr{\"a}chtigung bzw. ZNS-L{\"a}sionen zu eruieren, bedarf es weiterer Studien.}, subject = {Multiple Sklerose}, language = {de} } @article{VogtKollikowskiWeidneretal.2022, author = {Vogt, Marius L. and Kollikowski, Alexander M. and Weidner, Franziska and Strinitz, Marc and Feick, J{\"o}rn and Essig, Fabian and Neugebauer, Herrmann and Haeusler, Karl Georg and Pham, Mirko and Maerz, Alexander}, title = {Safety and Effectiveness of the New Generation APERIO® Hybrid Stent-retriever Device in Large Vessel Occlusion Stroke}, series = {Clinical Neuroradiology}, volume = {32}, journal = {Clinical Neuroradiology}, number = {1}, doi = {10.1007/s00062-021-01122-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-264817}, pages = {141-151}, year = {2022}, abstract = {Background It is unknown whether technological advancement of stent-retriever devices influences typical observational indicators of safety or effectiveness. Methods Observational retrospective study of APERIO® (AP) vs. new generation APERIO® Hybrid (APH) (Acandis®, Pforzheim, Germany) stent-retriever device (01/2019-09/2020) for mechanical thrombectomy (MT) in large vessel occlusion (LVO) stroke. Primary effectiveness endpoint was successful recanalization eTICI (expanded Thrombolysis In Cerebral Ischemia) ≥ 2b67, primary safety endpoint was occurrence of hemorrhagic complications after MT. Secondary outcome measures were time from groin puncture to first pass and successful reperfusion, and the total number of passes needed to achieve the final recanalization result. Results A total of 298 patients with LVO stroke who were treated by MT matched the inclusion criteria: 148 patients (49.7\%) treated with AP vs. 150 patients (50.3\%) treated with new generation APH. Successful recanalization was not statistically different between both groups: 75.7\% for AP vs. 79.3\% for APH; p = 0.450. Postinterventional hemorrhagic complications and particularly subarachnoid hemorrhage as the entity possibly associated with stent-retriever device type was significantly less frequent in the group treated with the APH: 29.7\% for AP and 16.0\% for APH; p = 0.005; however, rates of symptomatic hemorrhage with clinical deterioration and in domo mortality were not statistically different. Neither the median number of stent-retriever passages needed to achieve final recanalization, time from groin puncture to first pass, time from groin puncture to final recanalization nor the number of cases in which successful recanalization could only be achieved by using a different stent-retriever as bail-out device differed between both groups. Conclusion In the specific example of the APERIO® stent-retriever device, we observed that further technological developments of the new generation device were not associated with disadvantages with respect to typical observational indicators of safety or effectiveness.}, language = {en} } @phdthesis{Lintner2022, author = {Lintner, Hannes}, title = {Die Wertigkeit des Liquorbiomarkers CXCL-13 in der Diagnostik der Neuroborreliose und anderer neuroinflammatorischer Erkrankungen}, doi = {10.25972/OPUS-26047}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260471}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Zu den h{\"a}ufigsten Symptomen der Neuroborreliose z{\"a}hlen Meningopolyradikulitis, lymphozyt{\"a}re Meningitis und eine Beteiligung von Hirnnerven. Die Diagnosestellung erfolgt anhand klinischer Symptomatik, Liquoranalyse und Antik{\"o}rperuntersuchungen von Liquor und Serum. Besonders in der Fr{\"u}hphase der Infektion gestaltet sich die Diagnosesicherung aufgrund der noch fehlenden Antik{\"o}rperreaktion jedoch oftmals sehr schwierig. Die Ergebnisse mehrerer Studien legen nahe, dass CXCL-13 einen wertvollen Beitrag leisten k{\"o}nnte, um diese diagnostische L{\"u}cke zu schließen. Ziel der Studie war es, die Wertigkeit des