@article{UeceylerSchliesserEvdokimovetal.2022, author = {{\"U}{\c{c}}eyler, Nurcan and Schließer, Mira and Evdokimov, Dimitar and Radziwon, Jakub and Feulner, Betty and Unterecker, Stefan and Rimmele, Florian and Walter, Uwe}, title = {Reduced midbrain raphe echogenicity in patients with fibromyalgia syndrome}, series = {PloS One}, volume = {17}, journal = {PloS One}, number = {11}, doi = {10.1371/journal.pone.0277316}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300639}, year = {2022}, abstract = {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.}, language = {en} } @phdthesis{Oezkent2022, author = {{\"O}zkent, Helena}, title = {Untersuchung der Beteiligung der kleinen Nervenfasern bei Patient/-innen mit Antik{\"o}rper-assoziierten Neuropathien}, doi = {10.25972/OPUS-26929}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269293}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In der vorliegenden Studie wurden QST, QSART, Hautbiopsien und Frageb{\"o}gen genutzt, um die Beteiligung kleiner Nervenfasern bei verschiedenen Formen der Immunneuropathien zu untersuchen. Wir konnten hierbei eine signifikante Beeintr{\"a}chtigung der thermischen Reizleitung bei CIDP- und MADSAM-Patient/-innen nachweisen sowie eine signifikant reduzierte Schweißproduktion am distalen Unterschenkel bei MADSAM-Patient/-innen. Diese Ergebnisse belegen in allen drei Untergruppen der immunvermittelten Neuropathien eine Beteiligung kleiner auch unmyelinisierter Nervenfasertypen. MADSAM- und CIDP-Patient/-innen wiesen in der QST ein {\"a}hnliches Sch{\"a}digungsmuster auf. Dagegen unterschieden sie sich signifikant in der QSART. Diese Ergebnisse k{\"o}nnen als weiterer Hinweis auf unterschiedliche zugrundeliegende Pathomechanismen verstanden werden. MMN-Patient/-innen wiesen insgesamt die geringste Small-Fiber-Beteiligung in den quantitativen Testungen auf. Auch lagen bei MMN-Patient/-innen durchschnittlich die geringsten Schmerz-Scores und autonomen Symptome vor. Es zeigten sich wenig signifikante Unterschiede zwischen seropositiven und seronegativen Neuropathie-Patient/-innen. Diese jedoch best{\"a}tigten unsere Hypothese einer etwas geringeren Small-Fiber-Beteiligung bei seropositiven Patient/-innen. Bei der Vielzahl an unterschiedlichen Pathomechanismen innerhalb der immunvermittelten Neuropathien erscheinen weitere Subklassifizierungen f{\"u}r eine optimale Diagnosestellung und Therapie unabdingbar. Diese Arbeit konnte mit den oben genannten Untersuchungen einen weiteren Beitrag zur Identifikation von klinischen und quantitativen Unterschieden innerhalb dieser großen Erkrankungsgruppe leisten. K{\"u}nftige, gr{\"o}ßere Studien dieser Art k{\"o}nnen m{\"o}glicherweise hier nur als Tendenzen gesehene Erkenntnisse belegen und sollten durch zus{\"a}tzliche Informationen wie Korrelation zu Krankheitsdauer, Therapie, Laborchemie und elektrophysiologischen Untersuchen weitere interessante Erkenntnisse liefern.}, subject = {Polyneuropathie}, language = {de} } @article{OezdağAcarlıKleinEgenolfetal.2022, author = {{\"O}zdağ Acarl{\i}, Ay{\c{s}}e Nur and Klein, Thomas and Egenolf, Nadine and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {Subepidermal Schwann cell counts correlate with skin innervation - an exploratory study}, series = {Muscle \& Nerve}, volume = {65}, journal = {Muscle \& Nerve}, number = {4}, doi = {10.1002/mus.27496}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318726}, pages = {471 -- 479}, year = {2022}, abstract = {Introduction/Aims Schwann cell clusters have been described at the murine dermis-epidermis border. We quantified dermal Schwann cells in the skin of patients with small-fiber neuropathy (SFN) compared with healthy controls to correlate with the clinical phenotype. Methods Skin punch biopsies from the lower legs of 28 patients with SFN (11 men, 17 women; median age, 54 [range, 19-73] years) and 9 healthy controls (five men, four women, median age, 34 [range, 25-69] years) were immunoreacted for S100 calcium-binding protein B as a Schwann cell marker, protein-gene product 9.5 as a pan-neuronal marker, and CD207 as a Langerhans cell marker. Intraepidermal nerve fiber density (IENFD) and subepidermal Schwann cell counts were determined. Results Skin samples of patients with SFN showed lower IENFD (P < .05), fewer Schwann cells per millimeter (P < .01), and fewer Schwann cell clusters per millimeter (P < .05) than controls. When comparing SFN patients with reduced (n = 13; median age, 53 [range, 19-73] years) and normal distal (n = 15, median age, 54 [range, 43-68] years) IENFD, the number of solitary Schwann cells per millimeter (p < .01) and subepidermal nerve fibers associated with Schwann cell branches (P < .05) were lower in patients with reduced IENFD. All three parameters correlated positively with distal IENFD (P < .05 to P < .01), whereas no correlation was found between Schwann cell counts and clinical pain characteristics. Discussion Our data raise questions about the mechanisms underlying the interdependence of dermal Schwann cells and skin innervation in SFN. The temporal course and functional impact of Schwann cell presence and kinetics need further investigation.}, language = {en} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {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.}, language = {en} } @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} } @article{TuetuencueOlmaKunzeetal.2022, author = {T{\"u}t{\"u}nc{\"u}, Serdar and Olma, Manuel and Kunze, Claudia and Dietzel, Joanna and Schurig, Johannes and Fiessler, Cornelia and Malsch, Carolin and Haas, Tobias Eberhard and Dimitrijeski, Boris and Doehner, Wolfram and Hagemann, Georg and Hamilton, Frank and Honermann, Martin and Jungehulsing, Gerhard Jan and Kauert, Andreas and Koennecke, Hans-Christian and Mackert, Bruno-Marcel and Nabavi, Darius and Nolte, Christian H. and Reis, Joschua Mirko and Schmehl, Ingo and Sparenberg, Paul and Stingele, Robert and V{\"o}lzke, Enrico and Waldschmidt, Carolin and Zeise-Wehry, Daniel and Heuschmann, Peter U. and Endress, Matthias and Haeusler, Karl Georg}, title = {Off-label-dosing of non-vitamin K-dependent oral antagonists in AF patients before and after stroke: results of the prospective multicenter Berlin Atrial Fibrillation Registry}, series = {Journal of Neurology}, volume = {269}, journal = {Journal of Neurology}, number = {1}, issn = {1432-1459}, doi = {10.1007/s00415-021-10866-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266969}, pages = {470-480}, year = {2022}, abstract = {Aims We aimed to analyze prevalence and predictors of NOAC off-label under-dosing in AF patients before and after the index stroke. Methods The post hoc analysis included 1080 patients of the investigator-initiated, multicenter prospective Berlin Atrial Fibrillation Registry, designed to analyze medical stroke prevention in AF patients after acute ischemic stroke. Results At stroke onset, an off-label daily dose was prescribed in 61 (25.5\%) of 239 NOAC patients with known AF and CHA2DS2-VASc score ≥ 1, of which 52 (21.8\%) patients were under-dosed. Under-dosing was associated with age ≥ 80 years in patients on rivaroxaban [OR 2.90, 95\% CI 1.05-7.9, P = 0.04; n = 29] or apixaban [OR 3.24, 95\% CI 1.04-10.1, P = 0.04; n = 22]. At hospital discharge after the index stroke, NOAC off-label dose on admission was continued in 30 (49.2\%) of 61 patients. Overall, 79 (13.7\%) of 708 patients prescribed a NOAC at hospital discharge received an off-label dose, of whom 75 (10.6\%) patients were under-dosed. Rivaroxaban under-dosing at discharge was associated with age ≥ 80 years [OR 3.49, 95\% CI 1.24-9.84, P = 0.02; n = 19]; apixaban under-dosing with body weight ≤ 60 kg [OR 0.06, 95\% CI 0.01-0.47, P < 0.01; n = 56], CHA2DS2-VASc score [OR per point 1.47, 95\% CI 1.08-2.00, P = 0.01], and HAS-BLED score [OR per point 1.91, 95\% CI 1.28-2.84, P < 0.01]. Conclusion At stroke onset, off-label dosing was present in one out of four, and under-dosing in one out of five NOAC patients. Under-dosing of rivaroxaban or apixaban was related to old age. In-hospital treatment after stroke reduced off-label NOAC dosing, but one out of ten NOAC patients was under-dosed at discharge.