@article{IpWischhusen2023, author = {Ip, Chi Wang and Wischhusen, J{\"o}rg}, title = {Versatile guardians: regenerative regulatory T cells in Parkinson's disease rodent models}, series = {Signal Transduction and Targeted Therapy}, volume = {8}, journal = {Signal Transduction and Targeted Therapy}, doi = {10.1038/s41392-023-01681-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357674}, year = {2023}, abstract = {No abstract available.}, language = {en} } @article{HaarmannVollmuthKollikowskietal.2023, author = {Haarmann, Axel and Vollmuth, Christoph and Kollikowski, Alexander M. and Heuschmann, Peter U. and Pham, Mirko and Stoll, Guido and Neugebauer, Hermann and Schuhmann, Michael K.}, title = {Vasoactive soluble endoglin: a novel biomarker indicative of reperfusion after cerebral large-vessel occlusion}, series = {Cells}, volume = {12}, journal = {Cells}, number = {2}, issn = {2073-4409}, doi = {10.3390/cells12020288}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304995}, year = {2023}, abstract = {Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-β co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.}, language = {en} } @article{SilwedelHuettenSpeeretal.2023, author = {Silwedel, Christine and H{\"u}tten, Matthias C. and Speer, Christian P. and H{\"a}rtel, Christoph and Haarmann, Axel and Henrich, Birgit and Tijssen, Maud P. M. and Alnakhli, Abdullah Ahmed and Spiller, Owen B. and Schlegel, Nicolas and Seidenspinner, Silvia and Kramer, Boris W. and Glaser, Kirsten}, title = {Ureaplasma-driven neonatal neuroinflammation: novel insights from an ovine model}, series = {Cellular and Molecular Neurobiology}, volume = {43}, journal = {Cellular and Molecular Neurobiology}, number = {2}, doi = {10.1007/s10571-022-01213-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324285}, pages = {785-795}, year = {2023}, abstract = {Ureaplasma species (spp.) are considered commensals of the adult genitourinary tract, but have been associated with chorioamnionitis, preterm birth, and invasive infections in neonates, including meningitis. Data on mechanisms involved in Ureaplasma-driven neuroinflammation are scarce. The present study addressed brain inflammatory responses in preterm lambs exposed to Ureaplasma parvum (UP) in utero. 7 days after intra-amniotic injection of UP (n = 10) or saline (n = 11), lambs were surgically delivered at gestational day 128-129. Expression of inflammatory markers was assessed in different brain regions using qRT-PCR and in cerebrospinal fluid (CSF) by multiplex immunoassay. CSF was analyzed for UP presence using ureB-based real-time PCR, and MRI scans documented cerebral white matter area and cortical folding. Cerebral tissue levels of atypical chemokine receptor (ACKR) 3, caspases 1-like, 2, 7, and C-X-C chemokine receptor (CXCR) 4 mRNA, as well as CSF interleukin-8 protein concentrations were significantly increased in UP-exposed lambs. UP presence in CSF was confirmed in one animal. Cortical folding and white matter area did not differ among groups. The present study confirms a role of caspases and the transmembrane receptors ACKR3 and CXCR4 in Ureaplasma-driven neuroinflammation. Enhanced caspase 1-like, 2, and 7 expression may reflect cell death. Increased ACKR3 and CXCR4 expression has been associated with inflammatory central nervous system (CNS) diseases and impaired blood-brain barrier function. According to these data and previous in vitro findings from our group, we speculate that Ureaplasma-induced caspase and receptor responses affect CNS barrier properties and thus facilitate neuroinflammation.}, language = {en} } @article{OdorferYabeHiewetal.2023, author = {Odorfer, Thorsten M. and Yabe, Marie and Hiew, Shawn and Volkmann, Jens and Zeller, Daniel}, title = {Topological differences and confounders of mental rotation in cervical dystonia and blepharospasm}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-33262-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357713}, year = {2023}, abstract = {Mental rotation (mR) bases on imagination of actual movements. It remains unclear whether there is a specific pattern of mR impairment in focal dystonia. We aimed to investigate mR in patients with cervical dystonia (CD) and blepharospasm (BS) and to assess potential confounders. 