Reversal of anticoagulation in patients with intracerebral haemorrhage related to oral anticoagulants: State of the evidence - Seiffge, David; Polymeris, Alexandros; Pfeilschifter, Waltraud; Apostolaki-Hansson, Trine; Ip, Bonaventure; Kristoffersen, Espen Saxhaug; Kuramatsu, Joji; Siepen, Bernhard M. (European Stroke Journal, 2025)
PURPOSE: About 20%-25% of all intracerebral haemorrhages are associated with oral anticoagulation therapy. Reflecting changings prescription patterns in the general population, the spectrum of oral anticoagulation-associated intracerebral haemorrhage has substantially changed in the last decade. In many European countries, direct oral anticoagulant-associated intracerebral haemorrhage is now more frequent than vitamin K antagonist-associated intracerebral haemorrhage. Outcome in patients with anticoagulation-associated intracerebral haemorrhage is poor, likely mediated by a high incidence of haematoma expansion. Reversal of anticoagulation is an essential part of current care pathways for hyperacute treatment of intracerebral haemorrhage aiming to limit haematoma expansion and thereby improving outcome. METHODS: In this review, we summarise the latest evidence regarding reversal therapy for vitamin K antagonist-, direct thrombin inhibitor- and factor Xa inhibitor-associated intracerebral haemorrhage. FINDINGS: Two randomised controlled trials have shown that the use of prothrombin complex concentrate (compared to fresh frozen plasma) for reversing vitamin K antagonist-associated intracerebral haemorrhage and andexanet alfa (compared to usual care, mainly prothrombin complex concentrate) for factor Xa inhibitor-associated intracerebral haemorrhage had superior haemostatic efficacy. However, the incidence of thromboembolic complications was high in both trials. For reversal of Vitamin K antagonist-associated intracerebral haemorrhage, the overall rate was 18% but due to crossovers, it is impossible to determine the rate for any specific treatment. For factor-Xa inhibitor associated intracerebral haemorrhage, andexanet alfa led to an increase in the incidence of thromboembolic events. Moreover, these two randomised controlled trials were not powered to detect differences in mortality or functional outcomes and lacked long-term follow-up. Idarucizumab has shown promising results in a single-arm case series of patients with intracerebral haemorrhage associated with the direct thrombin inhibitor dabigatran, yet no randomised controlled trial is available to support these findings. CONCLUSION: Given that haematoma expansion is strongly associated with poor outcome, current evidence underlines the importance of rapid, targeted and effective reversal of anticoagulation in patients with anticoagulation-associated intracerebral haemorrhage. While haematoma expansion is a key prognostic factor, no randomised controlled trial has demonstrated a clear improvement in functional outcome. Future research should weigh the advantages of preventing haematoma expansion against the risks of increased thromboembolic events, and aim to identify the patients who would derive the most benefit from reversal treatments.
CRIS-Team Scopus Importer:2025-06-06
Keywords: andexan alfa; anticoagulation; direct oral anticoagulants; idarucizumab; Intracerebral haemorrhage; prothrombin complex concentrate; reversal; vitamin K antagonist

Reversal of oral anticoagulation in patients with acute intracerebral hemorrhage - Kuramatsu, Joji; Sembill, Jochen; Huttner, Hagen (Critical Care, 2019)
In light of an aging population with increased cardiovascular comorbidity, the use of oral anticoagulation (OAC) is steadily expanding. A variety of pharmacological alternatives to vitamin K antagonists (VKA) have emerged over recent years (direct oral anticoagulants, DOAC, i.e., dabigatran, rivaroxaban, apixaban, and edoxaban) which show a reduced risk for the occurrence of intracerebral hemorrhage (ICH). Yet, in the event of ICH under OAC (OAC-ICH), hematoma characteristics are similarly severe and clinical outcomes likewise substantially limited in both patients with VKA- and DOAC-ICH, which is why optimal acute hemostatic treatment in all OAC-ICH needs to be guaranteed. Currently, International Guidelines for the hemostatic management of patients with OAC-ICH are updated as several relevant large-sized observational studies and recent trials have established treatment approaches for both VKA- and DOAC-ICH. While the management of VKA-ICH is mainly based on the immediate reversal of elevated levels of international normalized ratio using prothrombin complex concentrates, hemostatic management of DOAC-associated ICH is challenging requiring specific antidotes, notably idarucizumab and andexanet alfa. This review will provide an overview of the latest studies and trials on hemostatic reversal agents and timing and summarizes the effects on hemorrhage progression and clinical outcomes in patients with OAC-ICH.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Anticoagulation reversal; Ciraparantag; Desmopressin; Intracerebral hemorrhage; Tranexamic acid

Rheumatoid vasculitis of the central nervous system - Lee, D. H.; Blinzler, C.; Stöckl, Thomas; Engelhorn, Tobias; Buslei, R.; Schwab, Sibylle; Linker, Ralf (Der Nervenarzt, 2015)
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Risk reduction in dominant temporal lobe epilepsy surgery combining fMRI/DTI maps, neuronavigation and intraoperative 1.5-Tesla MRI - Roessler, Karl; Sommer, Bjoern; Grummich, Peter; Hamer, Hajo; Pauli, Elisabeth; Coras, Roland; Blümcke, Ingmar; Buchfelder, Michael (Stereotactic and Functional Neurosurgery, 2015)
In dominant temporal lobe epilepsy surgery, speech, memory and visual systems are at risk.Functional magnetic resonance imaging (fMRI) and diffusion tensor imaging combined with intraoperative neuronavigation and MRI were investigated retrospectively regarding risk reductions for favorable neurological and seizure outcome.Functional imaging risk maps were generated for 14 patients suffering from dominant temporal lobe epilepsy [7 with hippocampal sclerosis (HS), 7 with various lesions] and used for neuronavigation-guided tailored resection. Postoperative neurological and seizure outcome and complications were evaluated.None of the patients had postoperative speech dysfunction despite 2.3/3.6-cm mean hippocampal/neocortical resection. Verbal memory decline was found in 2 of the 14 (14.3%) patients, correlating with surgical lesions in fMRI memory-activated functional areas in the dominant posterior parahippocampal gyrus. Verbal memory scores did not statistically differ between the HS and the lesional group, neither pre- nor postoperatively. A contralateral visual field defect occurred in 1 patient (7.1%). An Engel class I seizure outcome was found in 12 patients (85.7%), and 11 were completely seizure free (78.6%) at a mean follow-up of 19.5 months.This retrospectively investigated protocol led to an excellent neurological and seizure outcome and a low complication rate in dominant temporal lobe epilepsy surgery.
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RNA splicing modulator for Huntington's disease treatment induces peripheral neuropathy - Krach, Florian; Börstler, Tom; Neubert, Sebastian; Krumm, Laura; Regensburger, Martin; Winkler, Jürgen; Winner, Beate (iScience, 2025)
RNA splicing modulators, a new class of small molecules with the potential to modify the protein expression levels, have quickly been translated into clinical trials. These compounds hold promise for treating neurodegenerative disorders, including branaplam for lowering huntingtin levels in Huntington's disease. However, the VIBRANT-HD trial was terminated due to the emergence of peripheral neuropathy. Here, we describe the complex mechanism whereby branaplam activates p53, induces nucleolar stress in human induced pluripotent stem cell (iPSC)-derived motor neurons (iPSC-MN), and thereby enhanced expression of the neurotoxic p53-target gene BBC3. On the cellular level, branaplam disrupts neurite integrity, reflected by elevated neurofilament light chain levels. These findings illustrate the complex pharmacology of RNA splicing modulators with a small therapeutic window between lowering huntingtin levels and the clinically relevant off-target effect of neuropathy. Comprehensive toxicological screening in human stem cell models can complement pre-clinical testing before advancing RNA-targeting drugs to clinical trials.
CRIS-Team Scopus Importer:2025-05-09
Keywords: Biological sciences; Cell biology; Cellular neuroscience; Natural sciences; Neuroscience; Pharmacology

Rodent’s Stride Length Depends on Body Size: Implications for CatWalk Assay - Timotius, Ivanna; Moceri, Sandra; Plank, Anne-Christine; Habermeyer, Johanna; Canneva, Fabio; Casadei, Nicolas; Riess, Olaf; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn; von Hörsten, Stephan (Measuring Behavior 2018, 2018)
The analysis of gait is an essential part of rodent phenotyping. Regarding the complex nature of walking, preclinical gait analysis is normally based on several gait parameters (which have been progressively developed [1,2] in recent years) including the animal’s stride length, body speed, support, etc. The stride length is altered in several diseases [3–5] and this parameter can be easily translated from rodent models to human patients. However, we hypothesized that the stride length is affected by the body size [6,7], which becomes a challenge in analyzing gait. Using the gait parameters assessed by CatWalk system [8–10], we examined the correlation between body-length/body-weight with stride length using CatWalk-video-derived body silhouette length. To examine the effect of growth and aging in rodents, we studied wild-type Sprague-Dawley male rats and C57BL/6N mice. Moreover, we examined the body size difference between genotypes in BACSCNA transgenic rats [11,12] and BACHD transgenic mice [13]. The CatWalk data were collected as the rodents walked freely on top of a glass-floored corridor. The rat gait was monitored at 4 different age points (10, 26, 55 and 62 weeks old), whereas the mice were monitored at 3 different age points (20, 32, and 47 weeks old). The rodent numbers included in the experiments were: (a) wild-type male rats (n=16-27/time point), (b) BACSCNA rats (n=19-32/time point), (c) wild-type mice (n=12-13/time point), and (d) BACHD mice (n=9-11/time point). The rodents were maintained under specific-pathogen-free condition. All research and animal care procedures were performed in compliance with international animal welfare standards and approved by the district governments of Lower Franconia, Würzburg, Bavaria, Germany (RegUFr#55.2-2532-2-218). The correlations between front stride length (averaged from the left and right side) and the body-silhouette-length/body-weight are shown in Figure 1. Significant correlations are shown with both body silhouette lengths and body weight. The correlation between hind stride length and body size showed the similar relationship as the front stride length (data not shown). Besides body size differences due to growth, pathological body size differences were also observed as shown in Figure 2. Thus, we demonstrated that stride length is highly correlated with body silhouette length (based on the CatWalk video) and body weight. In the near future, we need to subject gait parameters to a scaling process using body weight or silhouette length, raising the possibility of normalization for differences in size as a potential confounding of gait measure
Keywords: Stride Length; Body Size; Rodent; CatWalk

Role of glial 14-3-3 gamma protein in autoimmune demyelination - Lee, De-Hyung; Steinacker, Petra; Seubert, Silvia; Turnescu-Uzat, Tanja; Melms, Arthur; Manzel, Arndt; Otto, Markus; Linker, Ralf (Journal of Neuroinflammation, 2015)
The family of 14-3-3 proteins plays an important role in the regulation of cell survival and death. Here, we investigate the role of the 14-3-3 gamma (14-3-3 ?) subunit for glial responses in autoimmune demyelination.Expression of 14-3-3 ? in glial cell culture was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. 14-3-3 ? knockout mice were subjected to murine myelin oligodendrocyte-induced experimental autoimmune encephalomyelitis (MOG-EAE), an animal model mimicking inflammatory features and neurodegenerative aspects of multiple sclerosis (MS).Expression studies in cell culture confined expression of 14-3-3 ? to both, oligodendrocytes (OL) and astrocytes. RT-PCR analysis revealed an increased expression of 14-3-3 ? mRNA in the spinal cord during the late chronic phase of MOG-EAE. At that stage, EAE was more severe in 14-3-3 ? knockout mice as compared to age- and gender-matched controls. Histopathological analyses on day 56 post immunization (p.i.) revealed significantly enhanced myelin damage as well as OL injury and secondary, an increase in axonal injury and gliosis in 14-3-3 ? -/- mice. At the same time, deficiency in 14-3-3 ? protein did not influence the immune response. Further histological studies revealed an increased susceptibility towards apoptosis in 14-3-3 ?-deficient OL in the inflamed spinal cord.These data argue for a pivotal role of 14-3-3 ?-mediated signalling pathways for OL protection in neuroinflammation.
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Role of Kv1.4 during remyelination and neuroinflammation - Alvarado, M. N. Gonzalez; Hasse, S.; Seubert, S.; Kuhbandner, Kristina; Lee, D. -H.; Linker, R. (GLIA, 2019)
CRIS-Team WoS Importer:2020-01-10

Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells - Hammer, Anna; Waschbisch, Anne; Knippertz, Ilka; Zinser, Elisabeth; Berg, Johannes; Joerg, Stefanie; Kuhbandner, Kristina; David, Christina; Pi, Jingbo; Bayas, Antonios; Lee, De-Hyung; Haghikia, Aiden; et al. (Frontiers in Immunology, 2017)
To date, the intracellular signaling pathways involved in dendritic cell (DC) function are poorly understood. The antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been shown to affect maturation, function, and subsequent DC-mediated T cell responses of murine and human DCs. In experimental autoimmune encephalomyelitis (EAE), as prototype animal model for a T helper cell-mediated autoimmune disease, antigen presentation, cytokine production, and costimulation by DCs play a major role. We explore the role of Nrf2 in DC function, and DC-mediated T cell responses during T cell-mediated autoimmunity of the central nervous system using genetic ablation and pharmacological activation in mice and men to corroborate our data in a translational setting. In murine and human DCs, monomethyl fumarate induced Nrf2 signaling inhibits DC maturation and DC-mediated T cell proliferation by reducing inflammatory cytokine production and expression of costimulatory molecules. In contrast, Nrf2-deficient DCs generate more activated T helper cells (Th1/Th17) but fewer regulatory T cells and foster T cell proliferation. Transfer of DCs with Nrf2 activation during active EAE reduces disease severity and T cell infiltration. Our data demonstrate that Nrf2 signaling modulates autoimmunity in murine and human systems via inhibiting DC maturation and function thus shedding further light on the mechanism of action of antioxidative stress pathways in antigen-presenting cells.
EVALuna2:22557

Role of occupational therapy in epilepsy patients after left temporal lobe surgery - Schwarz, Michael; Geismar, Lisa; Schneider, Katrin; Kasper, Burkhard; Walther, Katrin; Hamer, Hajo (British Journal of Occupational Therapy, 2022)
There is a relevant risk of psychosocial as well as cognitive impairments in epilepsy patients with resective surgery in the left temporal lobe. Surgery in the speech-dominant hemisphere can be associated with deterioration of speech related functions including verbal memory. There are only limited studies addressing the impact of occupational therapy in postoperative rehabilitation of epilepsy patients.Method: In this study, a mixed-methods design based on the grounded theory concept was administered. Seven patients with left temporal lobe epilepsy and a risk profile for postoperative cognitive decline were investigated over various time points. Neuropsychological assessments occurred before surgery, 1 week, 3 months, and 6 months postoperatively. According to our rehabilitation concept, every patient started occupational therapy 1 month before surgery. Therapy lasted for at least 6 months after surgery. For all patients, extensive qualitative interviews with the occupational therapists and anamnestic data were analyzed.Results: In all patients, postoperative psychosocial difficulties emerged. Language and memory tests showed a decline after 6 months specifically for name retrieval. Occupational therapy was adapted to find individual solutions for the patients problems and to implement effective coping strategies.Conclusion: Cognitive training lead to consistent improvements over time. The results show that occupational therapy can be an efficient tool in the treatment of psychosocial and cognitive impairments after epilepsy surgery.
CRIS-Team WoS Importer:2022-03-04

Role of the adipocyte immune brain axis in Parkinson's disease: friend or foe? - Regensburger, Martin; Kinfe, Thomas Mehari (Neural Regeneration Research, 2023)
CRIS-Team Scopus Importer:2023-06-30

Role of the receptor Mas in macrophage-mediated inflammation in vivo - Hammer, Anna; Yang, Guang; Friedrich, Juliane; Kovacs, Agnes; Lee, De-Hyung; Grave, Katharina; Joerg, Stefanie; Alenina, Natalia; Grosch, Janina; Winkler, Jürgen; Gold, Ralf; Bader, Michael; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2016)
Recently, an alternative renin-angiotensin system pathway has been described, which involves binding of angiotensin-(1-7) to its receptor Mas. The Mas axis may counterbalance angiotensin-II-mediated proinflammatory effects, likely by affecting macrophage function. Here we investigate the role of Mas in murine models of autoimmune neuroinflammation and atherosclerosis, which both involve macrophage-driven pathomechanisms. Mas signaling affected macrophage polarization, migration, and macrophage-mediated T-cell activation. Mas deficiency exacerbated the course of experimental autoimmune encephalomyelitis and increased macrophage infiltration as well as proinflammatory gene expression in the spleen and spinal cord. Furthermore, Mas deficiency promoted atherosclerosis by affecting macrophage infiltration and migration and led to increased oxidative stress as well as impaired endothelial function in ApoE-deficient mice. In summary, we identified the Mas axis as an important factor in macrophage function during inflammation of the central nervous and vascular system in vivo. Modulating the Mas axis may constitute an interesting therapeutic target in multiple sclerosis and/or atherosclerosis.
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Role of "Western diet" in inflammatory autoimmune diseases - Manzel, Arndt; Muller, Dominik N.; Hafler, David A.; Erdman, Susan E.; Linker, Ralf; Kleinewietfeld, Markus (Current Allergy and Asthma Reports, 2014)
Developed societies, although having successfully reduced the burden of infectious disease, constitute an environment where metabolic, cardiovascular, and autoimmune diseases thrive. Living in westernized countries has not fundamentally changed the genetic basis on which these diseases emerge, but has strong impact on lifestyle and pathogen exposure. In particular, nutritional patterns collectively termed the "Western diet", including high-fat and cholesterol, high-protein, high-sugar, and excess salt intake, as well as frequent consumption of processed and 'fast foods', promote obesity, metabolic syndrome, and cardiovascular disease. These factors have also gained high interest as possible promoters of autoimmune diseases. Underlying metabolic and immunologic mechanisms are currently being intensively explored. This review discusses the current knowledge relative to the association of "Western diet" with autoimmunity, and highlights the role of T cells as central players linking dietary influences to autoimmune pathology.
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Role of α-synuclein in adult neurogenesis and neuronal maturation in the dentate gyrus. - Winner, Beate; Regensburger, Martin; Prots, Iryna; Winkler, Jürgen; et al. (Journal of Neuroscience, 2012)
α-Synuclein has been reported to be important in modulating brain plasticity and to be a key protein in neurodegenerative diseases, including Lewy body dementia (LBD). We investigated how α-synuclein levels modulate adult neurogenesis and the development of dendritic arborization and spines in the dentate gyrus, in which new neurons are constantly added. In the human hippocampus, levels of endogenous α-synuclein were increased in LBD, and the numbers of SOX2-positive cells were decreased. We investigated whether newly generated neurons were modulated by endogenous α-synuclein, and we found increased adult neurogenesis in α/β-synuclein knock-out mice. In contrast, overexpression of human wild-type α-synuclein (WTS) decreased the survival and dendritic development of newborn neurons. Endogenous α-synuclein expression levels increased the negative impact of WTS on dendrite development, suggesting a toxic effect of increasing amounts of α-synuclein. To attempt a rescue of the dendritic phenotype, we administered rolipram to activate the cAMP response element-binding protein pathway, which led to a partial rescue of neurite development. The current work provides novel insights into the role of α-synuclein in adult hippocampal neurogenesis.