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and Homola, Gy{\"o}rgy A. and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure}, series = {ESC Heart Failure}, volume = {9}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312736}, pages = {2626-2634}, year = {2022}, abstract = {Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1\% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = -4.7; P < 0.001), alanine aminotransferase (T = -2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = -3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and G{\"o}pfert, Dennis and Homola, Gy{\"o}rgy and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients}, series = {Alzheimer's Research \& Therapy}, volume = {14}, journal = {Alzheimer's Research \& Therapy}, doi = {10.1186/s13195-022-01087-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300515}, year = {2022}, abstract = {Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1\% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60\% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @phdthesis{Stengel2022, author = {Stengel, Helena Maria}, title = {Paranodale und nodale Autoantik{\"o}rper: Charakterisierung der Anti-Neurofascin-Autoantik{\"o}rper-assoziierten Neuropathie und Untersuchung des Effektes von Anti-Contactin-1-Autoantik{\"o}rpern im Zellkulturmodell}, doi = {10.25972/OPUS-25466}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254662}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die (Para-)nodopathie ist neben der prim{\"a}r axonalen und der prim{\"a}r demyelinisierenden Polyneuropathie eine neue Krankheitsentit{\"a}t, die sich durch eine Sch{\"a}digung der Funktion des Ranvierschen Schn{\"u}rringes auszeichnet. Die Forschung zu (para-)nodalen Autoantik{\"o}rpern fokussierte sich bislang haupts{\"a}chlich auf Neurofascin-155- und Contactin-1-Autoantik{\"o}rper der Subklasse IgG4. In dieser Studie wurden die Seren von insgesamt 264 PatientInnen mit CIDP, GBS oder anderen Formen von Polyneuropathien mittels Bindungsassays an murinen Ischiadicuszupfnerven und gegebenenfalls ELISA auf (para-)nodale Autoantik{\"o}rper gescrennt. Positive Autoantik{\"o}rperbefunde wurden bei IgG-Autoantik{\"o}rpern mittels Bindungsassays an transfizierten HEK-293-Zellen und bei IgM-Autoantik{\"o}rpern mittels Western Blot best{\"a}tigt. ELISA Untersuchungen dienten zur n{\"a}heren Spezifizierung. Weiterhin wurde die zeitabh{\"a}ngige Wirkung von Contactin-1-Autoantik{\"o}rpern im Zellkulturmodell untersucht. Die im folgenden dargestellten Ergebnisse zeigen, dass die (Para-)nodopathie nicht auf die bisher am h{\"a}ufigsten beschriebene Erkrankung mit IgG4-Autoantik{\"o}rpern beschr{\"a}nkt werden sollte. Bei dem extrem schwer betroffenen IgG-Patient 1 konnte ein Pan-Neurofascin-IgG3-Autoantik{\"o}rper nachgewiesen werden. Als charakteristische Symptome f{\"u}r diese Autoantik{\"o}rper konnten in {\"U}bereinstimmung mit weiteren Fallberichten Tetraplegie, Beatmungspflichtigkeit sowie eine schwere Hirnnervenbeteiligung bis zur Locked-In-Symptomatik identifiziert werden. Diese Patienten heben sich deutlich von den PatientInnen mit den bisher haupts{\"a}chlich beschriebenen Neurofascin-155-IgG4-Autoantik{\"o}rpern ab, die wie IgG-Patient 2 charakteristischerweise in jungem Alter an einer CIDP mit Tremor ohne Besserung unter IVIG-Therapie leiden. Es wurden f{\"u}nf PatientInnen mit Neurofascin-155-IgM-Autoantik{\"o}rpern identifiziert, die eine akut beginnende Erkrankung mit Tetraparese, Tremor und neuropathischen Schmerzen zeigten. Ob sich dieser Ph{\"a}notyp als charakteristisch f{\"u}r eine Neurofascin-155-IgM-(Para-)nodopathie best{\"a}tigt, sollte in weiteren Studien untersucht werden. Im murinen Zellkulturmodell an cerebell{\"a}ren Neuronen und Spinalganglienneuronen zeigte sich nach Inkubation mit Contactin-1-IgG-Patientenantik{\"o}rpern eine zeitabh{\"a}ngige, rasch reversible Verminderung der Contactin-1-Protein-Expression in immunhistochemischen F{\"a}rbungen sowie Western Blots, die durch eine Internalisierung des Contactin-1-Proteins erkl{\"a}rbar w{\"a}re. Der Angriff von Autoantik{\"o}rpern an Spinalganglienneuronen und cerebell{\"a}ren Neurone sollte in weitere pathophysiologische {\"U}berlegungen miteinbezogen werden, da hierdurch typische Symptome der (Para-)nodopathie wie eine sensible Ataxie oder ein cerebell{\"a}rer Tremor erkl{\"a}rt werden k{\"o}nnten.}, subject = {Ranvier-Schn{\"u}rring}, language = {de} } @article{SpitzelWagnerBreyeretal.2022, author = {Spitzel, Marlene and Wagner, Elise and Breyer, Maximilian and Henniger, Dorothea and Bayin, Mehtap and Hofmann, Lukas and Mauceri, Daniela and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan}, title = {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}, series = {Cells}, volume = {11}, journal = {Cells}, number = {11}, issn = {2073-4409}, doi = {10.3390/cells11111730}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275186}, year = {2022}, abstract = {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.}, language = {en} } @article{Sommer2022, author = {Sommer, Claudia}, title = {Natural course of Guillain-Barr{\´e} syndrome}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {10}, doi = {10.1111/ene.15498}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318757}, pages = {2881 -- 2882}, year = {2022}, language = {en} } @phdthesis{Seager2022, author = {Seager, Anna}, title = {Die ur{\"a}mische Neuropathie - ein Vitamin-B\(_{12}\)-Mangel?}, doi = {10.25972/OPUS-29109}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291094}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Eine Vielzahl von Patienten mit fortgeschrittener, beziehungsweise dialysepflichtiger Niereninsuffizienz entwickeln eine Polyneuropathie. Die Pathogenese der ur{\"a}mischen Neuropathie (UN) ist nicht gekl{\"a}rt, sodass auf der Suche nach dem Pathomechanismus auch ein Vitamin-B12-Mangel diskutiert werden muss, da dieser {\"a}hnliche Symptome wie die UN hervorrufen kann. Ziel dieser Studie war es, den Zusammenhang zwischen den Parametern des Vitamin-B12-Stoffwechsels und der UN darzustellen. In einer prospektiven Studie mit insgesamt 54 teilnehmenden Patienten wurden diese vor und nach einer Vitamin-B12-Substitution laborchemisch untersucht. Zudem erhielten die Patienten neben einer klinischen Untersuchung eine elektroneurographische Diagnostik des N. suralis und des N. tibialis, sowie eine QST-Untersuchung.}, subject = {Ur{\"a}mie}, language = {de} } @article{SchulteBlum2022, author = {Schulte, Annemarie and Blum, Robert}, title = {Shaped by leaky ER: Homeostatic Ca\(^{2+}\) fluxes}, series = {Frontiers in Physiology}, volume = {13}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2022.972104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-287102}, year = {2022}, abstract = {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.}, language = {en} } @article{SchreglmannBurkeBatlaetal.2022, author = {Schreglmann, Sebastian R. and Burke, Derek and Batla, Amit and Kresojevic, Nikola and Wood, Nicholas and Heales, Simon and Bhatia, Kailash P.}, title = {Cerebellar and Midbrain Lysosomal Enzyme Deficiency in Isolated Dystonia}, series = {Movement Disorders}, volume = {37}, journal = {Movement Disorders}, number = {4}, doi = {10.1002/mds.28937}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318743}, pages = {875 -- 877}, year = {2022}, language = {en} } @article{SchreglmannBhatia2022, author = {Schreglmann, Sebastian R. and Bhatia, Kailash P.}, title = {HOPS-Associated Neurological Disorders: Lysosomal Dysfunction as an Emerging Concept Underlying Dystonia}, series = {Movement Disorders Clinical Practice}, volume = {9}, journal = {Movement Disorders Clinical Practice}, number = {4}, doi = {10.1002/mdc3.13405}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318736}, pages = {452 -- 453}, year = {2022}, language = {en} } @article{SchmidbauerFerseSalihetal.2022, author = {Schmidbauer, Moritz L. and Ferse, Caroline and Salih, Farid and Klingner, Carsten and Musleh, Rita and Kunst, Stefan and Wittstock, Matthias and Neumann, Bernhard and Schebesch, Karl-Michael and B{\"o}sel, Julian and Godau, Jana and Lochner, Piergiorgio and Adam, Elisabeth H. and Jahnke, Kolja and Knier, Benjamin and Schirotzek, Ingo and M{\"u}llges, Wolfgang and Notz, Quirin and Dengl, Markus and G{\"u}ldner, Andreas and Onur, Oezguer A. and Garcia Borrega, Jorge and Dimitriadis, Konstantinos and G{\"u}nther, Albrecht}, title = {COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm11030605}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255236}, year = {2022}, abstract = {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.