23 CD patients and 23 healthy controls (HC) as well as 21 BS and 19 hemifacial spasm (HS) patients were matched for sex, age, and education level. Handedness, finger dexterity, general reaction time, and cognitive status were assessed. Disease severity was evaluated by clinical scales. During mR, photographs of body parts (head, hand, or foot) and a non-corporal object (car) were displayed at different angles rotated within their plane. Subjects were asked to judge laterality of the presented image by keystroke. Both speed and correctness were evaluated. Compared to HC, CD and HS patients performed worse in mR of hands, whereas BS group showed comparable performance. There was a significant association of prolonged mR reaction time (RT) with reduced MoCA scores and with increased RT in an unspecific reaction speed task. After exclusion of cognitively impaired patients, increased RT in the mR of hands was confined to CD group, but not HS. While the question of whether specific patterns of mR impairment reliably define a dystonic endophenotype remains elusive, our findings point to mR as a useful tool, when used carefully with control measures and tasks, which may be capable of identifying specific deficits that distinguish between subtypes of dystonia.}, language = {en} } @article{DingSeusingNasseroleslamietal.2023, author = {Ding, Hao and Seusing, Nelly and Nasseroleslami, Bahman and Anwar, Abdul Rauf and Strauss, Sebastian and Lotze, Martin and Grothe, Matthias and Groppa, Sergiu and Muthuraman, Muthuraman}, title = {The role of ipsilateral motor network in upper limb movement}, series = {Frontiers in Physiology}, volume = {14}, journal = {Frontiers in Physiology}, issn = {1664-042X}, doi = {10.3389/fphys.2023.1199338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321805}, year = {2023}, abstract = {The execution of voluntary movements is primarily governed by the cerebral hemisphere contralateral to the moving limb. Previous research indicates that the ipsilateral motor network, comprising the primary motor cortex (M1), supplementary motor area (SMA), and premotor cortex (PM), plays a crucial role in the planning and execution of limb movements. However, the precise functions of this network and its interplay in different task contexts have yet to be fully understood. Twenty healthy right-handed participants (10 females, mean age 26.1 ± 4.6 years) underwent functional MRI scans while performing biceps brachii representations such as bilateral, unilateral flexion, and bilateral flexion-extension. Ipsilateral motor evoked potentials (iMEPs) were obtained from the identical set of participants in a prior study using transcranial magnetic stimulation (TMS) targeting M1 while employing the same motor tasks. The voxel time series was extracted based on the region of interest (M1, SMA, ventral PM and dorsal PM). Directed functinal connectivity was derived from the extracted time series using time-resolved partial directed coherence. We found increased connectivity from left-PMv to both sides M1, as well as right-PMv to both sides SMA, in unilateral flexion compared to bilateral flexion. Connectivity from left M1 to left-PMv, and left-SMA to right-PMd, also increased in both unilateral flexion and bilateral flexion-extension compared to bilateral flexion. However, connectivity between PMv and right-M1 to left-PMd decreased during bilateral flexion-extension compared to unilateral flexion. Additionally, during bilateral flexion-extension, the connectivity from right-M1 to right-SMA had a negative relationship with the area ratio of iMEP in the dominant side. Our results provide corroborating evidence for prior research suggesting that the ipsilateral motor network is implicated in the voluntary movements and underscores its involvement in cognitive processes such as movement planning and coordination. Moreover, ipsilateral connectivity from M1 to SMA on the dominant side can modulate the degree of ipsilateral M1 activation during bilateral antagonistic contraction.