Rotational coherent dot movement normalizes spatial disorientation of the subjective visual vertical in patients with rightsided stroke - Reinhart, S.; Schaadt, A. K.; Keller, I.; Hildebrandt, H.; Kerkhoff, G.; Utz, K. (Neuropsychologia, 2016)
Studies in healthy individuals indicate a significant influence of rotating visual motion on judgments of the subjective visual vertical (SVV). Moreover, sensory stimulation manoeuvres like horizontal coherent dot movement significantly modulate horizontal spatial deficits in patients with rightsided stroke. Here, we investigated whether rotational coherent dot movement (RCDM) modulates spatial orientation deficits of the SVV in the roll plane in right hemispheric stroke. We tested the perceptual judgment of the SVV in 20 patients with right-hemispheric, first ever stroke (10 of them with a disorder of the SVV and 10 without a disorder), and 10 healthy, age-matched subjects under three experimental conditions: (1) with a static background of small white dots, (2) with slow clockwise or (3) counterclockwise circular RCDM of these background stimuli. In the baseline condition with static background, the impaired patient group showed a counterclockwise tilt of the SVV. Clockwise RCDM normalized this deficit completely, while with counterclockwise RCDM a slight aggravation was observed. Similar but quantitatively much smaller effects were obtained in the SVV-unimpaired patients and the healthy individuals. These results demonstrate a strong modulatory effect of RCDM on the SVV in patients with a tilt of the SVV due to right-sided stroke. RCDM thus appears to influence higher spatial representations devoted to visuospatial perception of the SVV. Possible mechanisms as well as clinical implications for therapy of visuospatial disorientation (self-orientation in space) after stroke are discussed.
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Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome - Bien, Christian G.; Bien, Corinna I.; Onugoren, Muejgan; De Simoni, Desiree; Eigler, Verena; Haensch, Carl-Albrecht; Holtkamp, Martin; Ismail, Fatme S.; Kurthen, Martin; Melzer, Nico; Mayer, Kristina; Von Podewils, Felix; et al. (Journal of Neurology, 2020)
Objective To determine frequencies, interlaboratory reproducibility, clinical ratings, and prognostic implications of neural antibodies in a routine laboratory setting in patients with suspected neuropsychiatric autoimmune conditions. Methods Earliest available samples from 10,919 patients were tested for a broad panel of neural antibodies. Sera that reacted with leucine-rich glioma-inactivated protein 1 (LGI1), contactin-associated protein-2 (CASPR2), or the voltage-gated potassium channel (VGKC) complex were retested for LGI1 and CASPR2 antibodies by another laboratory. Physicians in charge of patients with positive antibody results retrospectively reported on clinical, treatment, and outcome parameters. Results Positive results were obtained for 576 patients (5.3%). Median disease duration was 6 months (interquartile range 0.6-46 months). In most patients, antibodies were detected both in CSF and serum. However, in 16 (28%) patients with N-methyl-d-aspartate receptor (NMDAR) antibodies, this diagnosis could be made only in cerebrospinal fluid (CSF). The two laboratories agreed largely on LGI1 and CASPR2 antibody diagnoses (kappa = 0.95). The clinicians (413 responses, 71.7%) rated two-thirds of the antibody-positive patients as autoimmune. Antibodies against the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), NMDAR (CSF or high serum titer), gamma-aminobutyric acid-B receptor (GABABR), and LGI1 had >= 90% positive ratings, whereas antibodies against the glycine receptor, VGKC complex, or otherwise unspecified neuropil had <= 40% positive ratings. Of the patients with surface antibodies, 64% improved after >= 3 months, mostly with >= 1 immunotherapy intervention. Conclusions This novel approach starting from routine diagnostics in a dedicated laboratory provides reliable and useful results with therapeutic implications. Counseling should consider clinical presentation, demographic features, and antibody titers of the individual patient.
CRIS-Team WoS Importer:2020-04-14

S1-Guideline for Diagnosis and Treatment of Erectile Dysfunction [S1-Leitlinie Diagnostik und Therapie der erektilen Dysfunktion] - Haensch, Carl Albrecht; Hilz, Max-Josef; Jost, Wolfgang; Kaufmann, Albert; Kessler, Thomas; Lahrmann, Heinz (Fortschritte der Neurologie - Psychiatrie, 2019)
The S1-Guideline Diagnosis and Therapy of Erectile Dysfunction (Association of the Scientific Medical Societies in Germany (AWMF) registration number 030/112) is available in a completely revised version. Erectile dysfunction (ED) is defined as the persistent or recurrent inability to acquire or sustain an erection of sufficient rigidity and duration for sexual intercourse. There is a high prevalence of ED in the general population in Germany. The frequency of sexual activity decreases with age, and sexual problems become more common with aging. Overall, the prevalence of ED is 2.3 % in men 20 to 30 years of age and 53.4 % in men in their 7th decade of life. The guideline offers firm recommendations for the diagnosis and treatment of patients suffering from ED. The introduction of new oral therapies has completely changed the diagnostic and therapeutic approach to ED, which is often carried out in a uncritical way.
CRIS-Team Scopus Importer:2019-05-09
Keywords: Erectile dysfunction; PDE-5 inhibitors; Sexual activity

Safety of Heparin for Prophylaxis of Venous Thromboembolism in Oral Anticoagulation-Associated Intracerebral Hemorrhage. - Sembill, Jochen; Sprügel, Maximilian; Kuramatsu, Joji; Gerner, Stefan; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen (STROKE, 2019)
CRIS-Team WoS Importer:2019-08-23

Salt-responsive gut commensal modulates TH17 axis and disease - Wilck, Nicola; Matus, Mariana G.; Kearney, Sean M.; Olesen, Scott W.; Forslund, Kristoffer; Bartolomaeus, Hendrik; Haase, Stefanie; Maehler, Anja; Balogh, Andras; Marko, Lajos; Vedenskaya, Olga V.; Kleiner, Friedrich H.; et al. (Nature, 2017)
A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.
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Same same but different: A Web-based deep learning application revealed classifying features for the histopathologic distinction of cortical malformations - Kubach, Joshua; Muhlebner-Fahrngruber, Angelika; Soylemezoglu, Figen; Miyata, Hajime; Niehusmann, Pitt; Honavar, Mrinalini; Rogerio, Fabio; Kim, Se-Hoon; Aronica, Eleonora; Garbelli, Rita; Vilz, Samuel; Popp, Alexander; et al. (Epilepsia, 2020)
Objective: The microscopic review of hematoxylin-eosin–stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine. Methods: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities. Results: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance. Significance: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning–aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.
CRIS-Team Scopus Importer:2020-03-06
Keywords: brain; convolutional neural network; cortical malformations; deep learning; digital pathology; epilepsy

SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres - Bolsinger, Magdalena; Drobny, Alice; Wilfling, Sibylle; Reischl, Stephanie; Krach, Florian; Moritz, Raul; Balta, Denise; Hehr, Ute; Sock, Elisabeth; Bleibaum, Florian; Hanses, Frank; Winner, Beate; et al. (Journal of Cellular Biochemistry, 2024)
Autophagy and lysosomal pathways are involved in the cell entry of SARS-CoV-2 virus. To infect the host cell, the spike protein of SARS-CoV-2 binds to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved. One possible mechanism is the endocytosis of the SARS-CoV-2–ACE2 complex and subsequent cleavage of the spike protein, mainly by the lysosomal protease cathepsin L. However, detailed molecular and dynamic insights into the role of cathepsin L in viral cell entry remain elusive. To address this, HeLa cells and iPSC-derived alveolarspheres were treated with recombinant SARS-CoV-2 spike protein, and the changes in mRNA and protein levels of cathepsins L, B, and D were monitored. Additionally, we studied the effect of cathepsin L deficiency on spike protein internalization and investigated the influence of the spike protein on cathepsin L promoters in vitro. Furthermore, we analyzed variants in the genes coding for cathepsin L, B, D, and ACE2 possibly associated with disease progression using data from Regeneron's COVID Results Browser and our own cohort of 173 patients with COVID-19, exhibiting a variant of ACE2 showing significant association with COVID-19 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS-CoV-2 spike protein in HeLa cells, accompanied by elevated mRNA levels of cathepsin B and D in alveolarspheres. Moreover, an increase in cathepsin L promoter activity was detected in vitro upon spike protein treatment. Notably, the knockout of cathepsin L resulted in reduced internalization of the spike protein. The study highlights the importance of cathepsin L and lysosomal proteases in the SARS-CoV-2 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID-19 and other viral infections.
CRIS-Team Scopus Importer:2024-07-19
Keywords: cathepsin L; cathepsins; lysosomes; SARS-CoV-2; spike protein

Satisfaction with and reliability of in-hospital video-EEG monitoring systems in epilepsy diagnosis – A German multicenter experience - Willems, Laurent M.; Baier, Hartmut; Bien, Christian G.; Bösebeck, Frank; Dümpelmann, Matthias; Hamer, Hajo; Kellinghaus, Christoph; Knake, Susanne; Schreiber, Melanie; Staack, Anke Maren; Surges, Rainer; Tergau, Frithjof; et al. (Clinical Neurophysiology, 2021)
Objective: To analyze satisfaction with and reliability of video-electroencephalography-monitoring systems (VEMS) in epilepsy diagnostics. Methods: A survey was conducted between December 2020 and January 2021 among German epilepsy centers using well-established customer satisfaction (CS) and quality assurance metrics. Results: Among 16 participating centers, CS with VEMS was low, with only 13% of customers actively recommending their system. Only 50% of users were satisfied with the overall performance of their VEMS, and a low 18% were satisfied with the manufacturer's customer service. User interface, software stability, lack of regular updates, and missing customer-oriented improvements were reported as frequent problems jeopardizing diagnosis in approximately every 10th patient. The greatest potential for improvement was identified for software and hardware stability as well as customer service. Conclusion: Satisfaction with VEMS and their customer service was low, and diagnostics were regularly affected by software or hardware errors. Even if this can be partly explained by the technical complexity of VEMS, there is an urgent need for improvements with regard to the reliability and durability of system components as well as signal synchrony and data management. Significance: This analysis highlights low consumer satisfaction of users with VEMS and uncovers frequent problems and potential for improvement.
CRIS-Team Scopus Importer:2021-07-02
Keywords: EEG; Medical technology; Quality; Safety; Telemedicine

Segmentation of Gait Sequences in Sensor-Based Movement Analysis: A Comparison of Methods in Parkinson's Disease. - Haji Ghassemi, Nooshin; Hannink, Julius; Martindale, Christine; Gaßner, Heiko; Müller, Meinard; Klucken, Jochen; Eskofier, Björn (Sensors, 2018)
Robust gait segmentation is the basis for mobile gait analysis. A range of methods have been applied and evaluated for gait segmentation of healthy and pathological gait bouts. However, a unified evaluation of gait segmentation methods in Parkinson's disease (PD) is missing. In this paper, we compare four prevalent gait segmentation methods in order to reveal their strengths and drawbacks in gait processing. We considered peak detection from event-based methods, two variations of dynamic time warping from template matching methods, and hierarchical hidden Markov models (hHMMs) from machine learning methods. To evaluate the methods, we included two supervised and instrumented gait tests that are widely used in the examination of Parkinsonian gait. In the first experiment, a sequence of strides from instructed straight walks was measured from 10 PD patients. In the second experiment, a more heterogeneous assessment paradigm was used from an additional 34 PD patients, including straight walks and turning strides as well as non-stride movements. The goal of the latter experiment was to evaluate the methods in challenging situations including turning strides and non-stride movements. Results showed no significant difference between the methods for the first scenario, in which all methods achieved an almost 100% accuracy in terms of F-score. Hence, we concluded that in the case of a predefined and homogeneous sequence of strides, all methods can be applied equally. However, in the second experiment the difference between methods became evident, with the hHMM obtaining a 96% F-score and significantly outperforming the other methods. The hHMM also proved promising in distinguishing between strides and non-stride movements, which is critical for clinical gait analysis. Our results indicate that both the instrumented test procedure and the required stride segmentation algorithm have to be selected adequately in order to support and complement classical clinical examination by sensor-based movement assessment.
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Segmentation of Gait Sequences in Sensor-Based Movement Analysis: A Comparison of Methods in Parkinson’s Disease - Haji Ghassemi, Nooshin; Hannink, Julius; Martindale, Christine; Gaßner, Heiko; Müller, Meinard; Klucken, Jochen; Eskofier, Björn (Sensors, 2018)
Keywords: Parkinson’s Disease; gait analysis; inertial sensors; step segmentation; stride segmentation; accelerometer; gyroscope

Segmentation of gait sequences using inertial sensor data in hereditary spastic paraplegia - Martindale, Christine; Strauss, Martin; Gaßner, Heiko; List, Julia; Müller, Meinard; Klucken, Jochen; Kohl, Zacharias; Eskofier, Björn (Engineering in Medicine and Biology Society (EMBC), 2017 39th Annual International Conference of the IEEE, 2017)
Gait analysis is an important tool for diagnosis, monitoring and treatment of neurological diseases. Among these are hereditary spastic paraplegias (HSPs) whose main characteristic is heterogeneous gait disturbance. So far HSP gait has been analysed in a limited number of studies, and within a laboratory set up only. Although the rarity of orphan diseases often limits larger scale studies, the investigation of these diseases is still important, not only to the affect population, but also for other diseases which share gait characteristics. In this paper we use foot-mounted inertial measurement units (IMU) as a mobile solution to measure the gait of 21 HSP patients while performing a 4 by 10 m walk at self-selected pace. Two algorithms common to other gait analysis solutions, the hidden Markov model (HMM) and dynamic time warping (DTW), were applied to these signals in order to investigate their effectiveness when faced with the heterogeneous nature and range of foot strike techniques of HSP gait, sometimes even lacking a heel strike. Using a nested cross validation for parameter choice and validation, the HMM was found to be superior for segmentation purposes with a mean segmentation error of 0.10 ± 0.05 s. Stride segmentation of such a diverse dataset is the first step towards creating a clinically relevant system which could assist physicians working with HSP patients by providing objective, automated gait parameters. To the best of the authors’ knowledge, this is the first paper to investigate solutions for mobile gait analysis of patients affected by HSPs. Ultimately, automated, mobile gait analysis of HSP patients would allow ongoing and long term monitoring, providing useful insights into this orphan diseas
Keywords: Hidden Markov models; segmentation; gait analysis; hereditary spastic paraplegia