}, language = {en} } @phdthesis{Schanz2022, author = {Schanz, Stefan}, title = {Rehabilitation des Schlaganfalls - Evaluation eines interdisziplin{\"a}ren Behandlungskonzepts auf einer spezialisierten Station}, doi = {10.25972/OPUS-26001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260011}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die Rehabilitation von Schlaganfallpatienten erfordert ein interdisziplin{\"a}res Vorgehen. Dies ist im klinischen Alltag oft nur schwer umsetzbar. Im Jahr 2011 wurde daher im Neurologischen Rehabilitationszentrum Quellenhof in Bad Wildbad ein spezielles Behandlungskonzept f{\"u}r Schlaganfallpatienten entwickelt. Mit dieser Studie sollte die Wirksamkeit dieses neuen Konzepts untersucht werden. Dabei wurde die Behandlung im Schlaganfallkonzept mit der bisher {\"u}blichen Behandlung verglichen. Zielparameter waren der Barthel-Index und die modifizierte Rankin-Skala bei Aufnahme und bei Entlassung. Die Ergebnisse zeigen, dass sowohl die bisherige Behandlung als auch die Behandlung im Schlaganfallkonzept effektiv sind. Im Schlaganfallkonzept konnte jedoch ein gr{\"o}ßerer Zugewinn an alltagsrelevanten F{\"a}higkeiten erzielt werden; zudem berichteten Pflegekr{\"a}fte und Therapeuten eine verbesserte Zusammenarbeit. Somit steigert das Schlaganfallkonzept nicht nur die Alltagskompetenz der Patienten, sondern auch den Wissenstransfer zwischen den Berufsgruppen und die Interdisziplinarit{\"a}t.}, subject = {Schlaganfall}, language = {de} } @article{SchanbacherBieberReindersetal.2022, author = {Schanbacher, Constanze and Bieber, Michael and Reinders, Yvonne and Cherpokova, Deya and Teichert, Christina and Nieswandt, Bernhard and Sickmann, Albert and Kleinschnitz, Christoph and Langhauser, Friederike and Lorenz, Kristina}, title = {ERK1/2 activity is critical for the outcome of ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {2}, issn = {1422-0067}, doi = {10.3390/ijms23020706}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-283991}, year = {2022}, abstract = {Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2\(^{wt}\)) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood-brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP\(^{wt}\)) and its phosphorylation-deficient mutant RKIP\(^{S153A}\), known inhibitors of the ERK1/2 signaling cascade. RKIP\(^{wt}\) and RKIP\(^{S153A}\) attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.}, language = {en} } @article{RolfesRuckDavidetal.2022, author = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {1}, issn = {1868-4483}, doi = {10.1007/s12975-021-00923-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924}, pages = {197-211}, year = {2022}, abstract = {Rag1\(^{-/-}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{-/-}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{-/-}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{-/-}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{-/-}\) were comparable in number and function to those in WT mice. Rag1\(^{-/-}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1-/- controls. Our results indicate that NK cells from Rag1-/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.}, language = {en} } @article{ReinholdKrugSalvadoretal.2022, author = {Reinhold, Ann Kristin and Krug, Susanne M. and Salvador, Ellaine and Sauer, Reine S. and Karl-Sch{\"o}ller, Franziska and Malcangio, Marzia and Sommer, Claudia and Rittner, Heike L.}, title = {MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury}, series = {Annals of the New York Academy of Sciences}, volume = {1515}, journal = {Annals of the New York Academy of Sciences}, number = {1}, doi = {10.1111/nyas.14816}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318226}, pages = {184 -- 195}, year = {2022}, abstract = {Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9.}, language = {en} } @article{RauschenbergerBehnkeGrotemeyeretal.2022, author = {Rauschenberger, Lisa and Behnke, Jennifer and Grotemeyer, Alexander and Knorr, Susanne and Volkmann, Jens and Ip, Chi Wang}, title = {Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson's disease}, series = {Neurobiology of Disease}, volume = {171}, journal = {Neurobiology of Disease}, doi = {10.1016/j.nbd.2022.105798}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300629}, year = {2022}, abstract = {The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm\(^{2}\)α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2-3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm\(^{2}\)α-SYN-39 mice with wildtype controls. At an age of 16-17 months, however, hm\(^{2}\)α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2-3 months transgenic mice and compared to 16-17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8\(^{+}\) T cell numbers with dopaminergic terminal loss of the striatum was found in hm\(^{2}\)α-SYN-39 mice, but not in wildtype controls. In the striatum of 16-17 months old wildtype mice a slightly elevated CD8\(^{+}\) T cell count and CD11b\(^{+}\) microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4\(^{+}\), CD8\(^{+}\) T cell and B220\(^{+}\) B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8\(^{+}\) T cells, GFAP\(^{+}\) astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm\(^{2}\)α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm\(^{2}\)α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm\(^{2}\)α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.}, language = {en} } @article{PozziPalmisanoReichetal.2022, author = {Pozzi, Nicol{\´o} G. and Palmisano, Chiara and Reich, Martin M. and Capetian, Philip and Pacchetti, Claudio and Volkmann, Jens and Isaias, Ioannis U.}, title = {Troubleshooting gait disturbances in Parkinson's disease with deep brain stimulation}, series = {Frontiers in Human Neuroscience}, volume = {16}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2022.806513}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274007}, year = {2022}, abstract = {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.}, language = {en} } @article{PolatWohllebenKosmalaetal.2022, author = {Polat, B{\"u}lent and Wohlleben, Gisela and Kosmala, Rebekka and Lisowski, Dominik and Mantel, Frederick and Lewitzki, Victor and L{\"o}hr, Mario and Blum, Robert and Herud, Petra and Flentje, Michael and Monoranu, Camelia-Maria}, title = {Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma}, series = {Cancer Cell International}, volume = {22}, journal = {Cancer Cell International}, issn = {1475-2867}, doi = {10.1186/s12935-022-02510-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301240}, year = {2022}, abstract = {Background Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. Methods Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. Results Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). Conclusions Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.}, language = {en} } @article{PohGreenAgostinellietal.2022, author = {Poh, Eugenia Z. and Green, Courtney and Agostinelli, Luca and Penrose-Menz, Marissa and Karl, Ann-Kathrin and Harvey, Alan R. and Rodger, Jennifer}, title = {Manipulating the level of sensorimotor stimulation during LI-rTMS can improve visual circuit reorganisation in adult ephrin-A2A5\(^{-/-}\) Mice}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms23052418}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284090}, year = {2022}, abstract = {Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique that has the potential to treat a variety of neurologic and psychiatric disorders. The extent of rTMS-induced neuroplasticity may be dependent on a subject's brain state at the time of stimulation. Chronic low intensity rTMS (LI-rTMS) has previously been shown to induce beneficial structural and functional reorganisation within the abnormal visual circuits of ephrin-A2A5\(^{-/-}\) mice in ambient lighting. Here, we administered chronic LI-rTMS in adult ephrin-A2A5\(^{-/-}\) mice either in a dark environment or concurrently with voluntary locomotion. One day after the last stimulation session, optokinetic responses were assessed and fluorescent tracers were injected to map corticotectal and geniculocortical projections. We found that LI-rTMS in either treatment condition refined the geniculocortical map. Corticotectal projections were improved in locomotion+LI-rTMS subjects, but not in dark + LI-rTMS and sham groups. Visuomotor behaviour was not improved in any condition. Our results suggest that the beneficial reorganisation of abnormal visual circuits by rTMS can be significantly influenced by simultaneous, ambient visual input and is enhanced by concomitant physical exercise. Furthermore, the observed pathway-specific effects suggest that regional molecular changes and/or the relative proximity of terminals to the induced electric fields influence the outcomes of LI-rTMS on abnormal circuitry.