}, language = {en} } @phdthesis{Spitzel2023, author = {Spitzel, Marlene}, title = {The impact of inflammation, hypoxia, and vasculopathy on pain development in the α-galactosidase A mouse model of Morbus Fabry}, doi = {10.25972/OPUS-34579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-345794}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by variants in the gene α-galactosidase A (GLA). As a consequence, the encoded homonymous enzyme GLA is not produced in sufficient amount or does not function properly. Subsequently, globotriaosylceradmide (Gb3), the target substrate of GLA, starts accumulating in several cell types, especially neurons and endothelial cells. FD patients suffer from multiorgan symptoms including cardiomyopathy, nephropathy, stroke, and acral burning pain. It is suggested that the impact of pathological Gb3 accumulation, inflammatory and hypoxic processes, and vasculopathy are contributing to the specific FD pain phenotype. Thus, we investigated the role of inflammation, hypoxia, and vasculopathy on molecular level in dorsal root ganglia (DRG) of the GLA knockout (KO) mouse model. Further, we investigated pain-like characteristics of GLA KO mice at baseline (BS), after capsaicin administration, and after repeated enzyme replacement therapy (ERT) administration for a period of 1.5 years. Acquired data showed disturbances in immune response markers represented by downregulated inflammation-associated genes and lower numbers of CD206+ macrophages in DRG of GLA KO mice. Hypoxic mechanisms were active in DRG of GLA KO mice reflected by increased gene expression of hypoxia- and DNA damage-associated targets, higher numbers of hypoxia-inducible factor 1α-positive (HIF1α+) and carbonic anhydrase 9-positive (CA9+) neurons in DRG of GLA KO mice, and DRG neuronal HIF1α cytosolic-nuclear translocation in GLA KO mice. Vascularization in DRG of GLA KO mice was reduced including lower numbers of blood vessel branches and reduced total blood vessel length. Pain-like behavior of the GLA KO mouse model revealed no mechanical hypersensitivity at BS but age-dependent heat hyposensitivity, which developed also age-matched wild type (WT) mice. Capsaicin administration under isoflurane anesthesia did not elicit the development of nocifensive behavior in GLA KO mice after mechanical or heat stimulation. Repeated ERT administration did not show a clear effect in GLA KO mice in terms of restored heat hyposensitivity to BS paw withdrawal latencies. In summary, we demonstrated the impact of disturbed immune response markers, active hypoxic mechanisms, and reduced vascularization on molecular FD pathophysiology.}, subject = {Fabry-Krankheit}, language = {en} } @article{FriedrichSchneiderBuerkleinetal.2023, author = {Friedrich, Maximilian U. and Schneider, Erich and Buerklein, Miriam and Taeger, Johannes and Hartig, Johannes and Volkmann, Jens and Peach, Robert and Zeller, Daniel}, title = {Smartphone video nystagmography using convolutional neural networks: ConVNG}, series = {Journal of Neurology}, volume = {270}, journal = {Journal of Neurology}, number = {5}, doi = {10.1007/s00415-022-11493-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324526}, pages = {2518-2530}, year = {2023}, abstract = {Background Eye movement abnormalities are commonplace in neurological disorders. However, unaided eye movement assessments lack granularity. Although videooculography (VOG) improves diagnostic accuracy, resource intensiveness precludes its broad use. To bridge this care gap, we here validate a framework for smartphone video-based nystagmography capitalizing on recent computer vision advances. Methods A convolutional neural network was fine-tuned for pupil tracking using > 550 annotated frames: ConVNG. In a cross-sectional approach, slow-phase velocity of optokinetic nystagmus was calculated in 10 subjects using ConVNG and VOG. Equivalence of accuracy and precision was assessed using the "two one-sample t-test" (TOST) and Bayesian interval-null approaches. ConVNG was systematically compared to OpenFace and MediaPipe as computer vision (CV) benchmarks for gaze estimation. Results ConVNG tracking accuracy reached 9-15\% of an average pupil diameter. In a fully independent clinical video dataset, ConVNG robustly detected pupil keypoints (median prediction confidence 0.85). SPV measurement accuracy was equivalent to VOG (TOST p < 0.017; Bayes factors (BF) > 24). ConVNG, but not MediaPipe, achieved equivalence to VOG in all SPV calculations. Median precision was 0.30°/s for ConVNG, 0.7°/s for MediaPipe and 0.12°/s for VOG. ConVNG precision was significantly higher than MediaPipe in vertical planes, but both algorithms' precision was inferior to VOG. Conclusions ConVNG enables offline smartphone video nystagmography with an accuracy comparable to VOG and significantly higher precision than MediaPipe, a benchmark computer vision application for gaze estimation. This serves as a blueprint for highly accessible tools with potential to accelerate progress toward precise and personalized Medicine.