Seizures among long-term survivors of conservatively treated ICH patients: incidence, risk factors, and impact on functional outcome - Madzar, Dominik; Kuramatsu, Joji; Gollwitzer, Stephanie; Lücking, Hannes; Kloska, Stephan; Hamer, Hajo; Köhrmann, Martin; Huttner, Hagen (Neurocritical Care, 2014)
Seizures are a common complication after intracerebral hemorrhage (ICH) but there is a substantial lack of information on the long-term incidence in ICH survivors and whether post-ICH seizures affect functional long-term outcome.Over a five-year period 464 consecutive patients with spontaneous ICH were analyzed. Focussing on 1-year ICH survivors, clinical, and radiological parameters were retrieved from institutional prospective databases. The occurrence of seizures was categorized as early (<=7 days) or late (>7 days). Functional outcome was assessed by mailed questionnaires and telephone interviews, and was categorized into good vs. poor (mRS: 0-2 vs. 3-5) and favorable vs. unfavorable (mRS: 0-3 vs. 4-5). Multivariate regression models were calculated to investigate risk factors associated with post-ICH seizures including an a priori defined subgroup analysis of lobar ICH patients.Among 203 long-term ICH survivors, 19.7 % developed seizures of which 55 % occurred late. Factors associated with seizures were lobar location (OR 8.10; 95 % CI 3.04-21.59; p < 0.001), sepsis (OR 4.59; 95 % CI 1.20-17.53; p = 0.026), and history of alcohol abuse (OR 3.36; 95 % CI 1.25-9.06; p = 0.017). Subgroup analysis of lobar ICH patients revealed history of alcohol abuse as the only independent predictor of post-ICH seizures (OR 5.22; 95 % CI 1.25-21.78; p = 0.024). Functional long-term outcome among survivors was slightly worse in patients with post-ICH seizures (p = 0.059). In multivariate regression modeling for prediction of poor outcome, the parameter "post-ICH seizures" again reached a statistical trend (p = 0.065), and established parameters such as age, GCS, and hemorrhage volume were independently related to poor outcome.Post-ICH seizures among long-term ICH survivors are common and may contribute to unfavorable functional outcome. Especially lobar ICH patients with a history of alcohol abuse are at risk to develop post-ICH seizures. Therefore, this subgroup may represent a target population for a prophylactic anticonvulsive treatment approach, preferably investigated in a prospective randomized trial.
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Sensomotorisches Laufbandtraining in der Rehabilitation von Gangstörungen bei Patienten mit Morbus Parkinson - Klamroth, Sarah; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (27. Rehabilitationswissenschaftliches Kolloquium: Rehabilitation bewegt!, 2018)

Sensor-based gait analysis distinguishes fallers from non-fallers in Parkinson's disease under clinical and real-life conditions - Gladow, Till; Gaßner, Heiko; Ullrich, Martin; Hannink, Julius; Roth, Nils; Marxreiter, Franz; Küderle, Arne; Kohl, Zacharias; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen (2019)
EVALuna2:213285

Sensor-based gait analysis in atypical parkinsonian disorders - Raccagni, Cecilia; Gaßner, Heiko; Eschlboeck, Sabine; Boesch, Sylvia; Krismer, Florian; Seppi, Klaus; Poewe, Werner; Eskofier, Björn; Winkler, Jürgen; Wenning, Gregor; Klucken, Jochen (Brain and Behavior, 2018)
BACKGROUND AND OBJECTIVES: Gait impairment and reduced mobility are typical features of idiopathic Parkinson's disease (iPD) and atypical parkinsonian disorders (APD). Quantitative gait assessment may have value in the diagnostic workup of parkinsonian patients and as endpoint in clinical trials. The study aimed to identify quantitative gait parameter differences in iPD and APD patients using sensor-based gait analysis and to correlate gait parameters with clinical rating scales. SUBJECTS AND METHODS: Patients with iPD and APD including Parkinson variant multiple system atrophy and progressive supranuclear palsy matched for age, gender, and Hoehn and Yahr (≤3) were recruited at two Movement Disorder Units and assessed using standardized clinical rating scales (MDS-UPDRS-3, UMSARS, PSP-RS). Gait analysis consisted of inertial sensor units laterally attached to shoes, generating as objective targets spatiotemporal gait parameters from 4 × 10 m walk tests. RESULTS: Objective sensor-based gait analysis showed that gait speed and stride length were markedly reduced in APD compared to iPD patients. Moreover, clinical ratings significantly correlated with gait speed and stride length in APD patients. CONCLUSION: Our findings suggest that patients with APD had more severely impaired gait parameters than iPD patients despite similar disease severity. Instrumented gait analysis provides complementary rater independent, quantitative parameters that can be exploited for clinical trials and care.
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Sensor-based gait analysis of individualized improvement during apomorphine titration in Parkinson's disease - Marxreiter, Franz; Gaßner, Heiko; Borozdina, Olga; Barth, Jens; Kohl, Zacharias; Schlachetzki, Johannes; Thun-Hohenstein, Caroline; Volc, Dieter; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen (Journal of Neurology, 2018)
Mobile, sensor-based gait analysis in Parkinson's disease (PD) facilitates the objective measurement of gait parameters in cross-sectional studies. Besides becoming outcome measures for clinical studies, the application of gait parameters in personalized clinical decision support is limited. Therefore, the aim of this study was to evaluate whether the individual response of PD patients to dopaminergic treatment may be measured by sensor-based gait analysis. 13 PD patients received apomorphine every 15 min to incrementally increase the bioavailable apomorphine dose. Motor performance (UPDRS III) was assessed 10 min after each apomorphine injection. Gait parameters were obtained after each UPDRS III rating from a 2 × 10 m gait sequence, providing 41.2 ± 9.2 strides per patient and injection. Gait parameters and UPDRS III ratings were compared cross-sectionally after apomorphine titration, and more importantly between consecutive injections for each patient individually. For the individual response, the effect size Cohen's d for gait parameter changes was calculated based on the stride variations of each gait sequence after each injection. Cross-sectionally, apomorphine improved stride speed, length, gait velocity, maximum toe clearance, and toe off angle. Between injections, the effect size for individual changes in stride speed, length, and maximum toe clearance correlated to the motor improvement in each patient. In addition, significant changes of stride length between injections were significantly associated with UPDRS III improvements. We therefore show, that sensor-based gait analysis provides objective gait parameters that support clinical assessment of individual PD patients during dopaminergic treatment. We propose clinically relevant instrumented gait parameters for treatment studies and especially clinical care.
EVALuna2:36376
Keywords: Parkinson’s disease; Sensor-based gait analysis; Apomorphine; Gait parameter; Precision medicine

Sensor-based Gait Parameter Extraction with Deep Convolutional Neural Networks. - Hannink, Julius; Kautz, Thomas; Pasluosta, Cristian Federico; Gaßmann, Karl-Günter; Klucken, Jochen; Eskofier, Björn (IEEE Journal of Biomedical and Health Informatics, 2017)
Measurement of stride-related, biomechanical parameters is the common rationale for objective gait impairment scoring. State-of-the-art double integration approaches to extract these parameters from inertial sensor data are, however, limited in their clinical applicability due to the underlying assumptions. To overcome this, we present a method to translate the abstract information provided by wearable sensors to context-related expert features based on deep convolutional neural networks. Regarding mobile gait analysis, this enables integration-free and data-driven extraction of a set of eight spatio-temporal stride parameters. To this end, two modelling approaches are compared: A combined network estimating all parameters of interest and an ensemble approach that spawns less complex networks for each parameter individually. The ensemble approach is outperforming the combined modelling in the current application. On a clinically relevant and publicly available benchmark dataset, we estimate stride length, width and medio-lateral change in foot angle up to -0.15 ±6.09 cm, -0.09 ±4.22 cm and 0.13 ±3.78 ° respectively. Stride, swing and stance time as well as heel and toe contact times are estimated up to ±0.07, ±0.05, ±0.07, ±0.07 and ±0.12 s respectively. This is comparable to and in parts outperforming or defining stateof- the-art. Our results further indicate that the proposed change in methodology could substitute assumption-driven doubleintegration methods and enable mobile assessment of spatiotemporal stride parameters in clinically critical situations as e.g. in the case of spastic gait impairments.

Sensory stimulation in post-stroke postural imbalance: A novel treatment approach? - Schmidt, Lena; Kerkhoff, Georg; Utz, Kathrin S. (Clinical Neurophysiology, 2016)

Serelaxin activates eNOS, suppresses inflammation, attenuates developmental delay and improves cognitive functions of neonatal rats after germinal matrix hemorrhage - Xu, Ming M.; Seyler, L.; Bäuerle, Tobias; Kalinichenko, Liubov; Müller, Christian P.; Huttner, Hagen; Schwab, Stefan; Manaenko, A. (Scientific Reports, 2020)
Germinal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats. We investigated whether effects of Serelaxin are mediated by its ability to activate the GMH-suppressed eNOS pathway resulting in attenuation of inflammatory marker overproduction. GMH was induced by intraparenchymal injection of bacterial collagenase (0.3U). Seven day old Sprague–Dawley rat pups (P7) were used (n = 63). GMH animals were divided in vehicle or serelaxin treated (3 µg once, 30 µg once, 30 µg multiple, i.p., starting 30 after GMH and then daily). Sham operated animals were used. We monitored the developmental profile working memory and spatial function (T-maze and open field test respectively). At day 28, all rats underwent MRI-scans for assessment of changes in cortical thickness and white matter loss. Effects of Serelaxin on eNOS pathway activation and post-GMH inflammation were evaluated. We demonstrated that Serelaxin dose-dependently attenuated GMH-induced developmental delay, protected brain and improved cognitive functions of rats after GMH. That was associated with the decreased post-GMH inflammation, mediated at least partly by amelioration of GMH-induced eNOS inhibition.
CRIS-Team Scopus Importer:2020-05-29

Serial Pupillometer Readings Predicting Intracranial Pressure Crisis - Giede-Jeppe, Antje; Koehn, Julia; Gerner, Stefan; Kuramatsu, Joji; Huttner, Hagen; Schwab, Stefan (2018)
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Serotonergic dysfunction in the A53T alpha-synuclein mouse model of Parkinson's disease - Deußer, Janina; Schmidt, Stefanie; Ettle, Benjamin; Ploetz, Sonja; Huber, Sabine; Müller, Christiane; Masliah, Eliezer; Winkler, Jürgen; Kohl, Zacharias (Journal of Neurochemistry, 2015)
Parkinson's disease, neuropathologically defined by the aggregation of ?-synuclein, is characterized by neuropsychiatric symptoms such as depression and anxiety preceding the onset of motor symptoms. A loss of serotonergic neurons or their projections into the hippocampus and alterations in serotonin release may be linked to these symptoms. Here, we investigate the effect of human A53T ?-synuclein on serotonergic neurons using 12-months-old transgenic mice. We detected human ?-synuclein in the perikarya of brainstem median and dorsal raphe neurons as well as in serotonergic fibers in the hippocampus. Despite intracellular ?-synuclein accumulation there was no loss of serotonergic neurons in dorsal and median raphe nuclei of A53T ?-synuclein mice. However, serotonin levels were significantly reduced in the brainstem. In addition, serotonergic fiber density in the dorsal dentate gyrus was significantly less dense in transgenic mice. Interestingly, we detected a significantly compromised increase in doublecortin+ neuroblasts after chronic treatment with fluoxetine at the site of reduced serotonergic innervation, the infrapyramidal blade of the dorsal dentate gyrus in A53T ?-synuclein mice. This suggests that ?-synuclein affects serotonergic projections in a spatially distinct pattern within the hippocampus thereby influencing the response to antidepressant treatment.
EVALuna2:23680

Serotonin in Parkinson's disease - Kohl, Zacharias; Winkler, Jürgen (Handbook of Behavioral Neuroscience, 2020)
Motor symptoms in Parkinson's disease (PD) are tightly linked to the degeneration of substantia nigra dopaminergic neurons and their projections into the striatum leading to the prototypical motor manifestations of the disease. However, the affection of various other neurotransmitters accounts for a large variety of motor as well as nonmotor symptoms in PD. The loss of serotonergic neurons and alterations of their projections into corresponding targets play an important role in a broad range of motor as well as nonmotor symptoms, including tremor, fluctuations of motor function, cognition, depression, anxiety, and psychosis. Here, we highlight current findings from neuropathological studies as well as animal models of PD, and relate them to recent clinical imaging results, underlining the importance of a compromised serotonergic system in PD and address potential future treatment strategies.
CRIS-Team Scopus Importer:2020-01-31
Keywords: 5-HT; Alpha-synuclein; Hippocampus; Hyperinnervation; Parkinson's disease; Serotonin receptor; Striatum; Synaptic loss

Serotonin transporter gene and stress reactivity in unipolar depression : Role of the HPA system as endophenotype of the SLC6A4 gene - Welper, H.; Aller, A.; Guttenthaler, V.; Hoefels, S.; Lennertz, L.; Pfeiffer, U.; Schwab, Stefan; Zobel, A. (Der Nervenarzt, 2014)
A length polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with both depression and hypothalamic-pituitary-adrenal (HPA) system activity. A dysregulation of the HPA system is considered to be a candidate endophenotype of depression. The objective of the present study was an investigation of a possible gene-endophenotype-interaction between 5-HTTLPR and HPA system activity in a sample of inpatients with major depression.A total of 237 inpatients with major depression were genotyped for 5-HTTLPR and participated in a combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) as well as using the Hamilton score (Hamilton rating scale for depression) to determine the severity of the psychopathology.Patients with the ss-genotype showed a significantly higher HPA -system activity in comparison to patients with the lI-genotype, but no association between 5-HTTLPR and the severity of psychopathology could be detected.The results of the current study demonstrate an influence of 5-HTTLPR on dysregulation of the HPA system in patients with major depression and support the hypothesis that 5-HTTLPR- and HPA-system-interaction constitutes an important component in the pathogenesis of depression.
EVALuna2:23614

Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC ?-synuclein transgenic rat model of Parkinson's disease - Kohl, Zacharias; Ben Abdallah, Nada; Vogelgsang, Jonathan; Tischer, Lucas; Deußer, Janina; Amato, Davide; Anderson, Scott; Müller, Christian P.; Riess, Olaf; Masliah, Eliezer; Nuber, Silke; Winkler, Jürgen (Neurobiology of Disease, 2016)
Parkinson's disease (PD) is a multisystem disorder, involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of alpha-synuclein, however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as anxiety and depression. The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating alpha-synuclein levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of human full-length alpha-synuclein on hippocampal cellular and synaptic plasticity, we used a recently generated BAC alpha-synuclein transgenic rat model showing important features of PD such as widespread and progressive alpha-synuclein aggregation pathology, dopamine loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of serotonin (5-HT) 1B receptor, decreased 5-HT neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/CA3 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, alpha-synuclein overexpression reduced proteins involved in vesicle release, in particular synapsin-1 and Rab3 interacting molecule (RIM3), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC alpha-synuclein rats showed an early anxiety-like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating alpha-synuclein severely affects hippocampal neurogenesis paralleled by impaired 5-HT neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic rat model of PD.
EVALuna2:23681

Severity assessment in maximally treated ICH patients: The max-ICH score - Sembill, Jochen; Gerner, Stefan; Volbers, Bastian; Bobinger, Tobias; Lücking, Hannes; Kloska, Stephan; Schwab, Stefan; Huttner, Hagen; Kuramatsu, Joji (Neurology, 2017)
As common prognostication models in intracerebral hemorrhage (ICH) are developed variably including patients with early (<24 hours) care limitations (ECL), we investigated its interaction with prognostication in maximally treated patients and sought to provide a new unbiased severity assessment tool.This observational cohort study analyzed consecutive ICH patients (n = 583) from a prospective registry over 5 years. We characterized the influence of ECL on overall outcome by propensity score matching and on conventional prognostication using receiver operating characteristic analyses. We established the max-ICH score based on independent predictors of 12-month functional outcome in maximally treated patients and compared it to existing models.Prevalence of ECL was 19.2% (n = 112/583) and all of these patients died. Yet propensity score matching displayed that 50.7% (n = 35/69) theoretically could have survived, with 18.8% (n = 13/69) possibly reaching favorable outcome (modified Rankin Scale score 0-3). Conventional prognostication seemed to be confounded by ECL, documented by a decreased predictive validity (area under the curve [AUC] 0.67, confidence interval [CI] 0.61-0.73 vs AUC 0.80, CI 0.76-0.83; p < 0.01), overestimating poor outcome (mortality by 44.8%, unfavorable outcome by 10.1%) in maximally treated patients. In these patients, the novel max-ICH score (0-10) integrates strength-adjusted predictors, i.e., NIH Stroke Scale score, age, intraventricular hemorrhage, anticoagulation, and ICH volume (lobar and nonlobar), demonstrating improved predictive accuracy for functional outcome (12 months: AUC 0.81, CI 0.77-0.85; p < 0.01). The max-ICH score may more accurately delineate potentials of aggressive care, showing favorable outcome in 45.4% (n = 214/471) and a long-term mortality rate of only 30.1% (n = 142/471).Care limitations significantly influenced the validity of common prognostication models resulting in overestimation of poor outcome. The max-ICH score demonstrated increased predictive validity with minimized confounding by care limitations, making it a useful tool for severity assessment in ICH patients.
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Severity of traumatic brain injury correlates with long-term cardiovascular autonomic dysfunction - Hilz, Max J.; Wang, Ruihao; Markus, Jörg; Ammon, Fabian; Hoesl, Katharina M.; Flanagan, Steven R.; Winder, Klemens; Koehn, Julia (Journal of Neurology, 2017)
After traumatic brain injury (TBI), central autonomic dysfunction might contribute to long-term increased mortality rates. Central autonomic dysfunction might depend on initial trauma severity. This study was performed to evaluate differences in autonomic modulation at rest and upon standing between patients with a history of mild TBI (post-mild-TBI patients), moderate or severe TBI (post-moderate-severe-TBI patients), and healthy controls. In 20 post-mild-TBI patients (6-78 months after TBI), age-matched 20 post-moderate-severe-TBI patients (6-94 months after TBI) and 20 controls, we monitored respiration, RR intervals (RRI) and systolic blood pressure (BPsys) at supine rest and upon standing. We determined mainly sympathetic low (LF) and parasympathetic high (HF) frequency powers of RRI fluctuations, sympathetically mediated LF-BPsys powers, LF/HF-RRI ratios, normalized (nu) LF-RRI and HF-RRI powers, and compared data between groups, at rest and upon standing (ANOVA with post hoc testing). We correlated autonomic parameters with initial Glasgow Coma Scale (GCS) scores (Spearman test; significance: p < 0.05). Supine BPsys and LFnu-RRI powers were higher while HFnu-RRI powers were lower in post-moderate-severe-TBI patients than post-mild-TBI patients and controls. LFnu-RRI powers were higher and HFnu-RRI powers were lower in post-mild-TBI patients than controls. Upon standing, only post-mild-TBI patients and controls increased LF-BPsys powers and BPsys and decreased HF-RRI powers. GCS scores correlated positively with LFnu-RRI powers, LF/HF-RRI ratios, and inversely with HFnu-RRI powers, at standing position. More than 6 months after TBI, there is autonomic dysfunction at rest and upon standing which is more pronounced after moderate-severe than mild TBI and in part correlates with initial trauma severity.
EVALuna2:22558