}, language = {en} } @article{PalmisanoKullmannHanafietal.2022, author = {Palmisano, Chiara and Kullmann, Peter and Hanafi, Ibrahem and Verrecchia, Marta and Latoschik, Marc Erich and Canessa, Andrea and Fischbach, Martin and Isaias, Ioannis Ugo}, title = {A fully-immersive virtual reality setup to study gait modulation}, series = {Frontiers in Human Neuroscience}, volume = {16}, journal = {Frontiers in Human Neuroscience}, issn = {1662-5161}, doi = {10.3389/fnhum.2022.783452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267099}, year = {2022}, abstract = {Objective: Gait adaptation to environmental challenges is fundamental for independent and safe community ambulation. The possibility of precisely studying gait modulation using standardized protocols of gait analysis closely resembling everyday life scenarios is still an unmet need. Methods: We have developed a fully-immersive virtual reality (VR) environment where subjects have to adjust their walking pattern to avoid collision with a virtual agent (VA) crossing their gait trajectory. We collected kinematic data of 12 healthy young subjects walking in real world (RW) and in the VR environment, both with (VR/A+) and without (VR/A-) the VA perturbation. The VR environment closely resembled the RW scenario of the gait laboratory. To ensure standardization of the obstacle presentation the starting time speed and trajectory of the VA were defined using the kinematics of the participant as detected online during each walking trial. Results: We did not observe kinematic differences between walking in RW and VR/A-, suggesting that our VR environment per se might not induce significant changes in the locomotor pattern. When facing the VA all subjects consistently reduced stride length and velocity while increasing stride duration. Trunk inclination and mediolateral trajectory deviation also facilitated avoidance of the obstacle. Conclusions: This proof-of-concept study shows that our VR/A+ paradigm effectively induced a timely gait modulation in a standardized immersive and realistic scenario. This protocol could be a powerful research tool to study gait modulation and its derangements in relation to aging and clinical conditions.}, language = {en} } @article{PalmisanoBeccariaHaufeetal.2022, author = {Palmisano, Chiara and Beccaria, Laura and Haufe, Stefan and Volkmann, Jens and Pezzoli, Gianni and Isaias, Ioannis U.}, title = {Gait initiation impairment in patients with Parkinson's disease and freezing of gait}, series = {Bioengineering}, volume = {9}, journal = {Bioengineering}, number = {11}, issn = {2306-5354}, doi = {10.3390/bioengineering9110639}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297579}, year = {2022}, abstract = {Freezing of gait (FOG) is a sudden episodic inability to produce effective stepping despite the intention to walk. It typically occurs during gait initiation (GI) or modulation and may lead to falls. We studied the anticipatory postural adjustments (imbalance, unloading, and stepping phase) at GI in 23 patients with Parkinson's disease (PD) and FOG (PDF), 20 patients with PD and no previous history of FOG (PDNF), and 23 healthy controls (HCs). Patients performed the task when off dopaminergic medications. The center of pressure (CoP) displacement and velocity during imbalance showed significant impairment in both PDNF and PDF, more prominent in the latter patients. Several measurements were specifically impaired in PDF patients, especially the CoP displacement along the anteroposterior axis during unloading. The pattern of segmental center of mass (SCoM) movements did not show differences between groups. The standing postural profile preceding GI did not correlate with outcome measurements. We have shown impaired motor programming at GI in Parkinsonian patients. The more prominent deterioration of unloading in PDF patients might suggest impaired processing and integration of somatosensory information subserving GI. The unaltered temporal movement sequencing of SCoM might indicate some compensatory cerebellar mechanisms triggering time-locked models of body mechanics in PD.}, language = {en} } @phdthesis{Palmisano2022, author = {Palmisano, Chiara}, title = {Supraspinal Locomotor Network Derangements: A Multimodal Approach}, doi = {10.25972/OPUS-26644}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266442}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Parkinson's Disease (PD) constitutes a major healthcare burden in Europe. Accounting for aging alone, ~700,000 PD cases are predicted by 2040. This represents an approximately 56\% increase in the PD population between 2005 and 2040, with a consequent rise in annual disease-related medical costs. Gait and balance disorders are a major problem for patients with PD and their caregivers, mainly because to their correlation with falls. Falls occur as a result of a complex interaction of risk factors. Among them, Freezing of Gait (FoG) is a peculiar gait derangement characterized by a sudden and episodic inability to produce effective stepping, causing falls, mobility restrictions, poor quality of life, and increased morbidity and mortality. Between 50-70\% of PD patients have FoG and/or falls after a disease duration of 10 years, only partially and inconsistently improved by dopaminergic treatment and Deep Brain Stimulation (DBS). Treatment-induced worsening has been also observed under certain conditions. Effective treatments for gait disturbances in PD are lacking, probably because of the still poor understanding of the supraspinal locomotor network. In my thesis, I wanted to expand our knowledge of the supraspinal locomotor network and in particular the contribution of the basal ganglia to the control of locomotion. I believe this is a key step towards new preventive and personalized therapies for postural and gait problems in patients with PD and related disorders. In addition to patients with PD, my studies also included people affected by Progressive Supranuclear Palsy (PSP). PSP is a rare primary progressive parkinsonism characterized at a very early disease stage by poor balance control and frequent backwards falls, thus providing an in vivo model of dysfunctional locomotor control. I focused my attention on one of the most common motor transitions in daily living, the initiation of gait (GI). GI is an interesting motor task and a relevant paradigm to address balance and gait impairments in patients with movement disorders, as it is associated with FoG and high risk of falls. It combines a preparatory (i.e., the Anticipatory Postural Adjustments [APA]) and execution phase (the stepping) and allows the study of movement scaling and timing as an expression of muscular synergies, which follow precise and online feedback information processing and integration into established feedforward patterns of motor control. By applying a multimodal approach that combines biomechanical assessments and neuroimaging investigations, my work unveiled the fundamental contribution of striatal dopamine to GI in patients with PD. Results in patients with PSP further supported the fundamental role of the striatum in GI execution, revealing correlations between the metabolic intake of the left caudate nucleus with diverse GI measurements. This study also unveiled the interplay of additional brain areas in the