Liquorbiomarkers CXCL-13 in der Diagnostik der Neuroborreliose und anderer neuroinflammatorischer Erkrankungen anhand eines großen unselektierten Kollektivs zu ermitteln, einen cut-off Wert f{\"u}r die Verwendung im klinischen Alltag zu definieren und die Ergebnisse mit der bestehenden Literatur zu vergleichen. Daf{\"u}r wurden am Klinikum Wels-Grieskirchen {\"u}ber einen Zeitraum von 3 Jahren alle Patienten analysiert, bei denen im Rahmen einer Liquorpunktion die CXCL-13 Konzentration bestimmt wurde. Die Patienten wurden anhand der Hauptdiagnose bei Entlassung in 12 Diagnosegruppen aufgeteilt, f{\"u}r die Einteilung der Neuroborreliose Patienten wurden die Diagnoseleitlinien der DGN herangezogen. Alle Liquorproben wurden routinem{\"a}ßig auf Zellzahl, Gesamteiweiß und Laktat untersucht, die CXCL-13 Konzentration wurde anhand eines enzyme-linked immunsorbent assay (CXCL-13 ELISA, Euroimmun) bestimmt. Unter den 1410 augewerteten Patienten fanden sich 29 F{\"a}lle mit gesicherter Neuroborreliose sowie 9 F{\"a}lle mit wahrscheinlicher/m{\"o}glicher Neuroborreliose. Beide Neuroborreliosegruppen zeigten eine deutlich erh{\"o}hte mediane CXCL-13 Konzentration (554pg/ml bzw. 649pg/ml), in der Gruppe der bakteriellen und Pilzinfektionen (n=6) fand sich ebenfalls ein deutlich erh{\"o}hter Median von 410pg/ml. Alle anderen Gruppen wiesen signifikant niedrigere CXCL-13 Konzentrationen auf (p<0,001), lediglich bei sechs Patienten aus der Gruppe der soliden Tumore, darunter ein kutanes Lymphom und f{\"u}nf hirneigene Tumore, wurden Werte {\"u}ber 500pg/ml gefunden. Anhand einer ROC-Kurve wurde der ideale cut-off f{\"u}r die Diagnose der gesicherten Neuroborreliose errechnet. Dieser lag bei 55,5pg/ml mit einer Sensitivit{\"a}t von 96,6\% (95\% KI 80,4-99,8\%) und einer Spezifit{\"a}t von 94,9\% (95\% KI 93,5-95,9\%). Bei 28 der 29 gesicherten Neuroborreliosef{\"a}lle konnte ein positiver Antik{\"o}rperindex nachgewiesen werden, dies entspricht einer Sensitivit{\"a}t von 96,6\%. Der direkte Erregernachweis mittels PCR wurde bei neun Patienten durchgef{\"u}hrt, er war lediglich in zwei F{\"a}llen positiv, die Sensitivit{\"a}t lag bei 22,2\%. Bei den Patienten mit wahrscheinlicher Neuroborreliose (n=5) war eine Bestimmung des Antik{\"o}rper-Index nicht m{\"o}glich, da entweder nur im Serum oder im Liquor borrelienspezifische Antik{\"o}rper vorlagen. Alle Patienten zeigten eine typische klinische Symptomatik, eine lymphozyt{\"a}re Pleozytose und deutlich erh{\"o}hte CXCL-13 Konzentrationen. Es erfolgte eine antibiotische Therapie mit Ceftriaxon, worauf die Symptomatik rasch r{\"u}ckl{\"a}ufig war. Die Ergebnisse der Studie best{\"a}tigen die hohe Wertigkeit von CXCL-13 f{\"u}r die Diagnose der Neuroborreliose und belegen die {\"U}bertragbarkeit der bisherigen Funde auf ein unselektiertes Patientenkollektiv. Die CXCL-13 Bestimmung ist dem direkten Erregernachweis deutlich {\"u}berlegen, dieser ist aufgrund der niedrigen Sensitivit{\"a}t lediglich als Best{\"a}tigungstest geeignet. Im Vergleich zum borrelienspezifischen Antik{\"o}rper-Index ist CXCL-13 als in etwa ebenb{\"u}rtig anzusehen. Besonders in der Fr{\"u}hphase der Infektion bietet die CXCL-13 Bestimmung aufgrund der Latenzzeit bis zur Nachweisbarkeit von Antik{\"o}rpern jedoch einen deutlichen Vorteil. Zus{\"a}tzlich f{\"a}llt die CXCL-13 Konzentration nach erfolgter Therapie rasch wieder ab, wodurch es sich auch als Verlaufsparameter eignet. Ein positiver Antik{\"o}rper-Index kann {\"u}ber viele Jahre persistieren, weshalb eine Unterscheidung zwischen akuter und abgelaufener Infektion unm{\"o}glich ist. Am sinnvollsten erscheint eine Kombination von CXCL-13 und Antik{\"o}rper-Index, in Verbindung mit der klinischen Pr{\"a}sentation ergibt sich so eine sehr hohe diagnostische Sicherheit in allen Stadien der Erkrankung.}, subject = {Borreliose}, language = {de} }