Sex differences in perihemorrhagic edema evolution after spontaneous intracerebral hemorrhage - Wagner, Irina; Volbers, Bastian; Kloska, Stephan; Schwab, Stefan; Staykov, Dimitre; Dörfler, Arnd (European Journal of Neurology, 2012)
Background and purpose: Clinical data on sex differences in perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH) are lacking. Methods: Patients with spontaneous supratentorial ICH who had received standard conservative treatment were identified retrospectively. PHE development was assessed over a 14-day period on follow-up CT scans (days 1, 2-4, 5-7, 8-11, and 12-14). ICH and PHE volumes were assessed semiautomatically and compared between men and women. Results: A total of 387 patients (233 men) were included. Starting at days 2-4, women showed lower PHE values (P<0.05;/ days 2-4, 8-11) or a trend toward significance (P≤0.1; days 5-7, 12-14). Conclusions: Female sex may predict lower PHE volumes. © 2012 The Author(s) European Journal of Neurology © 2012 EFNS.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Gender; Intracerebral hemorrhage; Perihemorrhagic edema

Sex-specific pleiotropic changes in emotional behavior and alcohol consumption in human α-synuclein A53T transgenic mice during early adulthood - Kalinichenko, Liubov; Kohl, Zacharias; Mühle, Christiane; Hassan, Zurina; Hahn, Agnes; Schmitt, Eva Maria; Macht, Kilian; Stoyanov, Lyubomir; Moghaddami-Fara, Schayan; Bilbao Canalejas, Roberto; Eulenburg, Volker; Winkler, Jürgen; et al. (Journal of neurochemistry, 2024)
Point mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns. In this study, we investigated whether the familial PD point mutation A53T is associated with changes in alcohol consumption behavior and emotional states at ages not yet characterized by α-synuclein accumulation. The affective and alcohol-drinking phenotypes remained unaltered in female PDGF-hA53T-synuclein-transgenic (A53T) mice during both early and late adulthood. Brain region-specific activation of ceramide-producing enzymes, acid sphingomyelinase (ASM), and neutral sphingomyelinase (NSM), known for their neuroprotective properties, was observed during early adulthood but not in late adulthood. In males, the A53T mutation was linked to a reduction in alcohol consumption in both early and late adulthood. However, male A53T mice displayed increased anxiety- and depression-like behaviors during both early and late adulthood. Enhanced ASM activity in the dorsal mesencephalon and ventral hippocampus may potentially contribute to these adverse behavioral effects of the mutation in males during late adulthood. In summary, the A53T gene mutation was associated with diverse changes in emotional states and alcohol consumption behavior long before the onset of PD, and these effects varied by sex. These alterations in behavior may be linked to changes in brain ceramide metabolism.
CRIS-Team Scopus Importer:2024-02-16
Keywords: A53T; alcohol; ceramide; depression; neutral sphingomyelinase; Parkinson's disorder

Sexual Dysfunction Seems to Trigger Depression in Female Multiple Sclerosis Patients - Hoesl, Katharina M.; Deutsch, Martina; Wang, Ruihao; Roy, Sankanika; Winder, Klemens; Niklewski, Guenter; Lee, De-Hyung; Linker, Ralf; Hilz, Max-Josef (European neurology, 2018)
BACKGROUND: In women with multiple sclerosis (MS), depression and sexual dysfunction (SD) are common. Whether SD promotes depression or vice versa remains unclear despite therapeutic relevance. Therefore, we aimed to assess whether SD more likely triggers depression or vice versa. METHODS: In 83 female MS patients and 21 age-matched healthy women, we assessed depression, using the Beck Depression Inventory-V (BDI-V), and SD using the Female Sexual Function Index (FSFI). We diagnosed depression with BDI-V-scores >35 and SD with FSFI scores < 26.55. We divided patients into groups with and without SD, with and without depression. Between groups, we compared prevalence of SD and depression (Fisher's-exact-test), age, MS-duration, MS-severity, BDI-V-, and FSFI scores (Mann-Whitney U-test; significance: p < 0.05). RESULTS: A total of 37/83 MS patients and 1/21 controls had SD; 28/83 patients and 3/21 controls had depression; 51.4% patients with SD but only 19.6% without SD had depression (p = 0.003). SD was present in 67.9% depressed and 32.7% non-depressed patients. BDI-V-scores were higher in patients with SD than in patients without SD. FSFI scores were lower in depressed than non-depressed patients. CONCLUSION: In conclusion, SD was more common than depression. SD afflicted 67.9% depressed MS patients and was also more common in non-depressed MS patients than controls. SD may occur independently from depression while increased depressiveness seems linked to coexistent SD.
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Shortage of antiseizure medication in Germany: How big is the problem? - Steidl, Josephine; Krebs, Sabine; Kostev, Karel; Schwab, Stefan; Hamer, Hajo (Epilepsy and Behavior, 2025)
Objectives: We determined the frequency of drug shortages of antiseizure medication (ASM) availability in Germany. Methods: Retrospective and descriptive analysis of databases of 2 pharmaceutical wholesalers in Germany with a market share of about 45% of the German market in July 2023 (chosen arbitrarily) focusing on antiseizure drug shortages (i.e. demand could not be met entirely) and disruptions (i.e. demand could not be met at all) on the level of formulations, ASM and of manufacturers. Results: 98/909 (10.8%) of formulations of ASM with Wholesaler A were listed with drug shortages and 131/872 (15%) of formulations were reported with drug shortages at Wholesaler B. 19 of 222 (8.6%) entire ASM at Wholesaler A and 12/213 (5.6%) of ASM with Wholesaler B were reported with drug shortages. 41/62 (66.1%) manufacturers at wholesaler A and 36/57 (63.2%) manufacturers at wholesaler B reported shortages. The three compounds affected most frequently by drug shortages were pregabalin, levetiracetam and carbamazepine. 1.7% (Wholesaler A) and 12.9% (Wholesaler B) of formulations were listed with disruptions. 16.7% (40/239) of ASM with drug shortages/disruptions were brand-name ASM and 83.3% (199/239) were generic ASM. Conclusions: 11% to 15% of ASM formulations had drug shortages in Germany in July 2023. Generic ASM were more frequently affected than brand-name ASM. About 2/3 of manufacturers were reported to have drug shortages.
CRIS-Team Scopus Importer:2024-12-06
Keywords: Antiseizure medication; Drug shortages; Epilepsy

Short inertial sensor-based gait tests reflect perceived state fatigue in multiple sclerosis - Ibrahim, Alzhraa; Flachenecker, Felix; Gaßner, Heiko; Rothammer, Veit; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (Multiple Sclerosis and Related Disorders, 2022)
Background: Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system, affecting more than 2.3 million people worldwide. Fatigue is among the most common symptoms in MS, resulting in reduced mobility and quality of life. The six-minute walking test (6MWT) is commonly used as a measure of fatigability for the assessment of state fatigue throughout treatment or rehabilitation programs. This ‘gold standard’ test is time-consuming and can be difficult and exhausting for some patients with high levels of disability or high rates of fatigue. Research question: Can short inertial sensor-based gait tests assess perceived state fatigue in MS patients? Methods: Sixty-five MS patients equipped with one sensor on each foot performed the 6 min walk test (6MWT) and the 25-foot walk (25FW, at both preferred and fastest speed). Perceived state fatigue was measured after each minute of the 6MWT, using the Borg rating. The highest of these ratings served as a measure of overall perceived state fatigue. Stride-wise spatio-temporal gait parameters were extracted from the 25FW and from the first minute, first 2 min, and first 4 min of the 6MWT. Principal component analysis was performed. Perceived state fatigue was predicted in a regression analysis, using the principal components of gait parameters as predictors. Statistical tests evaluated differences in performance between the full 6MWT, the shortened 6MWT, and the 25FW. Results: A mean absolute error of less than 2 points on the Borg rating was obtained using the shortened 6MWT and the 25FW. There were no significant differences between the prediction accuracy of the full 6MWT and that of the shortened gait tests. Significance: It is possible to use shortened gait tests when evaluating perceived state fatigue in MS patients using inertial sensors. Substituting them for long gait tests may reduce the burden of the testing on both patients and clinicians. Further, the approach taken here may prompt future work to explore the use of short bouts of real-world walking with unobtrusive inertial sensors for state fatigue assessment.
CRIS-Team Scopus Importer:2022-01-28
Keywords: Accelerometer; Fatigue; IMU; MS; Short gait test

Should non-convulsive Seizures and non-convulsive Status epilepticus be treated aggressively in the ICU: A Debate Comment - Madzar, D.; Hamer, Hajo (Klinische Neurophysiologie, 2020)
CRIS-Team WoS Importer:2021-01-08

Silhouette-Length-Scaled Gait Parameters for Motor Functional Analysis in Mice and Rats - Timotius, Ivanna; Moceri, Sandra; Plank, Anne-Christine; Habermeyer, Johanna; Canneva, Fabio; Winkler, Jürgen; Klucken, Jochen; Casadei, Nicolas; Riess, Olaf; Eskofier, Björn; von Hörsten, Stephan (eNeuro, 2019)
Gait analysis of transgenic mice and rats modeling human diseases often suffers from the condition that those models exhibit genotype-driven differences in body size, weight, and length. Thus, we hypothesized that scaling by the silhouette length improves the reliability of gait analysis allowing normalization for individual body size differences. Here, we computed video-derived silhouette length and area parameters from a standard markerless gait analysis system using image-processing techniques. By using length- and area-derived data along with body weight and age, we systematically scaled individual gait parameters. We compared these different scaling approaches and report here that normalization for silhouette length improves the validity and reliability of gait analysis in general. The application of this silhouette length scaling to transgenic Huntington disease mice and Parkinson´s disease rats identifies the remaining differences reflecting more reliable, body length-independent motor functional differences. Overall, this emphasizes the need for silhouette-length-based intra-assay scaling as an improved standard approach in rodent gait analysis.<br
Keywords: CatWalk; gait; Huntington; normalization; Parkinson; scaling

Simplified Edinburgh CT Criteria for Identification of Lobar Intracerebral Hemorrhage Associated With Cerebral Amyloid Angiopathy - Sembill, Jochen; Knott, Michael; Xu, Mingming; Röder, Sebastian; Hagen, Manuel; Sprügel, Maximilian; Mrochen, Anne; Borutta, Matthias; Hölter, Philip; Engelhorn, Tobias Martin; Rothhammer, Veit; Macha, Kosmas; et al. (Neurology, 2022)
BACKGROUND AND OBJECTIVES: In patients with lobar intracerebral hemorrhage (ICH), etiologic characterization represents a tradeoff between feasibility, resource allocation, and diagnostic certainty. This study investigated the accuracy and clinical utility of the simplified Edinburgh CT criteria to identify underlying cerebral amyloid angiopathy (CAA). METHODS: This external validation analyzed 210 consecutive patients with lobar ICH and available CT and MRI studies from a prospective single-center observational cohort study (2006-2015, Longitudinal Cohort Study on ICH Care [UKER-ICH,] NCT03183167). We investigated the interrater variability and diagnostic accuracy of the simplified Edinburgh CT-based criteria for identification of ICH associated with probable CAA according to MRI-based modified Boston criteria as a reference standard. We evaluated the utility of the simplified Edinburgh criteria by decision curve analysis, comparing the theoretical clinical net benefit (weighted benefit-harm at varying threshold probabilities) of the high-risk category (finger-like projections and subarachnoid hemorrhage) for ruling in and the low-risk category (neither finger-like projections nor subarachnoid hemorrhage) for ruling out with the assumptions of no or all patients having CAA (default strategies). RESULTS: Of 210 patients, 70 (33.3%) had high risk, 67 (31.9%) had medium risk, and 73 (34.8%) had low risk for CAA-associated ICH according to simplified Edinburgh CT criteria, showing moderate interrater variability. Discrimination was good (area under the receiver operating characteristics curve 0.74, 95% CI 0.67-0.81) without evidence of poor calibration (Hosmer-Lemeshow, p = 0.54) for validation of MRI-based diagnosis of probable CAA (n = 94 of 210, 44.8%). The rule-in criteria (high risk), had 87.1% (79.3%-92.3%) specificity, and the rule-out criteria (low risk), had 80.9% (71.1%-88.0%) sensitivity. Decision curve analysis suggested a theoretical clinical net benefit for ruling in but not for ruling out probable CAA compared to default strategies. DISCUSSION: Applying the simplified Edinburgh CT criteria during diagnostic workup seems clinically useful and may accurately identify CAA in patients with lobar ICH. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03183167. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with lobar hemorrhages, the simplified Edinburgh criteria accurately identify those at high risk of CAA.
CRIS-Team Scopus Importer:2022-06-03

Siponimod (BAF-312) Attenuates Perihemorrhagic Edema And Improves Survival in Experimental Intracerebral Hemorrhage - Bobinger, Tobias; Manaenko, Anatol; Burkardt, Petra; Beuscher, Vanessa; Sprügel, Maximilian; Röder, Sebastian; Bäuerle, Tobias; Seyler, Lisa; Nagel, Armin Michael; Linker, Ralf; Engelhorn, Tobias; Dörfler, Arnd; et al. (Stroke, 2019)
Background and Purpose- Perihemorrhagic edema (PHE) is associated with poor outcome after intracerebral hemorrhage (ICH). Infiltration of immune cells is considered a major contributor of PHE. Recent studies suggest that immunomodulation via S1PR (sphingosine-1-phosphate receptor) modulators improve outcome in ICH. Siponimod, a selective modulator of sphingosine 1-phosphate receptors type 1 and type 5, demonstrated an excellent safety profile in a large study of patients with multiple sclerosis. Here, we investigated the impact of siponimod treatment on perihemorrhagic edema, neurological deficits, and survival in a mouse model of ICH. Methods- ICH was induced by intracranial injection of 0.075 U of bacterial collagenase in 123 mice. Mice were randomly assigned to different treatment groups: vehicle, siponimod given as a single dosage 30 minutes after the operation or given 3× for 3 consecutive days starting 30 minutes after operation. The primary outcome of our study was evolution of PHE measured by magnetic resonance-imaging on T2-maps 72 hours after ICH, secondary outcomes included evolution of PHE 24 hours after ICH, survival and neurological deficits, as well as effects on circulating blood cells and body weight. Results- Siponimod significantly reduced PHE measured by magnetic resonance imaging (P=0.021) as well as wet-dry method (P=0.04) 72 hours after ICH. Evaluation of PHE 24 hours after ICH showed a tendency toward attenuated brain edema in the low-dosage group (P=0.08). Multiple treatments with siponimod significantly improved neurological deficits measured by Garcia Score (P=0.03). Survival at day 10 was improved in mice treated with multiple dosages of siponimod (P=0.037). Mice treated with siponimod showed a reduced weight loss after ICH (P=0.036). Conclusions- Siponimod (BAF-312) attenuated PHE after ICH, increased survival, and reduced ICH-induced sensorimotor deficits in our experimental ICH-model. Findings encourage further investigation of inflammatory modulators as well as the translation of BAF-312 to a human study of ICH patients.
EVALuna2:204480

Siponimod reduces perihemorrhagic edema and improves neurological outcome in experimental intracerebral hemorrhage - Bobinger, Tobias; Manaenko, A.; Baeurele, T.; Seyler, L.; Nagel, Armin Michael; Engelhorn, Tobias; Dörfler, Arnd; Kuramatsu, J. B.; Schwab, Stefan; Huttner, Hagen (JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2019)
CRIS-Team WoS Importer:2019-07-19