motor control of GI, namely the Thalamus, the Supplementary Motor Area (SMA), and the Cingulate cortex. Involvement of cortical areas was also suggested by the analysis of GI in patients with PD and FoG. Indeed, I found major alterations in the preparatory phase of GI in these patients, possibly resulting from FoG-related deficits of the SMA. Alterations of the weight shifting preceding the stepping phase were also particularly important in PD patients with FoG, thus suggesting specific difficulties in the integration of somatosensory information at a cortical level. Of note, all patients with PD showed preserved movement timing of GI, possibly suggesting preserved and compensatory activity of the cerebellum. Postural abnormalities (i.e., increased trunk and thigh flexion) showed no relationship with GI, ruling out an adaptation of the motor pattern to the altered postural condition. In a group of PD patients implanted with DBS, I further explored the pathophysiological functioning of the locomotor network by analysing the timely activity of the Subthalamic Nucleus (STN) during static and dynamic balance control (i.e., standing and walking). For this study, I used novel DBS devices capable of delivering stimulation and simultaneously recording Local Field Potentials (LFP) of the implanted nucleus months and years after surgery. I showed a gait-related frequency shift in the STN activity of PD patients, possibly conveying cortical (feedforward) and cerebellar (feedback) information to mesencephalic locomotor areas. Based on this result, I identified for each patient a Maximally Informative Frequency (MIF) whose power changes can reliably classify standing and walking conditions. The MIF is a promising input signal for new DBS devices that can monitor LFP power modulations to timely adjust the stimulation delivery based on the ongoing motor task (e.g., gait) performed by the patient (adaptive DBS). Altogether my achievements allowed to define the role of different cortical and subcortical brain areas in locomotor control, paving the way for a better understanding of the pathophysiological dynamics of the supraspinal locomotor network and the development of tailored therapies for gait disturbances and falls prevention in PD and related disorders.}, language = {en} } @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{MontellanoKluterRueckeretal.2022, author = {Montellano, Felipe A. and Kluter, Elisabeth J. and R{\"u}cker, Viktoria and Ungeth{\"u}m, Kathrin and Mackenrodt, Daniel and Wiedmann, Silke and Dege, Tassilo and Quilitzsch, Anika and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph and Heuschmann, Peter U.}, title = {Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study}, series = {BMC Neurology}, volume = {22}, journal = {BMC Neurology}, number = {1}, doi = {10.1186/s12883-022-03017-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300119}, year = {2022}, abstract = {Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, W{\"u}rzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95\% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014-02/2017. Of those, 203 (37\%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95\% CI 1.02-1.08), male sex (OR 2.65; 95\% CI 1.54-4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95\% CI 0.61-0.84), systolic dysfunction (OR 2.79; 95\% CI 1.22-6.37), diastolic dysfunction (OR 2.29; 95\% CI 1.29-4.02), atrial fibrillation (OR 2.30; 95\% CI 1.25-4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95\% CI 1.22-1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors.}, language = {en} } @phdthesis{MeyerzuAltenschildesche2022, author = {Meyer zu Altenschildesche, Caren}, title = {Genetische Variationen bei Patienten mit idiopathischer Small fiber Neuropathie}, doi = {10.25972/OPUS-28274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282742}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die Literatur beschreibt unter Patienten mit idiopathischer Small fiber Neuro-pathie (SFN) einen Anteil von etwa ein F{\"u}nftel bis Drittel mit Variationen unkla-rer pathogenetischer Relevanz in Schmerz-assoziierten Genen. Dies best{\"a}tig-te sich im Rahmen unserer klinischen Studie: {\"U}ber die Zeit von Mai 2015 bis Januar 2020 konnten bei 13 von 66 (21\%) eingeschlossenen Patienten mit klinischem Verdacht auf SFN genetische Variationen in Schmerz-assoziierten Genen detektiert werden. Solche Ver{\"a}nderungen k{\"o}nnen {\"u}ber Gain- oder Loss-of-Function-Mechanismen die Funktion codierter nozizeptiver Signalpro-teine modulieren und so potentiell zur SFN-Symptomatik f{\"u}hren. Im Rahmen der Studie erfolgte neben der genetischen Diagnostik eine umfangreiche Un-tersuchung der Teilnehmer. In der Diagnostik stachen die potentiell geneti-schen SFN-Patienten nicht heraus und auch klinisch fielen nur dezente Unter-schiede zu den {\"u}brigen Patienten auf: Wir zeigten, dass die Betroffenen h{\"a}ufi-ger von {\"a}ußeren Einflussfaktoren getriggerte Schmerzattacken erleiden und eine tendenziell weitl{\"a}ufigere Symptommanifestation aufwiesen. Dies {\"a}hnelt der Klinik anderer heredit{\"a}rer neuropathischer Schmerzsyndrome wie der pa-roxysmalen extremen Schmerzst{\"o}rung (PEPD) oder den famili{\"a}ren episodi-schen Schmerzsyndromen (FEPS). Die potentiell genetische Grundlage f{\"u}hrte bei unseren Patienten zu einer st{\"a}rkeren Limitation im t{\"a}glichen und berufli-chen Alltag und minderte die Lebensqualit{\"a}t der Betroffenen deutlich. M{\"o}gli-che Ursache hierf{\"u}r war auch die herausfordernde Therapie der Patienten mit Genvariationen: F{\"u}r den gleichen Behandlungserfolg mussten die Patienten mit potentiell genetischer SFN deutlich mehr Wirkstoffe einnehmen und {\"u}ber-haupt versuchen. Obwohl nur minimale klinische Hinweise eine potentiell ge-netische Genese andeuten, sollten diese fr{\"u}hzeitig durch eine strukturierte Anamnese erkannt werden. Die Sammlung von Daten zu betroffenen Familien kann die pathogenetische Relevanz der Variationen erh{\"a}rten. Auch wird im Feld der genetischen Schmerzforschung rasant an zielgerichteten Analgetika gearbeitet, die fehlregulierte Rezeptoren blockieren sollen. Damit k{\"o}nnte Be-troffenen k{\"u}nftig gezielt geholfen werden. Wir empfehlen auf Grundlage unse-rer Studie bei Vorliegen genannter hinweisender Charakteristika eine geneti-sche Testung und Beratung zus{\"a}tzlich zur weiteren {\"a}tiologischen Diagnostik. Das zu untersuchende Panel sollte m{\"o}glichst viele Schmerz-assoziierte Gene umfassen - vorrangig die Gene codierend f{\"u}r die spannungsabh{\"a}ngigen Nat-riumkan{\"a}le SCN9A, -10A und 11A und die TRP-Kanalproteine TRPA1, TRPV1 und -3.}, subject = {Neuropathie}, language = {de} } @article{LorenzMusacchioKunstmannetal.2022, author = {Lorenz, Delia and Musacchio, Thomas and Kunstmann, Erdmute and Grauer, Eva and Pluta, Natalie and Stock, Annika and Speer, Christian P. and Hebestreit, Helge}, title = {A case report of Sanfilippo syndrome - the long way to diagnosis}, series = {BMC Neurology}, volume = {22}, journal = {BMC Neurology}, number = {1}, doi = {10.1186/s12883-022-02611-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300465}, year = {2022}, abstract = {Background Mucopolysaccharidosis type III (Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in the heparan-N-sulfatase enzyme involved in the catabolism of the glycosaminoglycan heparan sulfate. It is characterized by early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild somatic features. In this patient group with a broad clinical spectrum a significant genotype-phenotype correlation with some mutations leading to a slower progressive, attenuated course has been demonstrated. Case presentation Our patient had complications in the neonatal period and was diagnosed with Mucopolysaccharidosis IIIa only at the age of 28 years. He was compound heterozygous for the variants p.R245H and p.S298P, the latter having been shown to lead to a significantly milder phenotype. Conclusions The diagnostic delay is even more prolonged in this patient population with comorbidities and a slowly progressive course of the disease.