}, language = {en} } @phdthesis{Yin2023, author = {Yin, Jing}, title = {Progressive alterations of pro- and antidegeneration markers in the nigrostriatal tract of the AAV1/2-A53T-α synuclein rat model of Parkinson's disease}, doi = {10.25972/OPUS-26064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260645}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Neurodegeneration plays an essential role in Parkinson's disease (PD). Several crucial neuronal pro-and antidegeneration markers were described to be altered in disease models accompanied by neurodegeneration. In the AAV1/2-A53T-aSyn PD rat model progressive time-dependent motor impairment and neurodegeneration in the nigrostriatal tract starting from 2 weeks after PD model induction could be found. Downregulation of Nrf2 in SN and nigrostriatal axon localization, a trend of Tau downregulation in SN and upregulation in axon localization in the AAV1/2-A53T-aSyn PD rat model were observed, indicating potential therapeutic value of these two molecular targets in PD. No alterations of SARM1 and NMNAT2 could be detected, indicating little relevance of these two molecules with our AAV1/2-A53T-aSyn rat model.}, language = {en} } @article{DelVecchioHanafiPozzietal.2023, author = {Del Vecchio, Jasmin and Hanafi, Ibrahem and Pozzi, Nicol{\´o} Gabriele and Capetian, Philipp and Isaias, Ioannis U. and Haufe, Stefan and Palmisano, Chiara}, title = {Pallidal recordings in chronically implanted dystonic patients: mitigation of tremor-related artifacts}, series = {Bioengineering}, volume = {10}, journal = {Bioengineering}, number = {4}, issn = {2306-5354}, doi = {10.3390/bioengineering10040476}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313498}, year = {2023}, abstract = {Low-frequency oscillatory patterns of pallidal local field potentials (LFPs) have been proposed as a physiomarker for dystonia and hold the promise for personalized adaptive deep brain stimulation. Head tremor, a low-frequency involuntary rhythmic movement typical of cervical dystonia, may cause movement artifacts in LFP signals, compromising the reliability of low-frequency oscillations as biomarkers for adaptive neurostimulation. We investigated chronic pallidal LFPs with the Percept\(^{TM}\) PC (Medtronic PLC) device in eight subjects with dystonia (five with head tremors). We applied a multiple regression approach to pallidal LFPs in patients with head tremors using kinematic information measured with an inertial measurement unit (IMU) and an electromyographic signal (EMG). With IMU regression, we found tremor contamination in all subjects, whereas EMG regression identified it in only three out of five. IMU regression was also superior to EMG regression in removing tremor-related artifacts and resulted in a significant power reduction, especially in the theta-alpha band. Pallido-muscular coherence was affected by a head tremor and disappeared after IMU regression. Our results show that the Percept PC can record low-frequency oscillations but also reveal spectral contamination due to movement artifacts. IMU regression can identify such artifact contamination and be a suitable tool for its removal.}, language = {en} } @article{GrohAbdelwahabKattimanietal.2023, author = {Groh, Janos and Abdelwahab, Tassnim and Kattimani, Yogita and H{\"o}rner, Michaela and Loserth, Silke and Gudi, Viktoria and Adalbert, Robert and Imdahl, Fabian and Saliba, Antoine-Emmanuel and Coleman, Michael and Stangel, Martin and Simons, Mikael and Martini, Rudolf}, title = {Microglia-mediated demyelination protects against CD8\(^+\) T cell-driven axon degeneration in mice carrying PLP defects}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-42570-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357641}, year = {2023}, abstract = {Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8\(^+\) T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.}, language = {en} }