Site and size of multiple sclerosis lesions predict enhanced or decreased female orgasmic function - Winder, Klemens; Seifert, Frank; Koehn, Julia; Deutsch, Martina; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Linker, Ralf; Hilz, Max-Josef (Journal of Neurology, 2015)
Neuroimaging identified brain areas involved in female orgasm. In women with multiple sclerosis (MS), associations between orgasmic function and the site and size of MS-related magnetic resonance imaging (MRI) changes are undetermined. This study intended to correlate MS-associated cerebral lesion load and location with clinical scores of female orgasmic function. In 50 women with MS (mean age 37.0 ± 9.9 years), we assessed Female Sexual Function Index (FSFI) scores for orgasmic frequency, difficulty and satisfaction. We determined disease duration, Expanded Disability Status Scale (EDSS) scores, and cerebral MS-lesion load and location using T2-weighed 1.5 T MRIs. We correlated FSFI scores for orgasm with patient age, disease duration, EDSS scores, and cerebral MS-lesion load (Spearman rank correlation; significance: p < 0.05). FSFI scores for orgasm correlated inversely with MS-lesion load in the left temporal periventricular white matter and right middle-inferior occipital area, but directly with MS-lesion load in the right frontal primary motor cortex, left prefrontal/inferior frontal cortex, right amygdala, left temporal middle-inferior and fusiform areas, and midbrain. FSFI scores for orgasm did not correlate with patient age, disease duration and EDSS scores (p > 0.05). In conclusion, our results indicate that MS-lesions in left temporal periventricular and right visual association areas deteriorate orgasmic function. In contrast, direct correlations between frontotemporal or midbrain lesions and higher FSFI scores, indicating enhanced or disinhibited orgasmic function, suggest that these brain regions normally buffer orgasmic responses. Moreover, our results indicate that orgasmic dysfunction in women with MS evolves independently of disease duration and physical disability.
EVALuna2:22361

Situation of breastfeeding in multiple sclerosis - a questionnaire survey in Germany - Aigner, S.; Huhn, Konstantin; Cepek, L.; Hellwig, K.; Nickel, Florian; Bayas, A. (MULTIPLE SCLEROSIS JOURNAL, 2022)
CRIS-Team WoS Importer:2022-12-09

Skin sodium is increased in male patients with multiple sclerosis and related animal models - Huhn, Konstantin; Linz, Peter; Pemsel, Franziska; Michalke, Bernhard; Seyferth, Stefan; Kopp, Christoph; Chaudri, Mohammad Anwar; Rothhammer, Veit; Dörfler, Arnd; Uder, Michael; Nagel, Armin M.; Müller, Dominik N.; et al. (Proceedings of the National Academy of Sciences of the United States of America, 2021)
Novel MRI techniques allow a noninvasive quantification of tissue sodium and reveal the skin as a prominent compartment of sodium storage in health and disease. Since multiple sclerosis (MS) immunopathology is initiated in the periphery and increased sodium concentrations induce proinflammatory immune cells, the skin represents a promising compartment linking high sodium concentrations and MS immunopathology. We used a 7-T sodium MRI (23Na-MRI) and inductively coupled plasma mass spectrometry to investigate the skin sodium content in two mouse models of MS. We additionally performed 3-T 23Na-MRI of calf skin and muscles in 29 male relapsing-remitting MS (RRMS) patients and 29 matched healthy controls. Demographic and clinical information was collected from interviews, and disease activity was assessed by expanded disability status scale scoring. 23Na-MRI and chemical analysis demonstrated a significantly increased sodium content in the skin during experimental autoimmune encephalomyelitis independent of active immunization. In male patients with RRMS, 23Na-MRI demonstrated a higher sodium signal in the area of the skin compared to age- and biological sex-matched healthy controls with higher sodium, predicting future disease activity in cranial MRI. In both studies, the sodium enrichment was specific to the skin, as we found no alterations of sodium signals in the muscle or other tissues. Our data add to the recently identified importance of the skin as a storage compartment of sodium and may further represent an important organ for future investigations on salt as a proinflammatory agent driving autoimmune neuroinflammation such as that in MS.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Experimental autoimmune encephalomyelitis; Multiple sclerosis; Skin; Sodium magnetic resonance imaging

Slow-theta power decreases during item-place encoding predict spatial accuracy of subsequent context recall - Crespo-Garcia, Maite; Zeiller, Monika; Leupold, Claudia; Kreiselmeyer, Gernot; Rampp, Stefan; Hamer, Hajo; Dalal, Sarang S. (NeuroImage, 2016)
Human hippocampal theta oscillations play a key role in accurate spatial coding. Associative encoding involves similar hippocampal networks but, paradoxically, is also characterized by theta power decreases. Here, we investigated how theta activity relates to associative encoding of place contexts resulting in accurate navigation. Using MEG, we found that slow-theta (2-5Hz) power negatively correlated with subsequent spatial accuracy for virtual contextual locations in posterior hippocampus and other cortical structures involved in spatial cognition. A rare opportunity to simultaneously record MEG and intracranial EEG in an epilepsy patient provided crucial insights: during power decreases, slow-theta in right anterior hippocampus and left inferior frontal gyrus phase-led the left temporal cortex and predicted spatial accuracy. Our findings indicate that decreased slow-theta activity reflects local and long-range neural mechanisms that encode accurate spatial contexts, and strengthens the view that local suppression of low-frequency activity is essential for more efficient processing of detailed information.
EVALuna2:22490

Sobetirome rescues α-synuclein-mediated demyelination in an in vitro model of multiple system atrophy - Meszaros, Lisa; Himmler, Marcus; Schneider, Yanni; Arnold, Philipp; Dörje, Frank; Schubert, Dirk W.; Winkler, Jürgen (European Journal of Neuroscience, 2023)
Multiple system atrophy (MSA) is a rare and rapidly progressive atypical parkinsonian disorder characterized by oligodendroglial cytoplasmic inclusions containing α-synuclein (α-syn), demyelination, inflammation and neuronal loss. To date, no disease-modifying therapy is available. Targeting α-syn-driven oligodendroglial dysfunction and demyelination presents a potential therapeutic approach for restricting axonal dysfunction, neuronal loss and disease progression. The present study investigated the promyelinogenic potential of sobetirome, a blood–brain barrier permeable and central nervous system selective thyromimetic in the context of an in vitro MSA model. Oligodendrocyte precursor cells (OPCs) were obtained from transgenic mice overexpressing human α-syn specifically in oligodendrocytes (MBP29 mouse line), a well-described MSA model, and non-transgenic littermates. mRNA and protein expression analyses revealed a substantial rescue effect of sobetirome on myelin-specific proteins in control and α-syn overexpressing oligodendrocytes. Furthermore, myelination analysis using nanofibres confirmed that sobetirome increases both the length and number of myelinated segments per oligodendrocyte in primary murine α-syn overexpressing oligodendrocytes and their respective control. These results suggest that sobetirome may be a promising thyromimetic compound targeting an important neuropathological hallmark of MSA.
CRIS-Team Scopus Importer:2023-12-22
Keywords: MSA; myelin; oligodendrocytes; sobetirome; thyromimetics; α-synuclein

Sociodemographic disparities in administration of antiepileptic drugs to adults with epilepsy in Germany: a retrospective, database study of drug prescriptions - Hamer, Hajo; Kostev, Karel (Cns Drugs, 2014)
Large epidemiological databases facilitate the study of medical care in different subgroups of the population and how such care compares with standard treatment guidelines. This study aimed for such analyses regarding utilization of antiepileptic drugs (AEDs) for epilepsy in Germany.The data source was the Disease Analyzer(®) database that is representative for the German population and assembles anonymous demographic and medical (diagnoses, prescriptions) data obtained from the practice computer system of general practitioners and specialists throughout Germany. A total of 43,712 adult patients with an epilepsy diagnosis (International Classification of Diseases, 10th edition [ICD10] code: G40.X) seen in 2010-2012 by 346 neurologists were retrospectively analysed according to sociodemographic characteristics, comorbidity, and AED treatment. Multivariate logistic regression was applied to calculate adjusted odds ratios (ORs) with 95 % confidence intervals (CIs).As compared with women, men were less likely to receive lamotrigine (OR 0.68; 95 % CI 0.65-0.72; p < 0.001) and were treated preferably with carbamazepine (OR 1.29; 95 % CI 1.23-1.35; p < 0.001). As compared with patients covered by private health insurance (PHI), patients with statutory health insurance (SHI) were treated more often with valproate (OR 1.19; 95 % CI 1.07-1.31; p < 0.001) and showed a higher rate of obesity (SHI: 3.1 %; PHI: 1.6 %; p < 0.001), while PHI was associated with administration of levetiracetam (OR 1.27; 95 % CI 1.16-1.4; p < 0.001). Carbamazepine (OR 1.25; 95 % CI 1.17-1.31; p < 0.001) and primidone (OR 1.23; 95 % CI 1.08-1.38; p < 0.001) were administered to a larger extent in rural versus urban areas. Lamotrigine (OR 1.31; 95 % CI 1.23-1.39; p < 0.001) was used more often in West than in East Germany. Living in an urban community raised the likelihood of being treated with levetiracetam (OR 1.23; 95 % CI 1.17-1.28; p < 0.001).In spite of common guidelines, AED treatment differed significantly among adults with epilepsy in Germany. Besides gender, type of health insurance and place of residence strongly influenced AED administration.
EVALuna2:22317

Sodium chloride triggers Th17 mediated autoimmunity - Haase, Stefanie; Wilck, Nicola; Kleinewietfeld, Markus; Mueller, Dominik N.; Linker, Ralf (Journal of Neuroimmunology, 2019)
The detrimental effects of a high-salt diet on human health have received much attention in the past few years. While it has been well established that high dietary salt intake is related to cardiovascular diseases, there is growing evidence that excess salt also affects the immune system and might be considered as a risk factor in autoimmune diseases such as multiple sclerosis (MS). Several studies have implicated T helper 17 cells (Th17) in the pathogenesis of MS. We and others recently demonstrated that excessive salt enhances the differentiation of Th17 cells, inducing a highly pathogenic phenotype that aggravates experimental neuroinflammation. Moreover, a diet rich in sodium affects intestinal microbiota alongside increased intestinal Th17 cells, thus linking the detrimental effects of high salt consumption to the gut-immune axis. First human studies revealed an association of increased MS disease activity with elevated sodium chloride consumption, while more recent epidemiology studies in larger cohorts suggest no correlation between salt intake and MS. However, it is known that ordinary urinary sodium analyses and nutritional questionnaires do not necessarily correspond to the actual sodium load and more sophisticated analyses are needed. Moreover, studies revealed that sodium can temporarily be stored in the body. This review summarizes recent findings on the impact of salt on the immune system and discusses potential challenges investigating dietary salt intake as a risk factor in MS.
CRIS-Team WoS Importer:2019-04-09

Sollte man nicht konvulsive Anfälle und den nicht konvulsiven Status epilepticus auf der Intensivstation aggressiv behandeln: Eine Debatte - Madzar, Dominik; Hamer, Hajo (Klinische Neurophysiologie, 2020)
CRIS-Team Scopus Importer:2021-04-19

Spasticity treatment with onabotulinumtoxin A: data from a prospective German real-life patient registry - Schramm, Axel; Ndayisaba, Jean-Pierre; Brinke, Matthias Auf Dem; Hecht, Martin; Herrmann, Christoph; Huber, Martin; Lobsien, Elmar; Mehnert, Sabine; Reuter, Iris; Stenner, Andrea; Van Der Ven, Christian; Winterholler, Martin; et al. (Journal of Neural Transmission, 2014)
This study aimed at providing real-life baseline, injection and outcome data for the treatment of various forms of spasticity with onabotulinumtoxin A in Germany. Prospective data were collected in an open multicenter patient registry from 2005 until 2010, encompassing the experience of ten specialized German centers in the treatment of spasticity using onabotulinumtoxin A in 508 patients with a total of 2005 treatment sessions. Disease entities comprised spasticity following stroke (both ischemic and hemorrhagic), traumatic brain injury, multiple sclerosis, cerebral palsy, and anoxia. Sustained improvement was observed in a variety of outcome parameters including goal attainment and motor performance scores for up to five repeated injection sessions. No significant differences between disease entities or between upper and lower limb treatment were observed with regard to efficacy and safety following onabotulinumtoxin A treatment. Minor to moderate side effects were reported in <1 % of the study population. We conclude that repetitive treatment of focal and multifocal spasticity with onabotulinumtoxin A provides a safe and efficacious therapeutic strategy for patients with different disease entities of the central nervous system.
EVALuna2:22323

Specialized neurological neurosurgical intensive care medicine - Kuramatsu, J. B.; Huttner, Hagen; Schwab, Sibylle (Der Nervenarzt, 2016)
In Germany dedicated neurological-neurosurgical critical care (NCC) is the fastest growing specialty and one of the five big disciplines integrated within the German critical care society (Deutsche Interdisziplinäre Vereinigung für Intensiv- und Notfallmedizin; DIVI). High-quality investigations based on resilient evidence have underlined the need for technical advances, timely optimization of therapeutic procedures, and multidisciplinary team-work to treat those critically ill patients. This evolution has repeatedly raised questions, whether NCC-units should be run independently or better be incorporated within multidisciplinary critical care units, whether treatment variations exist that impact clinical outcome, and whether nowadays NCC-units can operate cost-efficiently? Stroke is the most frequent disease entity treated on NCC-units, one of the most common causes of death in Germany leading to a great socio-economic burden due to long-term disabled patients. The main aim of NCC employs surveillance of structural and functional integrity of the central nervous system as well as the avoidance of secondary brain damage. However, clinical evaluation of these severely injured commonly sedated and mechanically ventilated patients is challenging and highlights the importance of neuromonitoring to detect secondary damaging mechanisms. This multimodal strategy not only requires medical expertise but also enforces the need for specialized teams consisting of qualified nurses, technical assistants and medical therapists. The present article reviews most recent data and tries to answer the aforementioned questions.
EVALuna2:22466

Specialized Staff for the Care of People with Parkinson's Disease in Germany: An Overview - Prell, Tino; Siebecker, Frank; Lorrain, Michael; Toenges, Lars; Warnecke, Tobias; Klucken, Jochen; Wellach, Ingmar; Buhmann, Carsten; Wolz, Martin; Lorenzl, Stefan; Herbst, Heinz; Eggers, Carsten; et al. (Journal of Clinical Medicine, 2020)
Access to specialized care is essential for people with Parkinson ' s disease (PD). Given the growing number of people with PD and the lack of general practitioners and neurologists, particularly in rural areas in Germany, specialized PD staff (PDS), such as PD nurse specialists and Parkinson Assistants (PASS), will play an increasingly important role in the care of people with PD over the coming years. PDS have several tasks, such as having a role as an educator or adviser for other health professionals or an advocate for people with PD to represent and justify their needs. PD nurse specialists have been established for a long time in the Netherlands, England, the USA, and Scandinavia. In contrast, in Germany, distinct PDS models and projects have been established. However, these projects and models show substantial heterogeneity in terms of access requirements, education, theoretical and practical skills, principal workplace (inpatient vs. outpatient), and reimbursement. This review provides an overview of the existing forms and regional models for PDS in Germany. PDS reimbursement concepts must be established that will foster an implementation throughout Germany. Additionally, development of professional roles in nursing and more specialized care in Germany is needed.
CRIS-Team WoS Importer:2020-09-18

Specific cerebral multiple sclerosis lesions are associated with sympathetic cardiovascular activation - Winder, K.; Linker, R. A.; Seifert, F.; Wang, R.; Lee, D-H.; Engelhorn, Tobias; Dörfler, Arnd; Fröhlich, Katharina; Hilz, M. J. (EUROPEAN JOURNAL OF NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-07-30

Specific Lobar Affection Reveals a Rostrocaudal Gradient in Functional Outcome in Spontaneous Intracerebral Hemorrhage - Gerner, Stefan; Kuramatsu, Joji; Möller, Sebastian; Huber, Angelika; Lücking, Hannes; Kloska, Stephan; Madzar, Dominik; Sembill, Jochen; Schwab, Stefan; Huttner, Hagen (Stroke, 2017)
Several studies have reported a better functional outcome in lobar intracerebral hemorrhage (ICH) compared with deep location. However, among lobar ICH, a correlation of hemorrhage site-involving the specific lobes-with functional outcome has not been established.Conservatively treated patients with supratentorial ICH, admitted to our hospital over a 5-year period (2008-2012), were retrospectively analyzed. Lobar patients were classified as isolated or overlapping ICH according to affected lobes. Demographic, clinical, and radiological characteristics were recorded and compared among lobar ICH patients using above subclassification. Functional outcome-dichotomized into favorable (modified Rankin Scale, 0-3) and unfavorable (modified Rankin Scale, 4-6)-was assessed after 3 and 12 months. Multivariate regression analysis was performed to identify predictors for favorable outcome.Of overall 553 patients, 260 had lobar ICH. In isolated lobar ICH, median hematoma-volume decreased from rostral (frontal, 22.4 mL [7.3-55.5 mL]) to caudal (occipital, 7.1 mL [5.2-16.4 mL]; P=0.045), whereas the proportion of patients with favorable outcome increased (frontal: 23/63 [36.5%] versus occipital: 10/12 [83.3%]; P=0.003). Patients with overlapping lobar ICH had larger ICH volumes than isolated lobar ICH (overlapping, 48.9 mL [22.6-78.5 mL] versus 15.3 mL [5.0-44.6 mL]; P<0.001) and poorer clinical status on admission (Glasgow Coma Scale and National Institutes of Health Stroke Scale). Correlations with anatomic aspects provided evidence of a rostrocaudal gradient with increasing gray/white-matter ratio and decreasing hematoma-volume and rate of hematoma enlargement from frontal to occipital ICH location. Multivariate analysis revealed affection of occipital lobe (odds ratio, 3.75 [1.38-10.22]) and affection of frontal lobe (odds ratio, 0.52 [0.28-0.94]) to be independent predictors for favorable outcome and unfavorable outcome, respectively.Among patients with lobar ICH radiological and outcome characteristics differed according to location. Especially affection of the frontal lobe was frequent and associated with unfavorable outcome after 3 months.
EVALuna2:22482