}, 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} } @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{Leinfelder2022, author = {Leinfelder, Teresa}, title = {Untersuchung von Trainingseffekten bei der Verwendung einer auditorischen P300-basierten EEG Gehirn-Computer Schnittstelle mittels fMRI Analyse}, doi = {10.25972/OPUS-29068}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290683}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {In dieser Dissertation untersuchten wir die neuronalen Korrelate des Training-Effektes einer auditorischen P300 Gehirn-Computer Schnittstelle mittels fMRI Analyse in einem pr{\"a}-post Design mit zehn gesunden Testpersonen. Wir wiesen in drei Trainings-sitzungen einen Trainingseffekt in der EEG-Analyse der P300 Welle nach und fanden entsprechende Kontraste in einer pr{\"a}-post Analyse von fMRI Daten, wobei in allen f{\"u}nf Sitzungen das gleiche Paradigma verwendet wurde. In der fMRI Analyse fanden wir fol-gende Ergebnisse: in einem Target-/ Nichttarget Kontrast zeigte sich verst{\"a}rkte Aktivie-rung in Generatorregionen der P300 Welle (temporale und inferiore frontale Regionen) und interessanterweise auch in motorassoziierten Arealen, was h{\"o}here kognitiver Pro-zesse wie Aufmerksamkeitslenkung und Arbeitsspeicher widerspiegeln k{\"o}nnte. Der Kon-trast des Trainingseffektes zeigte nach dem Training einen st{\"a}rkeren Rebound Effekt im Sinne einer verst{\"a}rkten Aktivierung in Generatorregionen der P300 Welle, was eine ver-besserte Erkennung und Prozessierung von Target-Stimuli reflektieren k{\"o}nnte. Eine Ab-nahme von Aktivierung in frontalen Arealen in diesem Kontrast k{\"o}nnte durch effizientere Abl{\"a}ufe kognitiver Prozesse und des Arbeitsged{\"a}chtnis erkl{\"a}rt werden.}, subject = {Gehirn-Computer-Schnittstelle}, language = {de} } @article{LauUeceylerCairnsetal.2022, author = {Lau, Kolja and {\"U}{\c{c}}eyler, Nurcan and Cairns, Tereza and Lorenz, Lora and Sommer, Claudia and Schindeh{\"u}tte, Magnus and Amann, Kerstin and Wanner, Christoph and Nordbeck, Peter}, title = {Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {5}, doi = {10.1002/mgg3.1912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312817}, year = {2022}, abstract = {Background Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future. Methods This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years. Results Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy. Conclusion These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.}, language = {en} } @article{KraemerSchuhmannVolkmannetal.2022, author = {Kr{\"a}mer, Stefanie D. and Schuhmann, Michael K. and Volkmann, Jens and Fluri, Felix}, title = {Deep brain stimulation in the subthalamic nucleus can improve skilled Forelimb movements and retune dynamics of striatal networks in a rat stroke model}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {24}, doi = {10.3390/ijms232415862}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312828}, year = {2022}, abstract = {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.}, language = {en} } @article{KraftSchuhmann2022, author = {Kraft, Peter and Schuhmann, Michael K.}, title = {Cellular and molecular targets in acute ischemic stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {19}, issn = {1422-0067}, doi = {10.3390/ijms231911097}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288294}, year = {2022}, abstract = {No abstract available}, language = {en} } @article{KollikowskiPhamMaerzetal.2022, author = {Kollikowski, Alexander M. and Pham, Mirko and M{\"a}rz, Alexander G. and Papp, Lena and Nieswandt, Bernhard and Stoll, Guido and Schuhmann, Michael K.}, title = {Platelet Activation and Chemokine Release Are Related to Local Neutrophil-Dominant Inflammation During Hyperacute Human Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {3}, issn = {1868-601X}, doi = {10.1007/s12975-021-00938-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270194}, pages = {364-369}, year = {2022}, abstract = {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.}, language = {en} } @article{KlineLoessleinKurianetal.2022, author = {Kline, Rachel A. and L{\"o}ßlein, Lena and Kurian, Dominic and Aguilar Mart{\´i}, Judit and Eaton, Samantha L. and Court, Felipe A. and Gillingwater, Thomas H. and Wishart, Thomas M.}, title = {An optimized comparative proteomic approach as a tool in neurodegenerative disease research}, series = {Cells}, volume = {11}, journal = {Cells}, number = {17}, issn = {2073-4409}, doi = {10.3390/cells11172653}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285912}, year = {2022}, abstract = {Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability.}, language = {en} } @article{KleinGrohYuanetal.2022, author = {Klein, Dennis and Groh, Janos and Yuan, Xidi and Berve, Kristina and Stassart, Ruth and Fledrich, Robert and Martini, Rudolf}, title = {Early targeting of endoneurial macrophages alleviates the neuropathy and affects abnormal Schwann cell differentiation in a mouse model of Charcot-Marie-Tooth 1A}, series = {Glia}, volume = {70}, journal = {Glia}, number = {6}, doi = {10.1002/glia.24158}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318714}, pages = {1100 -- 1116}, year = {2022}, abstract = {We have previously shown that targeting endoneurial macrophages with the orally applied CSF-1 receptor specific kinase (c-FMS) inhibitor PLX5622 from the age of 3 months onwards led to a substantial alleviation of the neuropathy in mouse models of Charcot-Marie-Tooth (CMT) 1X and 1B disease, which are genetically-mediated nerve disorders not treatable in humans. The same approach failed in a model of CMT1A (PMP22-overexpressing mice, line C61), representing the most frequent form of CMT. This was unexpected since previous studies identified macrophages contributing to disease severity in the same CMT1A model. Here we re-approached the possibility of alleviating the neuropathy in a model of CMT1A by targeting macrophages at earlier time points. As a proof-of-principle experiment, we genetically inactivated colony-stimulating factor-1 (CSF-1) in CMT1A mice, which resulted in lower endoneurial macrophage numbers and alleviated the neuropathy. Based on these observations, we pharmacologically ablated macrophages in newborn CMT1A mice by feeding their lactating mothers with chow containing PLX5622, followed by treatment of the respective progenies after weaning until the age of 6 months. We found that peripheral neuropathy was substantially alleviated after early postnatal treatment, leading to preserved motor function in CMT1A mice. Moreover, macrophage depletion affected the altered Schwann cell differentiation phenotype. These findings underscore the targetable role of macrophage-mediated inflammation in peripheral nerves of inherited neuropathies, but also emphasize the need for an early treatment start confined to a narrow therapeutic time window in CMT1A models and potentially in respective patients.}, language = {en} } @phdthesis{Karus2022, author = {Karus, Christine}, title = {Untersuchung der Architektur von Proteinstrukturen des Ranvier-Schn{\"u}rrings mittels der super-hochaufl{\"o}senden Mikroskopiemethode dSTORM}, doi = {10.25972/OPUS-27456}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-274568}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Ranvier-Schn{\"u}rringe spielen eine entscheidende Rolle bei der schnellen Weiterleitung von elektrischen Impulsen in Nervenzellen. Bei bestimmten neurologischen Erkrankungen, den Neuropathien, kann es zu St{\"o}rungen in der ultrastrukturellen Organisation verschiedener Schn{\"u}rring-Proteine kommen (Doppler et al., 2018, Doppler et al., 2016). Eine detailliertere Kenntnis der genauen Anordnung dieser Schn{\"u}rring-Proteine und eventueller Abweichungen von dieser Anordnung im Krankheitsfall, k{\"o}nnte der Schl{\"u}ssel zu einer vereinfachten Diagnostik von bestimmten Neuropathie- Formen sein. Ziel meiner Arbeit war es daher, die Untersuchung der ultrastrukturellen Architektur der (para-)nodalen Adh{\"a}sionsproteine Neurofascin-155 und Caspr1 unter Verwendung der super-hochaufl{\"o}senden Mikroskopiemethode dSTORM (direct Stochastic Optical Reconstruction Microscopy) an murinen Zupfnervenpr{\"a}paraten zu etablieren. Nach erster Optimierung der Probenpr{\"a}paration f{\"u}r die 2-Farben-dSTORM sowie der korrelationsbasierten Bildanalyse, konnte ich mittels modellbasierter Simulation die zugrundeliegende Molek{\"u}lorganisation identifizieren und mit Hilfe der Ergebnisse aus fr{\"u}heren Untersuchungen validieren. In einem translationalen Ansatz habe ich anschließend humane Zupfnervenpr{\"a}parate von 14 Probanden mit unterschiedlichen Formen einer Neuropathie mikroskopiert und ausgewertet, um die Anwendbarkeit dieses Ansatzes in der Diagnostik zu testen. Obgleich keine signifikanten Unterschiede zwischen physiologischem und pathologischem neurologischem Gewebe hinsichtlich Neurofascin-155 und Caspr1 festgestellt werden konnten, scheint der Ansatz grunds{\"a}tzlich dennoch vielversprechend zu sein, bedarf jedoch noch weiteren Anstrengungen hinsichtlich Probenpr{\"a}paration, Auswertungs- und Versuchsprotokollen und einer gr{\"o}ßeren Anzahl an humanen Biopsien mit homogenerem Krankheitsbild.