Spectral fingerprints or spectral tilt? Evidence for distinct oscillatory signatures of memory formation - Fellner, Marie-Christin; Gollwitzer, Stephanie; Rampp, Stefan; Kreiselmeyr, Gernot; Bush, Daniel; Diehl, Beate; Axmacher, Nikolai; Hamer, Hajo; Hanslmayr, Simon (Plos Biology, 2019)
Decreases in low-frequency power (2-30 Hz) alongside high-frequency power increases (>40 Hz) have been demonstrated to predict successful memory formation. Parsimoniously, this change in the frequency spectrum can be explained by one factor, a change in the tilt of the power spectrum (from steep to flat) indicating engaged brain regions. A competing view is that the change in the power spectrum contains several distinct brain oscillatory fingerprints, each serving different computations. Here, we contrast these two theories in a parallel magnetoencephalography (MEG)-intracranial electroencephalography (iEEG) study in which healthy participants and epilepsy patients, respectively, studied either familiar verbal material or unfamiliar faces. We investigated whether modulations in specific frequency bands can be dissociated in time and space and by experimental manipulation. Both MEG and iEEG data show that decreases in alpha/beta power specifically predicted the encoding of words but not faces, whereas increases in gamma power and decreases in theta power predicted memory formation irrespective of material. Critically, these different oscillatory signatures of memory encoding were evident in different brain regions. Moreover, high-frequency gamma power increases occurred significantly earlier compared to low-frequency theta power decreases. These results show that simple spectral tilt cannot explain common oscillatory changes and demonstrate that brain oscillations in different frequency bands serve different functions for memory encoding.
CRIS-Team WoS Importer:2019-08-23

Spectral properties of bursts in therapeutic burst suppression predict successful treatment of refractory status epilepticus - Gollwitzer, Stephanie; Hopfengärtner, Rüdiger; Rampp, Stefan; Welte, Tamara; Madžar, Dominik; Lang, Johannes; Reindl, Caroline; Stritzelberger, Jenny; Köhn, Julia; Kuramatsu, Joji; Schwab, Stefan; Huttner, Hagen B.; et al. (Epilepsy and Behavior, 2024)
Burst suppression (BS) on EEG induced by intravenous anesthesia (IVAT) is standard therapy for refractory status epilepticus (RSE). If BS has any independent therapeutic effect on RSE is disputed. We aimed to define EEG characteristics of BS predicting termination or recurrence of status after weaning. All RSE patients treated with IVAT while undergoing continuous EEG monitoring on the neurological intensive care unit between 2014 and 2019 were screened for inclusion. A one hour-period of visually preselected BS-EEG was analyzed. Bursts were segmented by a special thresholding technique and underwent power spectral analysis. Out of 48 enrolled patients, 25 (52.1 %) did not develop seizure recurrence (group Non SE) after weaning from IVAT; in 23 patients (47.9 %), SE reestablished (group SE). In group Non SE, bursts contained higher amounts of EEG delta power (91.59 % vs 80.53 %, p < 0.0001), while faster frequencies were more pronounced in bursts in group SE (theta: 11.38 % vs 5.41 %, p = 0.0008; alpha: 4.89 % vs 1.82 %, p < 0.0001; beta: 3.23 % vs 1.21 %, p = 0.0002). Spectral profiles of individual bursts closely resembled preceding seizure patterns in group SE but not in group Non SE. Accordingly, persistence of spectral composition of initial ictal patterns in bursts, suggests ongoing SE, merely interrupted but not altered by BS. Fast oscillations in bursts indicate a high risk of status recurrence after weaning from IVAT. EEG guided individualized sedation regimes might therefore be superior to standardized anesthesia protocols.
CRIS-Team Scopus Importer:2024-11-08
Keywords: Intravenous anesthesia; Multimodal monitoring; Quantitative EEG

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis - Ruf, Wolfgang P.; Boros, Matej; Freischmidt, Axel; Brenner, David; Grozdanov, Veselin; de Meirelles, Joao; Meyer, Thomas; Grehl, Torsten; Petri, Susanne; Grosskreutz, Julian; Weyen, Ute; Guenther, Rene; et al. (Brain Communications, 2023)
Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02–2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12–0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.
CRIS-Team Scopus Importer:2023-06-30
Keywords: amyotrophic lateral sclerosis; genetics; motor neuron disease

Sporadic Parkinson's disease derived neuronal cells show disease-specific mRNA and small RNA signatures with abundant deregulation of piRNAs - Schulze, Markus; Sommer, Annika; Plotz, Sonja; Farrell, Michaela; Winner, Beate; Grosch, Janina; Winkler, Jürgen; Riemenschneider, Markus J. (Acta Neuropathologica Communications, 2018)
Differentiated neurons established via iPSCs from patients that suffer from familial Parkinson's disease (PD) have allowed insights into the mechanisms of neurodegeneration. In the larger cohort of patients with sporadic PD, iPSC based information on disease specific cellular phenotypes is rare. We asked whether differences may be present on genomic and epigenomic levels and performed a comprehensive transcriptomic and epigenomic analysis of fibroblasts, iPSCs and differentiated neuronal cells of sporadic PD-patients and controls. We found that on mRNA level, although fibroblasts and iPSCs are largely indistinguishable, differentiated neuronal cells of sporadic PD patients show significant alterations enriched in pathways known to be involved in disease aetiology, like the CREB-pathway and the pathway regulating PGC1a. Moreover, miRNAs and piRNAs/piRNA-like molecules are largely differentially regulated in cells and post-mortem tissue samples between control-and PD-patients. The most striking differences can be found in piRNAs/piRNA-like molecules, with SINE-and LINE-derived piRNAs highly downregulated in a disease specific manner. We conclude that neuronal cells derived from sporadic PD-patients help to elucidate novel disease mechanisms and provide relevant insight into the epigenetic landscape of sporadic Parkinson's disease as particularly regulated by small RNAs.
EVALuna2:35781

Sport and Physical Activity in Epilepsy - van den Bogard, Fanziska; Hamer, Hajo; Sassen, Robert; Reinsberger, Claus (Deutsches Ärzteblatt international, 2020)
BACKGROUND: For many years, people with epilepsy were advised not to engage in sports. In this systematic review, we investigated whether persons with epilepsy exercise less than the general population, and what effect physical activity has on epilepsy. METHODS: A literature search was carried out in PubMed and the Web of Science, and 14 269 studies were entered into the selection process. The selected studies were assessed for their methodological quality and accordingly assigned an evidence level. RESULTS: 42 studies were included in the review; 10 were classified as evidence level 3, 27 as evidence level 2-, 2 as evidence level 2+, and 3 as evidence level 1-. Persons with epilepsy are less physically active and less physically fit than the general population. Reduced physical activity is associ- ated with a higher frequency of comorbidities and lower quality of life. Physical interventions can improve quality of life. In most cases, physical exercise did not increase seizure frequency. CONCLUSION: There is no reason to forbid persons with epilepsy to participate in sports; they should, rather, be encour- a particular type of sport should, however, be taken individually in each case.
CRIS-Team Scopus Importer:2020-02-11

Sport und MS. Einfluss von physischer Aktivität auf die Immunregulation. - Waschbisch, Anne; Wenny, Ingrid; Tallner, Alexander; Pfeifer, Klaus; Mäurer, Mathias (Der Nervenarzt, 2010)

SRD5A3-CDG: Twins with an intragenic tandem duplication - Rieger, Melissa; Türk, Matthias; Kraus, Cornelia; Uebe, Steffen; Ekici, Arif Bülent; Krumbiegel, Mandy; Huchzermeyer, Cord; Wiesmann da Silva Reis, André; Thiel, Christian (European Journal of Medical Genetics, 2022)
Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare metabolic disease mainly characterized by psychomotor disability, visual impairment, and variable eye malformations caused by bi-allelic pathogenic variants in SRD5A3. So far, only 23 distinct mutations were described. Exome sequencing in 32-year old monozygotic male twins revealed only the heterozygous splice variant c.562+3delG in SRD5A3, but no second variant. The twins presented with psychomotor deficit and a complex eye disease including retinal dystrophy, pallor of the papilla, nystagmus, and strabismus suggestive of SRD5A3-CDG. Only when applying exome-based copy number analysis, we identified as a second compound heterozygous variant a previously not reported tandem duplication of exons 2–4 in SRD5A3. Next to the typical skeletal anomalies of SRD5A3-CDG such as kyphosis and scoliosis, extension deficits of the proximal interphalangeal (PIP) joints IV were observed. Since similar contractures were described once in a patient with SRD5A3-CDG, we suggest that this rare symptom is possibly associated with SRD5A3-CDG. Our findings further expand the mutational and clinical spectrum of SRD5A3-CDG and emphasize the importance of an intragenic copy number analysis in patients with strong clinical suspicion of SRD5A3-CDG and only one detectable sequence variant.
CRIS-Team Scopus Importer:2022-04-15
Keywords: CDG; Exon duplication; SRD5A3

Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke - Winkel, Per; Bath, Philip M.; Gluud, Christian; Lindschou, Jane; Van Der Worp, H. Bart; Macleod, Malcolm R.; Szabo, Istvan; Durand-Zaleski, Isabelle; Schwab, Stefan (Trials, 2017)
BACKGROUND: Cooling may reduce infarct size and improve neurological outcomes in patients with ischaemic stroke. In phase II trials, cooling awake patients with ischaemic stroke has been shown to be feasible and safe, but the effects in functional outcomes has not yet been investigated in an adequately sized randomised clinical trial. METHODS/DESIGN: The EuroHYP-1 trial is a multinational, randomised, superiority phase III clinical trial with masked outcome assessment testing the benefits and harms of therapeutic cooling in awake adult patients with acute ischaemic stroke. The outcomes dealt with here include the primary outcome the Rankin score (mRS) at day 91 +/-14 days after randomisation. The secondary and exploratory outcomes at day 91 +/-14 days unless otherwise stated encompassing: (1) death or dependency, defined as mRS score > 2; (2) death; (3) National Institutes of Health Stroke Score; (4) brain infarct size at 48 +/-24 hours; (5) EQ-5D-5 L score, and (6) WHODAS 2.0 score. Other outcomes are: the primary safety outcome serious adverse events; and the incremental cost-effectiveness, and cost utility ratios. The analysis sets include (1) the intention-to-treat population, and (2) the per protocol population. The sample size is estimated to 800 patients (5% type 1 and 20% type 2 errors). All analyses are adjusted for the protocol-specified stratification variables (nationality of centre), and the minimisation variables. In the analysis, we use ordinal regression (the primary outcome), logistic regression (binary outcomes), general linear model (continuous outcomes), and the Poisson or negative binomial model (rate outcomes). DISCUSSION: Major adjustments compared with the original statistical analysis plan encompass: (1) adjustment of analyses by nationality; (2) power calculations for the secondary outcomes; (3) to address the multiplicity problem using of a fixed-sequence testing procedure starting with the primary outcome followed by the secondary outcomes ordered according to falling power; (4) assignment of worst possible score to patients who are not alive at the planned date of measurement of the continuous scores; (5) improved imputations; (6) outline of a supplementary exploratory analysis of the temperature measurements and time to death; and (7) substantial reduction of sample size. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT01833312 . 4 April 2013.
EVALuna2:33128

Status epilepticus-Detection and treatment in the intensive care unit - Reindl, Caroline; Madzar, Dominik; Hamer, Hajo (Der Nervenarzt, 2022)
Status epilepticus is characterized by persistent or repetitive seizures which, without successful treatment, can lead to neuronal damage, neurological deficits and death of the patient. While status epilepticus with motor symptoms can usually be clinically diagnosed, nonconvulsive status epilepticus is often clinically overlooked due to its ambiguous semiology, so that electroencephalography (EEG) recording is necessary. The treatment of status epilepticus is performed in four treatment steps, whereby a difficult to treat status epilepticus is present from the third step at the latest and intensive medical care of the patient is necessary. Timely initiation of treatment and sufficient dosage of anticonvulsive medication are decisive for the success of treatment. There is little evidence for the "late " stages of treatment. Intensive medical measures pose the risk of complications that worsen the prognosis. Especially in nonconvulsive status epilepticus, the use of anesthetics must be weighed against possible complications of mechanical ventilation.
CRIS-Team WoS Importer:2023-01-13

Status epilepticus in patients with glioblastoma: Clinical characteristics, risk factors, and epileptological outcome - Stritzelberger, Jenny; Gesmann, Anna; Fuhrmann, Imke; Balk, Stefanie; Reindl, Caroline; Madzar, Dominik; Uhl, Martin; Welte, Tamara; Brandner, Sebastian; Eisenhut, Felix; Dörfler, Arnd; Coras, Roland; et al. (Seizure-European Journal of Epilepsy, 2023)
Purpose: Epilepsy is a common comorbidity in patients with glioblastoma, however, clinical data on status epilepticus (SE) in these patients is sparse. We aimed to investigate the risk factors associated with the occurrence and adverse outcomes of SE in glioblastoma patients. Methods: We retrospectively analysed electronic medical records of patients with de-novo glioblastoma treated at our institution between 01/2006 and 01/2020 and collected data on patient, tumour, and SE characteristics. Results: In the final cohort, 292/520 (56.2 %) patients developed seizures, with 48 (9.4 % of the entire cohort and 16.4 % of patients with epilepsy, PWE) experiencing SE at some point during the course of their disease. SE was the first symptom of the tumour in 6 cases (1.2 %) and the first manifestation of epilepsy in 18 PWE (6.2 %). Most SE episodes occurred postoperatively (n = 37, 77.1 %). SE occurrence in PWE was associated with postoperative seizures and drug-resistant epilepsy. Adverse outcome (in-house mortality or admission to palliative care, 10/48 patients, 20.8 %), was independently associated with higher status epilepticus severity score (STESS) and Charlson Comorbidity Index (CCI), but not tumour progression. 32/48 SE patients (66.7 %) were successfully treated with first- and second-line agents, while escalation to third-line agents was successful in 6 (12.5 %) cases. Conclusion: Our data suggests a link between the occurrence of SE, postoperative seizures, and drug-resistant epilepsy. Despite the dismal oncological prognosis, SE was successfully treated in 79.2 % of the cases. Higher STESS and CCI were associated with adverse SE outcomes.
CRIS-Team Scopus Importer:2023-09-29
Keywords: Glioblastoma; Status epilepticus; Status epilepticus severity score (STESS)

Status of clinical research in neurology in Germany—A national survey - Lohmann, Lisa; Lammerskitten, Anna; Korsen, Melanie; Dodel, Richard; Gaul, Charly; Hamer, Hajo; Kleineberg, Nina N.; Ludolph, Albert C.; Mayer, Geert; Poli, Sven; Saur, Dorothee; Steinhoff, Bernhard J.; et al. (European Journal of Neurology, 2021)
Background and purpose: To provide an overview on the status of clinical research in neurology in Germany. Methods: German university hospitals, nonuniversity hospitals, and neurological medical practices were surveyed regarding their clinical research activities during the period 2013 to 2017. Results: Fifty percent of university hospitals, 10.6% of nonuniversity hospitals, and 5.2% of medical practices in Germany responded to our questionnaire. More than 80% of the clinical studies conducted have been phase III/IV and noninterventional trials (NISs), whereas <1% have been phase I and 3.5% investigator-initiated trials (IITs). University hospitals have conducted most of the phase II–IV trials. NISs have been predominantly performed by medical practices. Fifty-six percent of the university hospitals and less of the nonuniversity institutions confirmed the implementation of standard operating procedures (SOPs). In university hospitals, on average, 11 physicians had acquired a good clinical practice certificate. Overall, 43% of all trials have been performed in neuroimmunology. Conclusions: The status of clinical research in neurology in Germany is predominated by NISs and late-phase trials, potentially due to a general lack of easily accessible funding, which leads to a highly competitive environment and fewer opportunities to perform early-phase clinical trials as well as IITs. Our results indicate that there is substantial need for structured support for creating and implementing SOPs to maintain quality standards and guarantee uniformity of performance. This survey assessed many aspects of clinical research and serves as guidance for providing ideas for structured improvement of clinical research in neurology in Germany.
CRIS-Team Scopus Importer:2021-03-19
Keywords: clinical research; Germany; good clinical practice; survey

Stem cell quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-β signaling in an animal model of huntington disease - Kandasamy, Mahesh; Couillard-Despres, Sebastien; Raber, Kerstin A.; Stephan, Michael; Lehner, Bernadette; Winner, Beate; Kohl, Zacharias; Rivera, Francisco J.; Nguyen, Huu Phuc; Riess, Olaf; Bogdahn, Ulrich; Winkler, Jürgen; et al. (Journal of Neuropathology and Experimental Neurology, 2010)
Cellular proliferation, differentiation, integration, and survival within the adult neural stem cell niche are altered under pathological conditions, but the molecular cues regulating the biology of this niche are mostly unknown. We examined the hippocampal neural stem cell niche in a transgenic rat model of Huntington disease. In this model, progressive cognitive deficits develop at the age of 9months, suggesting possible hippocampal dysfunction. We found a disease-associated progressive decline in hippocampal progenitor cell proliferation accompanied by an expansion of the pool of 5-bromo-2-deoxyuridine label-retaining Sox-2-positive quiescent stem cells in the transgenic animals. Increments in quiescent stem cells occurred at the expense of cAMP-responsive element-binding protein-mediated neuronal differentiation and survival. Because elevated levels of transforming growth factor-β1 (TGF-β1) impair neural progenitor proliferation, we investigated hippocampal TGF-β signaling and determined that TGF-β1 induces the neural progenitors to exit the cell cycle. Although phospho-Smad2, an effector of TGF-β signaling, is normally absent in subgranular stem cells, it accumulated progressively in Sox2/glial fibrillary acidic protein-expressing cells of the subgranular zone in the transgenic rats. These results indicate that alterations in neurogenesis in transgenic Huntington disease rats occur in successive phases that are associated with increasing TGF-β signaling. Thus, TGF-β1 signaling seems to be a crucial modulator of neurogenesis in Huntington disease and may represent a target for future therapy. © 2010 by the American Association of Neuropathologists, Inc.
CRIS-Team Scopus Importer:2024-08-07
Keywords: Adult neurogenesis; Huntington disease; Neural stem cells; Neuronal differentiation; Proliferation; Transforming growth factor-β

Stent-Assisted Coiling Using Leo+ Baby Stent: Immediate and Mid-Term Results - Lücking, Hannes; Struffert, Tobias; Gölitz, Philipp; Engelhorn, Tobias; Brandner, Sebastian; Kuramatsu, Joji; Lang, Stefan; Schmidt, Manuel; Dörfler, Arnd (Clinical Neuroradiology, 2020)
Background: Stent-assisted coiling is well-established for treatment of cerebral aneurysms. The technique enables treatment of wide-neck, bifurcation and recurrent aneurysms with high packing rates. While described in extenso for laser cut stents, the results of patients treated with the Leo+ Baby (Balt, Montmorency, France) braided microstent are presented. Material and Methods: Patients were included if treated with a Leo+ Baby and with digital subtraction angiography (DSA) follow-up available of at least 6 months. Data were evaluated for successful deployment, aneurysm occlusion according to the modified Raymond-Roy classification (MRRC), stent patency and procedure-related morbidity and mortality. Results: A total of 81 patients were included and Leo+ Baby deployment was successful in all cases. Coils were used in 80 cases. In 1 case 2 stents were used stent-in-stent without additional coiling. Initial aneurysm occlusion rates were MRRCi1 51.9%, MRRCi2 11.1%, MRRCi3a 24.7% and MRRCi3b 12.3%. Occlusion rates after 6 months were MRRC6m1 78.9%, MRRC6m2 3.9%, MRRC6m3a 6.6% and MRRC6m3b 10.5%. Procedure-related morbidity was 1 case of acute stent thrombosis successfully treated with tirofiban and 1 case with transient hemiparesis due to stent thrombosis after 4 months. There was 1 case of coil-associated subarachnoid hemorrhage (SAH) which caused prolonged hospitalization. No procedure-related mortality was observed. Conclusion: The results confirm that stent-assisted coiling with the Leo+ Baby stent is safe and efficient for treatment of wide neck or recurrent cerebral aneurysms. Spontaneous progressive aneurysm occlusion over 6 months supports the theory of considerable flow-modulating effects of Leo+ Baby.
CRIS-Team Scopus Importer:2020-05-15
Keywords: Bifurcation aneurysm; Braided stent; Cerebral aneurysm; Coiling; Low profile stent

Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia - Winner, Beate; Rizo Garza, Tania; Gebhardt, Lisa; Riedlberger, Julia; Eberhardt, Esther; Fester, Lars; Alansary, Dalia; Winkler, Jürgen; Turan, Sören; Arnold, Philipp; Niemeyer, Barbara; Fischer, Michael (2022)
Pathogenic variants in SPAST, the gene coding for spastin, are the single most common cause of hereditary spastic paraplegia, a progressive motor neuron disease. Spastin regulates key cellular functions, including microtubule-severing and endoplasmic reticulum-morphogenesis. However, it remains unclear how alterations in these cellular functions due to SPAST pathogenic variants result in motor neuron dysfunction. Since spastin influences both microtubule network and endoplasmic reticulum structure, we hypothesized that spastin is necessary for the regulation of Ca2+ homeostasis via store-operated calcium entry. Here, we show that the lack of spastin enlarges the endoplasmic reticulum and reduces store-operated calcium entry. In addition, elevated levels of different spastin variants induced clustering of STIM1 within the endoplasmic reticulum, altered the transport of STIM1 to the plasma membrane and reduced store-operated calcium entry, which could be rescued by exogenous expression of STIM1. Importantly, store-operated calcium entry was strongly reduced in induced pluripotent stem cell-derived neurons from hereditary spastic paraplegia patients with pathogenic variants in SPAST resulting in spastin haploinsufficiency. These neurons developed axonal swellings in response to lack of spastin. We were able to rescue both store-operated calcium entry and axonal swellings in SPAST patient neurons by restoring spastin levels, using CRISPR/Cas9 to correct the pathogenic variants in SPAST. These findings demonstrate that proper amounts of spastin are a key regulatory component for store-operated calcium entry mediated Ca2+ homeostasis and suggest store-operated calcium entry as a disease relevant mechanism of spastin-linked motor neuron disease.Rizo et al. use iPSC-derived neurons from patients to investigate how pathogenic variants in SPAST give rise to hereditary spastic paraplegia. They show that dysregulation of spastin, a microtubule- and ER-remodelling protein encoded by SPAST, alters the dynamics of the ER, resulting in aberrant Ca2+ regulation.
Keywords: spastin; STIM1; microtubules; endoplasmic reticulum; store-operated calcium entry

Stress, seizures, and epilepsy: Patient narratives - Lang, Johannes D.; Taylor, David C.; Kasper, Burkhard (Epilepsy and Behavior, 2018)
In epilepsy, individual seizures can be triggered by a variety of external and internal stimuli. One of the most common trigger factors reported by patients is stress. However prevalent, stress-related triggering of episodes seems underappreciated in epilepsy for various reasons, and its misinterpretation often leads to other diagnoses, e.g., psychogenic nonepileptic seizures (PNES) or normal reactions. This article illustrates the significant role of stress as a seizure-provoking factor by referring to nine patient narratives. From this perspective, it appears that there are characteristic patterns of stress triggering, e.g., stress-induced sleep disruption, forms of acute stress, or relaxation after stress. Sometimes seizures are mistaken as symptoms of stress. Patient narratives contain interesting clues relating reports about stress and seizure histories to different epilepsy syndromes as well as nonepileptic episodes in a way that can strongly support the diagnostic process. A narrative approach is particularly valuable in this context. Therefore, accounts of stress triggering in seizures and other episodes should not be neglected, but rather taken seriously, sought and actively explored as a crucial element when taking clinical histories in patients with episodic attacks.
EVALuna2:201938

Stresswahrnehmung, Persönlichkeitsmerkmale, psychosoziale Beeinträchtigungen und Bewältigungsstrategien bei Patienten mit chronisch-entzündlichen Darmerkrankungen - Petruo, Vanessa A.; Krauss, Ekaterina; Kleist, Anika; Hardt, Juliane; Hake, Karsten; Peirano, Julia; Krause, Thomas; Ehehalt, Robert; von Arnauld de la Perriére, Philipp; Büning, Jürgen; Treml, Oliver; Krauss, Norbert; et al. (Zeitschrift für Gastroenterologie, 2019)
BACKGROUND AND AIMS: This study examined differences in personality, psychological distress, and stress coping in inflammatory bowel disease (IBD) depending on type of disease and disease activity. We compared patients suffering from Crohn's disease (CD) and ulcerative colitis (UC) with controls. While the literature is replete with distinctive features of the pathogenesis of IBD, the specific differences in psychological impairments are not well studied. METHODS: In this German national multicenter study, participants were recruited from 32 centers. Two hundred ninety-seven questionnaires were included, delivering vast information on disease status and psychological well-being based on validated instruments with a total of 285 variables. RESULTS: CD patients were more affected by psychological impairments than patients suffering from UC or controls. Importantly, patients with active CD scored higher in neuroticism (p < 0.01), psychological distress (p < 0.001) and maladaptive stress coping (escape, p = 0.03; rumination, p < 0.03), but less need for social support (p = 0.001) than controls. In contrast, patients suffering from active UC showed psychological distress (p < 0.04) and maladaptive coping (avoidance, p < 0.03; escape, p = 0.01). Patients in remission seemed to be less affected. In particular, patients with UC in remission were not inflicted by psychological impairments. The group of CD patients in remission however, showed insecurity (p < 0.01) and paranoid ideation (p = 0.04). CONCLUSIONS: We identified specific aspects of psychological impairment in IBD depending on disease and disease activity. Our results underscore the need for psychological support and treatment particularly in active CD.
CRIS-Team Scopus Importer:2019-05-02

Stride Segmentation During Free Walk Movements Using Multi-dimensional Subsequence Dynamic Time Warping on Inertial Sensor Data - Barth, Jens; Oberndorfer, Cäcilia; Pasluosta, Cristian Federico; Schülein, Samuel; Gaßner, Heiko; Reinfelder, Samuel; Kugler, Patrick; Schuldhaus, Dominik; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (Sensors, 2015)
UnivIS-Import:2015-04-14:Pub.2015.tech.IMMD.IMMD5.stride
Keywords: inertial sensors; stride segmentation; accelerometer; gyroscope; dynamic time warping; free walk; gait analysis; Parkinsons disease; geriatric patients; movement impairments

STROKE CARE PERFORMANCE MEASURES DURING THE COVID-19 PANDEMIC - OVER THE WAVES - Gaßmann, Luise; Haupenthal, David; Kallmünzer, Bernd; Köhn, Julia; Schwab, Stefan; Kuramatsu, Joji (INTERNATIONAL JOURNAL OF STROKE, 2022)
CRIS-Team WoS Importer:2022-11-18

STROKE SIMULATION TRAINING IN A RURAL TELESTROKE NETWORK SETTING IN NORTHERN BAVARIA (STENO): PRELIMINARY RESULTS - Volbers, Bastian; Schwab, Stefan (INTERNATIONAL JOURNAL OF STROKE, 2022)
CRIS-Team WoS Importer:2022-11-18

Stroma cells promote a S100A8/A9(high) subset of chemoresistant AML blasts with distinct metabolic features in a Jak/STAT-dependent manner - Böttcher, Martin; Panagiotidis, Konstantinos; Mentz, K.; Popp, Sebastian; Geyh, S.; Jaeger, P.; Schroeder, T.; Bruns, Heiko; Mackensen, Andreas; Mougiakakos, Dimitrios; Völkl, Simon (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-10-23

Structural and functional properties of meprin β metalloproteinase with regard to cell signaling - Li, Wenjia; Lueckstaedt, Wiebke; Wöhner, Birte; Bub, Simon; Schulz, Antonia; Socher, Eileen; Arnold, Philipp (Biochimica Et Biophysica Acta-Molecular Cell Research, 2021)
The metalloproteinase meprin β plays an important role during collagen I deposition in the skin, mucus detachment in the small intestine and also regulates the abundance of different cell surface proteins such as the interleukin-6 receptor (IL-6R), the triggering receptor expressed on myeloid cells 2 (TREM2), the cluster of differentiation 99 (CD99), the amyloid precursor protein (APP) and the cluster of differentiation 109 (CD109). With that, regulatory mechanisms that control meprin β activity and regulate its release from the cell surface to enable access to distant substrates are increasingly important. Here, we will summarize factors that alternate meprin β activity and thereby regulate its proteolytic activity on the cell surface or in the supernatant. We will also discuss cleavage of the IL-6R and TREM2 on the cell surface and compare it to CD109. CD109, as a substrate of meprin β, is cleaved within the protein core thereby releasing defined fragments from the cell surface. At last, we will also summarize the role of proteases in general and meprin β in particular in substrate release on extracellular vesicles.
Keywords: meprin β; CD109; proteolysis; metalloproteases; substrates; extracellular vesicles

Structural Connectivity Patterns of Side Effects Induced by Subthalamic Deep Brain Stimulation for Parkinson's Disease - Kohl, Zacharias; Strotzer, Quirin D.; Kohl, Zacharias; Anthofer, Judith M.; Faltermeier, Rupert; Schmidt, Nils O.; Torka, Elisabeth; Greenlee, Mark W.; Fellner, Claudia; Schlaier, Juergen R.; Beer, Anton L. (Brain Connectivity, 2022)
Background: Tractography based on diffusion-weighted magnetic resonance imaging (DWI) models the structural connectivity of the human brain. Deep brain stimulation (DBS) targeting the subthalamic nucleus is an effective treatment for advanced Parkinson's disease, but may induce adverse effects. This study investigated the relationship between structural connectivity patterns of DBS electrodes and stimulation-induced side effects. Materials and Methods: Twenty-one patients with Parkinson's disease treated with bilateral subthalamic DBS were examined. Overall, 168 electrode contacts were categorized as inducing or noninducing depending on their capability for inducing side effects such as motor effects, paresthesia, dysarthria, oculomotor effects, hyperkinesia, and other complications as assessed during the initial programming session. Furthermore, the connectivity of each contact with target regions was evaluated by probabilistic tractography based on DWI. Finally, stimulation sites and structural connectivity patterns of inducing and noninducing contacts were compared. Results: Inducing contacts differed across the various side effects and from those mitigating Parkinson's symptoms. Although contacts showed a largely overlapping spatial distribution within the subthalamic region, they could be distinguished by their connectivity patterns. In particular, inducing contacts were more likely connected with supplementary motor areas (hyperkinesia, dysarthria), frontal cortex (oculomotor), fibers of the internal capsule (paresthesia), and the basal ganglia-thalamo-cortical circuitry (dysarthria). Discussion: Side effects induced by DBS seem to be associated with distinct connectivity patterns. Cerebellar connections are hardly associated with side effects, although they seem relevant for mitigating motor symptoms in Parkinson's disease. A symptom-specific, connectivity-based approach for target planning in DBS may enhance treatment outcomes and reduce adverse effects. Tractography based on diffusion-weighted magnetic resonance imaging has become a prominent technique for investigating the connectivity of human brain networks in vivo. However, the relationship between structural connections and brain function is still hardly known. The present study examined the relationship between adverse behavioral effects induced by deep brain stimulation (DBS) and tractography patterns in individual brains. The results suggest that DBS-based side effects depend on the structural connections of electrode contacts rather than their location. Network-based target planning in DBS may improve treatment by avoiding side effects. Moreover, the adopted approach may serve as a paragon for investigating structure/function relationships.
CRIS-Team Scopus Importer:2022-06-03
Keywords: Deep brain stimulation; Diffusion tractography; Parkinson's disease; Structure/function relationship; Subthalamic nucleus

Subliminal galvanic-vestibular stimulation recalibrates the distorted visual and tactile subjective vertical in right-sided stroke - Oppenlaender, Karin; Utz, Kathrin S.; Reinhart, Stefan; Keller, Ingo; Kerkhoff, Georg; Schaadt, Anna-Katharina (Neuropsychologia, 2015)
Stroke of the right cerebral hemisphere often causes deficits in the judgement of the subjective visual vertical (SVV) and subjective tactile vertical (STV) which are related to central vestibular functioning. Clinically, deficits in the SVV/STV are linked to balance problems and poor functional outcome. Galvanic Vestibular Stimulation (GVS) is a non-invasive, save stimulation technique that induces polarity-specific changes in the cortical vestibular systems. Subliminal GVS induces imperceptible vestibular stimulation without unpleasant side effects. Here, we applied bipolar subliminal GVS over the mastoids (mean intensity: 0.7 mA, 20 min duration per session) to investigate its online-influence on constant errors, difference thresholds and range values in the SVV and STV. 24 patients with subacute, single, unilateral right hemisphere stroke were studied and assigned to two patient groups (impaired vs. normal in the SVV and STV) on the basis of cut-off scores from healthy controls. Both groups performed these tasks under three experimental conditions on three different days: a) sham GVS where electric current was applied only for 30s and then turned off, b) left-cathodal GVS and c) right-cathodal GVS, for a period of 20 min per session. Left-cathodal GVS, but not right-cathodal GVS significantly reduced all parameters in the SVV. Concerning STV GVS also reduced constant error and range numerically, though not significantly. These effects occurred selectively in the impaired patient group. In conclusion, we found that GVS rapidly influences poststroke verticality deficits in the visual and tactile modality, thus highlighting the importance of the vestibular system in the multimodal elaboration of the subjective vertical.
EVALuna2:22409