}, language = {de} } @phdthesis{Karina2022, author = {Karina, Karina}, title = {Beschreibung der Maßnahmen zur Beschleunigung und Verbesserung der Notfallversorgung von Patienten mit akutem Schlaganfall in einer l{\"a}ndlichen Neurologischen Klinik und sequentielle Messung relevanter Qualit{\"a}tsindikatoren}, doi = {10.25972/OPUS-29174}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-291749}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Die hohe Mortalit{\"a}t und hohe Rate an Langzeitbehinderungen nach einem erlittenen Schlaganfall verdeutlichen die Relevanz bestm{\"o}glicher Akutversorgung bei Schlaganfallpatienten. Daher ist es unentbehrlich, dass die Akuttherapie bei Schlaganfall stets {\"u}berpr{\"u}ft und bei Bedarf optimiert wird. Der Großteil der Studien, die sich mit Verbesserungsmaßnahmen in der akuten Schlaganfallversorgung befassen, wird in großen st{\"a}dtischen Krankenh{\"a}usern bzw. Universit{\"a}tsklinika durchgef{\"u}hrt. Studien zu diesem Sachverhalt, die in l{\"a}ndlichen Kliniken durchgef{\"u}hrt wurden, sind noch begrenzt vorhanden. Mit dieser Studie evaluieren wir, ob sich durch die Implementierung neuer Optimierungsmaßnahmen Verbesserungen in den relevanten Qualit{\"a}tsindikatoren ergeben. Die Ergebnisse sind daher von besonderer Bedeutung, da es f{\"u}r nicht-universit{\"a}re Kliniken nur eine begrenzte Anzahl an Studien gibt, die sich mit dieser Thematik besch{\"a}ftigen.}, subject = {Verbesserung}, language = {de} } @article{KarikariMcFlederRibechinietal.2022, author = {Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, J{\"o}rg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang}, title = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice}, series = {Brain, Behavior, and Immunity}, volume = {101}, journal = {Brain, Behavior, and Immunity}, doi = {10.1016/j.bbi.2022.01.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300600}, pages = {194 -- 210}, year = {2022}, abstract = {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.}, language = {en} } @phdthesis{Karch2022, author = {Karch, Katharina}, title = {Mapping and Neutralization of Antibodies against Neurofascin, Contactin 1, Contactin associated protein 1 and Cortactin}, doi = {10.25972/OPUS-28022}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-280223}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Immune-mediated polyneuropathies like chronic inflammatory demyelinating polyradiculoneuropathy or Guillain-Barr{\´e} syndrome are rare diseases of the peripheral nervous system. A subgroup of patients harbors autoantibodies against nodal or paranodal antigens, associated with a distinct phenotype and treatment response. In a part of patients with pathologic paranodal or nodal immunoreactivity the autoantigens remain difficult or impossible to determine owing to limitations of the used detection approach - usually ELISAs (enzyme-linked-immunosorbent-assays) - and incomplete knowledge of the possible autoantigens. Due to their high-throughput, low sample consumption and high sensitivity as well as the possibility to display many putative nodal and paranodal autoantigens simultaneously, peptide microarray-based approaches are prime candidates for the discovery of novel autoantigens, point-of-care diagnostics and, in addition, monitoring of pathologic autoimmune response. Current applications of peptide microarrays are however limited by high false-positive rates and the associated need for detailed follow-up studies and validation. Here, robust peptide microarray-based detection of antibodies and the efficient validation of binding signals by on-chip neutralization is demonstrated. First, autoantigens were displayed as overlapping peptide libraries in microarray format. Copies of the biochips were used for the fine mapping of antibody epitopes. Next, binding signals were validated by antibody neutralization in solution. Since neutralizing peptides are obtained in the process of microarray fabrications, neither throughput nor costs are significantly altered. Similar in-situ validation approaches could contribute to future autoantibody characterization and detection methods as well as to therapeutic research. Areas of application could be expanded to any autoimmune-mediated neurological disease as a long-term vision.}, subject = {Microarray}, language = {en} } @article{JirůHillmannGabrielSchuleretal.2022, author = {J{\´i}rů-Hillmann, Steffi and Gabriel, Katharina M. A. and Schuler, Michael and Wiedmann, Silke and M{\"u}hler, Johannes and D{\"o}tter, Klaus and Soda, Hassan and Rascher, Alexandra and Benesch, Sonka and Kraft, Peter and Pfau, Mathias and Stenzel, Joachim and von Nippold, Karin and Benghebrid, Mohamed and Schulte, Kerstin and Meinck, Ralf and Volkmann, Jens and Haeusler, Karl Georg and Heuschmann, Peter U.}, title = {Experiences of family caregivers 3-months after stroke: results of the prospective trans-regional network for stroke intervention with telemedicine registry (TRANSIT-Stroke)}, series = {BMC Geriatrics}, volume = {22}, journal = {BMC Geriatrics}, doi = {10.1186/s12877-022-02919-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313330}, year = {2022}, abstract = {Background Long-term support of stroke patients living at home is often delivered by family caregivers (FC). We identified characteristics of stroke patients being associated with receiving care by a FC 3-months (3 M) after stroke, assessed positive and negative experiences and individual burden of FC caring for stroke patients and determined factors associated with caregiving experiences and burden of FC 3 M after stroke. Methods Data were collected within TRANSIT-Stroke, a regional telemedical stroke-network comprising 12 hospitals in Germany. Patients with stroke/TIA providing informed consent were followed up 3 M after the index event. The postal patient-questionnaire was accompanied by an anonymous questionnaire for FC comprising information on positive and negative experiences of FC as well as on burden of caregiving operationalized by the Caregiver Reaction Assessment and a self-rated burden-scale, respectively. Multivariable logistic and linear regression analyses were performed. Results Between 01/2016 and 06/2019, 3532 patients provided baseline and 3 M-follow-up- data and 1044 FC responded to questionnaires regarding positive and negative caregiving experiences and caregiving burden. 74.4\% of FC were older than 55 years, 70.1\% were women and 67.5\% were spouses. Older age, diabetes and lower Barthel-Index in patients were significantly associated with a higher probability of receiving care by a FC at 3 M. Positive experiences of FC comprised the importance (81.5\%) and the privilege (70.0\%) of caring for their relative; negative experiences of FC included financial difficulties associated with caregiving (20.4\%). Median overall self-rated burden was 30 (IQR: 0-50; range 0-100). Older age of stroke patients was associated with a lower caregiver burden, whereas younger age of FC led to higher burden. More than half of the stroke patients in whom a FC questionnaire was completed did self-report that they are not being cared by a FC. This stroke patient group tended to be younger, more often male with less severe stroke and less comorbidities who lived more often with a partner. Conclusions The majority of caregivers wanted to care for their relatives but experienced burden at the same time. Elderly patients, patients with a lower Barthel Index at discharge and diabetes are at higher risk of needing care by a family caregiver. Trial registration The study was registered at "German Clinical Trial Register": DRKS00011696. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML\&TRIAL_ID=DRKS00011696}, language = {en} } @phdthesis{Haehnel2022, author = {H{\"a}hnel, Luzia Maria}, title = {Evaluation von Beta-2-Mikroglobulin, Laktat und Angiotensin-Converting Enzyme im Liquor als Biomarker der Multiplen Sklerose}, doi = {10.25972/OPUS-25850}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258503}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {This study investigates the suitability of beta-2-microglobulin (β2-microglobulin), lactate and angiotensin-converting enzyme (ACE) as biomarkers, given the good availability of these parameters in routine diagnostics but lack of data in this regard. For this purpose, 6,310 CSF samples obtained at the Neurological Clinic of the University Hospital of W{\"u}rzburg were analyzed. Closer analysis was carried out of 276 cases with non-inflammatory neurological diseases (NIND; control group) and 438 MS cases not taking an immunotherapy treatment (study group). In the MS cases, the form of progression of the disease and the disease activity (clinical relapses, progression index) were recorded. A clear correlation could be seen between age and CSF levels of β2-microglobulin, lactate and ACE in both the MS and control groups, whereby a correction was required for the subsequent comparison studies; this could also at least partly explain the contradictory data obtained in other studies to date. The MS cases showed elevated β2-microglobulin and lactate levels and decreased ACE levels in CSF compared to the controls. In both groups, there was a positive correlation between β2-microglobulin and ACE levels. In the separate analysis of the forms of progression of MS, cases with clinically-isolated syndrome (CIS) and relapsing-remitting MS (RRMS) revealed elevated β2-microglobulin levels, whilst cases with secondary-progressive or primary-progressive MS (SPMS or PPMS) did not. Lactate levels were only increased in cases of CIS. Cases with a relapsing course showed reduced ACE levels. The disease activity could not reliably be mapped by the parameters. Lactate levels tended to be elevated during a relapse, but this result was no longer significant after correction. Lactate levels also showed a positive correlation with the progression index. Our findings in this study provide evidence that the examined analysis parameters cannot be used in isolation to assess progression, disease activity and duration of disease. However, the significant differences between relapsing and chronic-progressive courses support the hypothesis of different underlying mechanisms of pathogenesis, and could serve as a starting basis for further studies.}, subject = {Multiple Sklerose}, language = {de} } @article{HussAbdelhakMayeretal.2022, author = {Huss, Andr{\´e} and Abdelhak, Ahmed and Mayer, Benjamin and Tumani, Hayrettin and M{\"u}ller, Hans-Peter and Althaus, Katharina and Kassubek, Jan and Otto, Markus and Ludolph, Albert C. and Yilmazer-Hanke, Deniz and Neugebauer, Hermann}, title = {Association of serum GFAP with functional and neurocognitive outcome in sporadic small vessel disease}, series = {Biomedicines}, volume = {10}, journal = {Biomedicines}, number = {8}, issn = {2227-9059}, doi = {10.3390/biomedicines10081869}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285973}, year = {2022}, abstract = {Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients.}, language = {en} } @phdthesis{Hochheimer2022, author = {Hochheimer, Vanessa Christine}, title = {Of cells and enzymes: How dermal fibroblasts can impact pain in Fabry Disease and Why looking at the 3D-structure of α-Galactosidase A may be worthwhile for clinical management of Fabry patients}, doi = {10.25972/OPUS-29660}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-296607}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2022}, abstract = {Fabry Disease (FD) is a genetic lysosomal storage disorder based on mutations in the gene encoding α-Galactosidase A (α-GalA) leading to accumulation of globotriaosylceramide (Gb3). Missense mutations induce an amino acid exchange (AAE) in the α-GalA. Pain is a predominant symptom in FD and the pathophysiology is unclear. Skin punch biopsies were obtained from 40 adult FD patients and ten healthy controls and dermal fibroblast cultures were generated for cell culture experiments to investigate Gb3 load, gene and protein expression patterns and ion channel activity. The 3D-structure of α-GalA was downloaded into Pymol Graphics System and the AAE was depicted and located in order to investigate the correlation between the AAE location type in the α-GalA and the clinical FD phenotype. FD dermal fibroblasts showed high Gb3 load depending on treatment interval and expressed Kca1.1 channels. Activity was reduced in FD cells at baseline, but increased over-proportionately upon Gb3-cleavage by enzyme replacement therapy. Gene and protein expression of Kca1.1 was increased in FD cells. FD dermal fibroblasts showed higher gene expression of Notch1 and several cytokines. Further, it was shown that three different AAE location types can be differentiated: mutations in the active site ('active site'), those buried in the core of α-GalA ('buried') and those at another location, mostly on the protein surface ('other'). FD patients carrying active site or buried mutations showed a severe clinical phenotype with multi-organ manifestation and early disease onset. Patients with other mutations were less severely affected with oligo-organ manifestation sparing the nervous system and later disease onset. These results show that dermal fibroblasts may be involved in FD-associated pain and that stratification of FD patients carrying missense mutations by AAE location type may be an advantageous parameter that can help in the management of FD patients.}, subject = {Fabry-Krankheit}, language = {en} } @article{HiewNguemeniZeller2022, author = {Hiew, Shawn and Nguemeni, Carine and Zeller, Daniel}, title = {Efficacy of transcranial direct current stimulation in people with multiple sclerosis: a review}, series = {European Journal of Neurology}, volume = {29}, journal = {European Journal of Neurology}, number = {2}, doi = {10.1111/ene.15163}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259424}, pages = {648-664}, year = {2022}, abstract = {Background and purpose Multiple sclerosis (MS) is a chronic inflammatory disease causing a wide range of symptoms including motor and cognitive impairment, fatigue and pain. Over the last two decades, non-invasive brain stimulation, especially transcranial direct current stimulation (tDCS), has increasingly been used to modulate brain function in various physiological and pathological conditions. However, its experimental applications for people with MS were noted only as recently as 2010 and have been growing since then. The efficacy for use in people with MS remains questionable with the results of existing studies being largely conflicting. Hence, the aim of this review is to paint a picture of the current state of tDCS in MS research grounded on studies applying tDCS that have been done to date. Methods A keyword search was performed to retrieve articles from the earliest article identified until 14 February 2021 using a combination of the groups (1) 'multiple sclerosis', 'MS' and 'encephalomyelitis' and (2) 'tDCS' and 'transcranial direct current stimulation'. Results The analysis of the 30 articles included in this review underlined inconsistent effects of tDCS on the motor symptoms of MS based on small sample sizes. However, tDCS showed promising benefits in ameliorating fatigue, pain and cognitive symptoms. Conclusion Transcranial direct current stimulation is attractive as a non-drug approach in ameliorating MS symptoms, where other treatment options remain limited. The development of protocols tailored to the individual's own neuroanatomy using high definition tDCS and the introduction of network mapping in the experimental designs might help to overcome the variability between studies.}, language = {en} }