Successful Pharmacologic Treatment of Self-Bloodletting with Factitious Chronic Anemia (Lasthénie de Ferjol Syndrome) with High-Dose Serotonergic Medication: A Case Report - Mestermann, Stefan; Rudtke, Laura; Brazdis, Razvan Marius; Tsaktanis, Thanos; Kornhuber, Johannes; Thürauf, Norbert (Behavioral Sciences, 2024)
Self-induced bloodletting (SBL) is a very rare form of self-injury (SI) seen primarily in adolescents and young adults with personality and eating disorders. It can result in complications like malaise, fatigue, or iron-deficiency anemia (Lasthénie de Ferjol syndrome, LFS), and poses a risk of accidental death or suicide. The condition often goes undetected due to patient concealment. There is no specific treatment established, and pharmacological strategies remain uncertain. We discuss the case of a 22-year-old female patient treated at our Psychiatry and Psychotherapy Department following a suicide attempt via SBL. She self-administered a venous cannula, losing 1.5 L of blood. Diagnosed with iron-deficiency anemia (LFS), she was initially treated with mirtazapine, risperidone, lithium, and later off-label high-dose clomipramine (300 mg/d). Clomipramine significantly reduced her SBL and suicidal thoughts, and her hemoglobin levels re-normalized under iron-substitution therapy. Despite improvement and later discharge, she attempted suicide by SBL again three months later, having stopped clomipramine due to adverse side effects. High-dose escitalopram was administered, leading to a decrease and eventual cessation of her SBL urges. This case demonstrates that patients with SBL/LFS can benefit from high-dose clomipramine or escitalopram. Despite its rarity, the consideration of high-dose serotonergic antidepressants is crucial in psychiatric diagnostics and treatment for patients affected by SBL/LFS.
CRIS-Team Scopus Importer:2024-04-05
Keywords: clomipramine; escitalopram; Lasthénie de Ferjol syndrome; mental health; self-bloodletting; self-harm; self-injury behavior

SUDEP kompakt – praxisrelevante Erkenntnisse und Empfehlungen zum plötzlichen, unerwarteten Tod bei Epilepsie - Surges, Rainer; Conrad, Stefan; Hamer, Hajo; Schulze-Bonhage, Andreas; Staack, Anke M.; Steinhoff, Bernhard J.; Strzelczyk, Adam; Trinka, Eugen (Der Nervenarzt, 2021)
Sudden unexpected death in epilepsy (SUDEP) is the sudden and unexpected death of an epilepsy patient, which occurs under benign circumstances without evidence of typical causes of death. SUDEP concerns all epilepsy patients. The individual risk depends on the characteristics of the epilepsy and seizures as well as on living conditions. Focal to bilateral and generalized tonic-clonic seizures (TCS), nocturnal seizures and lack of nocturnal supervision increase the risk. Most SUDEP cases are due to a fatal cascade of apnea, hypoxemia and asystole in the aftermath of a TCS. Two thirds of SUDEP cases in unsupervised epilepsy patients with TCS could probably be prevented. Wearables can detect TCS and alert caregivers. SUDEP information is desired by most patients and relatives, has a favorable impact on treatment adherence and behavior and has no negative effects on mood and quality of life. Recommendations of the committee on patient safety of the German Society of Epileptology: the ultimate treatment goal is seizure freedom. If this cannot be achieved, control of TCS should be sought. All epilepsy patients and their relatives should be informed about SUDEP and risk factors. Patients and relatives should be informed about measures to counteract the elevated risk and imminent SUDEP. The counselling should be performed during a face-to-face discussion, at the time of first diagnosis or during follow-up visits. The counselling should be documented. Wearables for TCS detection can be recommended. If TCS persist, therapeutic efforts should be continued. The bereaved should be contacted after a SUDEP.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Asystole; Counselling; Premature mortality; Sudden death in epilepsy; Wearables

Sulfasalazine impacts on ferroptotic cell death and alleviates the tumor microenvironment and glioma-induced brain edema. - Sehm, Tina; Fan, Zheng; Ghoochani, Ali; Rauh, Manfred; Engelhorn, Tobias; Minakaki, Georgia; Dörfler, Arnd; Klucken, Jochen; Buchfelder, Michael; Eyüpoglu, Ilker Yasin; Savaskan, Nicolai (Oncotarget, 2016)
The glutamate transporter xCT (SCL7a11, system Xc-, SXC) is an emerging key player in glutamate/cysteine/glutathione homeostasis in the brain and in cancer. xCT expression correlates with the grade of malignancy. Here, we report on the use of the U.S. Food and Drug Administration and EMA-approved xCT inhibitor, sulfasalazine (SAS) in gliomas. SAS does not affect cell viability in gliomas at concentrations below 200 µM. At higher concentrations SAS becomes gliomatoxic. Mechanistically SAS inhibits xCT and induces ferroptotic cell death in glioma cells. There is no evidence for impact on autophagic flux following SAS application. However, SAS can potentiate the efficacy of the standard chemotherapeutic and autophagy-inducing agent temozolomide (Temcat, Temodal or Temodar®). We also investigated SAS in non-transformed cellular constituents of the brain. Neurons and brain tissue are almost non-responding to SAS whereas isolated astrocytes are less sensitive towards SAS toxicity compared to gliomas. In vivo SAS treatment does not affect experimental tumor growth and treated animals revealed comparable tumor volume as untreated controls. However, SAS treatment resulted in reduced glioma-derived edema and, hence, total tumor volume burden as revealed by T2-weighted magnetic resonance imaging. Altogether, we show that SAS can be utilized for targeting the glutamate antiporter xCT activity as a tumor microenvironment-normalizing drug, while crucial cytotoxic effects in brain tumors are minor.

Supratentorial lesions contribute to trigeminal neuralgia in multiple sclerosis - Fröhlich, Katharina; Winder, Klemens; Linker, Ralf; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Hilz, Max-Josef; Schwab, Stefan; Seifert, Frank (Cephalalgia, 2018)
Background It has been proposed that multiple sclerosis lesions afflicting the pontine trigeminal afferents contribute to trigeminal neuralgia in multiple sclerosis. So far, there are no imaging studies that have evaluated interactions between supratentorial lesions and trigeminal neuralgia in multiple sclerosis patients. Methods We conducted a retrospective study and sought multiple sclerosis patients with trigeminal neuralgia and controls in a local database. Multiple sclerosis lesions were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed a voxel-wise subtraction analysis. Secondly, we conducted a voxel-wise non-parametric analysis using the Liebermeister test. Results From 12,210 multiple sclerosis patient records screened, we identified 41 patients with trigeminal neuralgia. The voxel-wise subtraction analysis yielded associations between trigeminal neuralgia and multiple sclerosis lesions in the pontine trigeminal afferents, as well as larger supratentorial lesion clusters in the contralateral insula and hippocampus. The non-parametric statistical analysis using the Liebermeister test yielded similar areas to be associated with multiple sclerosis-related trigeminal neuralgia. Conclusions Our study confirms previous data on associations between multiple sclerosis-related trigeminal neuralgia and pontine lesions, and showed for the first time an association with lesions in the insular region, a region involved in pain processing and endogenous pain modulation.
EVALuna2:34503

Surgical hematoma evacuation of cortical intracerebral hemorrhage ≥10 ml reduces risk of subsequent epilepsy by more than 70%: A retrospective monocenter study - Welte, Tamara; Steidl, Josephine; Stritzelberger, Jenny; Gollwitzer, Stephanie; Lang, Johannes; Reindl, Caroline; Rampp, Stefan; Maslarova, Anna; Brandner, Sebastian; Hock, Stefan; Mühlen, Iris; Dörfler, Arnd; et al. (European Journal of Neurology, 2022)
Aim: The aim of this study was to re-evaluate risk factors for post-ICH epilepsy (PICHE) and examine the impact of surgical hematoma evacuation on epilepsy development after ICH. Background and purpose: Epilepsy is a common complication after intracerebral hemorrhage (ICH). Information on risk factors is still scarce and the role of ICH evacuation remains uncertain. Methods: We retrospectively included patients with spontaneous ICH treated in our hospital in 2006–2019. Patients' medical records were analyzed. In addition, mailed questionnaires and telephone interviews were used to complete the dataset. Uni- and multivariable hazard ratios (HRs) were applied to investigate risk factors for PICHE and the impact of surgical ICH evacuation. Results: Among 587 ICH patients available for analyses, 139 (23.7%) developed PICHE (mean follow-up 1795 ± 1378 days). The median time of epilepsy onset was 7 months after ICH (range 1–132 months). Risk factors associated with PICHE were cortical hemorrhage (multivariable HR 1.65 [95% CI 1.14–2.37]; p = 0.008), ICH volume > 10 ml (multivariable HR 1.91 [95% CI 1.33–2.73]; p < 0.001) and acute symptomatic seizures (multivariable HR 1.81 [95% CI 1.20–2.75]; p = 0.005). Patients with cortical ICH > 10 ml who underwent surgical hematoma evacuation were less likely to develop epilepsy than those with conservative treatment alone (multivariable HR 0.26 [95% CI 0.08–0.84]; p = 0.025). Conclusions: Post-ICH epilepsy is frequent and predicted by large cortical ICH and acute symptomatic seizures. Hematoma evacuation reduced the risk of PICHE by more than 70% in patients with large cortical ICH. This finding could be considered in the clinical decision making on the acute treatment of ICH.
CRIS-Team Scopus Importer:2022-10-21
Keywords: CAVE score; hematoma evacuation; intracerebral hemorrhage; post-stroke epilepsy

Surgical management of epilepsy due to cerebral cavernomas using neuronavigation and intraoperative MR imaging - Sommer, Bjoern; Kasper, Burkhard S.; Coras, Roland; Blümcke, Ingmar; Hamer, Hajo; Buchfelder, Michael; Roessler, Karl (Neurological Research, 2013)
Objectives: Cure from seizures due to cavernomas might be surgically achieved dependent on both, the complete removal of the cavernoma as well as its surrounding hemosiderin rim. High field intraoperative MRI imaging (iopMRI) and neuronavigation might play a crucial role to achieve both goals. We retrospectively investigated the long-term results and impact of intraoperative 1.5T MRI (iopMRI) and neuronavigation on the completeness of surgical removal of a cavernous malformation (CM) and its perilesional hemosiderin rim as well as reduction of surgical morbidity. Methods: 26 patients (14 female, 12 male, mean age 39.1 years, range: 17-63 years) with CM related epilepsy were identified. Eighteen patients suffered from drug resistant epilepsy (69.2%). Mean duration of epilepsy was 11.9 years in subjects with drug resistant epilepsy (n = 18) and 0.3 years in subjects presenting with first-time seizures (n = 8). We performed 24 lesionectomies and two lesionectomies combined with extended temporal resections. Seven lesions were located extratemporally. Results: Complete CM removal was documented by postsurgical MRI in all patients. As direct consequence of iopMRI, refined surgery was necessary in 11.5% of patients to achieve complete cavernoma removal and in another 11.5% for complete resection of additional adjacent epileptogenic cortex. Removal of the hemosiderin rim was confirmed by iopMRI in 92% of patients. Two patients suffered from mild (7.7%) and one from moderate (3.8%) visual field deficits. Complete seizure control (Engel class 1A) was achieved in 80.8% of patients with a mean follow-up period of 47.7 months. Discussion: We report excellent long-term seizure control with minimal surgical morbidity after complete resection of CM using our multimodal approach. © W. S. Maney & Son Ltd 2013.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Cavernous hemangioma; Epilepsy outcome; Intraoperative high field MRI; Surgical morbidity

Surgical planning, histopathology findings and postoperative outcome in MR-negative extra-temporal epilepsy using intracranial EEG, functional imaging, magnetoencephalography, neuronavigation and intraoperative MRI. - Maslarova, Anna; Zhao, Yining; Rösch, Julie; Dörfler, Arnd; Coras, Roland; Blümcke, Ingmar; Lang, Johannes; Schmidt, Manuel; Hamer, Hajo; Reindl, Caroline; Welte, Tamara; Rampp, Stefan; et al. (Clinical Neurology and Neurosurgery, 2023)
OBJECTIVE: MRI-negative drug-resistant epilepsy presents a challenge when it comes to surgical planning, and surgical outcome is worse than in cases with an identified lesion. Although increasing implementation of more powerful MRI scanners and artificial intelligence has led to the detection of previously unrecognizable lesions, in some cases even postoperative pathological evaluation of electrographically epileptogenic zones shows no structural alterations. While in temporal lobe epilepsy a standardized resection approach can usually be performed, the surgical management of extra-temporal lesions is always individual. Here we present a strategy for treating patients with extra-temporal MRI-negative epilepsy focus and report our histological findings and patient outcome. METHODS: Patients undergoing epilepsy surgery in the Department of Neurosurgery at the University Hospital Erlangen between 2012 and 2020 were included in the study. Inclusion criteria were: (1) failure to identify a structural lesion on preoperative high-resolution 3 Tesla MRI with a standardized epilepsy protocol and (2) preoperative intracranial EEG (iEEG) diagnostics. RESULTS: We identified 8 patients corresponding to the inclusion criteria. Second look MRI analysis by an experienced neuroradiologist including the most recent analysis algorithm utilized in our clinic revealed a possible lesion in two patients. One of the patients with a clear focal cortical dysplasia (FCD) finding on a second look was excluded from further analysis. Of the other 7 patients, in one patient iEEG was performed with subdural electrodes, whereas the other 6 were evaluated with depth electrodes. MEG was performed preoperatively in all but one patient. An MEG focus was implemented in resection planning in 3 patients. FDG PET was performed in all, but only implemented in one patient. Histopathological evaluation revealed one non-lesional case, 4 cases of FCD and 2 cases with mild developmental malformation. All patients were free from permanent neurological deficits and presented with Engel 1A or 1B outcome on the last follow-up. CONCLUSION: We demonstrate that extra-temporal MRI-negative epilepsy can be treated successfully provided an extensive preoperative planning is performed. The most important diagnostic was stereo-EEG, whereas additional data from MEG was helpful and FDG PET was rarely useful in our cohort.
EVALuna2:522951

Switching the manufacturer of antiepileptic drugs is associated with higher risk of seizures: A nationwide study of prescription data in Germany - Lang, Johannes D.; Kostev, Karel; Onugoren, Muejgan Dogan; Gollwitzer, Stephanie; Graf, Wolfgang; Müller, Tamara; Olmes, David G.; Hamer, Hajo (Annals of Neurology, 2018)
OBJECTIVE: Despite bioequivalence, the exchangeability of antiepileptic drugs in clinical settings is disputed. Therefore, we investigated the risk for recurrent seizures after switching the manufacturer of the same drug in a large German cohort. METHODS: Anonymous patient data from practice neurologists throughout Germany between 2011 and 2016 were collected using the IMS Disease Analyzer database (QuintilesIMS, Frankfurt, Germany). People with epilepsy were included if at least 2 prescriptions within 360 days and 1 within 180 days prior to the index date were available. The cohort was separated into a seizure group and seizure-free controls. Both groups were matched 1:1 according to age, gender, insurance status, and treating physician. The risk for breakthrough seizures after a manufacturer switch of the same antiepileptic drug was analyzed using multivariate regression models. RESULTS: A total of 3,530 people with epilepsy were included (each group, n = 1,765; age = 53.7 ± 19.8 years). Patients with seizures had switched the drug manufacturer more often than controls (26.8% vs 14.2%; odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.08-1.69, p = 0.009), both from branded to generic (5.5% vs 2.4%; OR = 1.85, 95% CI = 1.30-2.64, p < 0.001) and between generic drugs (14.7% vs 7.1%; OR = 1.45, 95% CI = 1.13-1.87, p = 0.004). INTERPRETATION: In previously seizure-free patients, switching the manufacturer of antiepileptic medications was associated with a higher risk for seizure recurrence. Our retrospective approach does not allow us to determine whether other changes in medical care at the same time could contribute to the recurrence. However, it would be prudent to avoid switching the manufacturer of anticonvulsants in seizure-free patients. Ann Neurol 2018;84:918-925.
EVALuna2:201934

Symmetric tract-based spatial statistics of patients with left versus right mesial temporal lobe epilepsy with hippocampal sclerosis - Mennecke, Angelika; Rösch, Julie; Kasper, Burkhard; Schmidt, Manuel; Roessler, Karl; Coras, Roland; Hamer, Hajo; Dörfler, Arnd; Laun, Frederik Bernd (NeuroReport, 2018)
This study aims to investigate the diffusion metrics of left versus right temporal lobe epilepsy in a well-defined subgroup of patients with mesial temporal lobe epilepsy (mTLE) because of unilateral hippocampal sclerosis while taking into account interhemispheric differences. Eighteen patients with TLE [nine left temporal lobe epilepsy (LTLE) and nine right temporal lobe epilepsy (RTLE)] and a norm group of 36 nonepileptic individuals were scanned with a multiband accelerated diffusion tensor imaging protocol at 3T. The scalar diffusion tensor parameters fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) and, after projection on a symmetric skeleton, their hemispheric difference (dFA, dMD, and dRD) were analyzed using tract-based spatial statistics. In the cluster with significantly (P<0.008) different dFA, dMD, and dRD between right TLE and left TLE, the hemispheric difference in the mean scalar indices (dmFA, dmMD, and dmRD) was assessed and tested for differences using a one-way analysis of variance and for correlation with patient age, seizure onset, or duration of epilepsy using Pearson's correlation. Patients with LTLE showed lower dFA, higher dMD, and higher dRD (P<0.008) compared with patients with RTLE in a cluster including parts of the uncinated and inferior longitudinal fasciculus and the inferior fronto-occipital fasciculus. dmFA, dmMD, and dmRD differed significantly between groups (P<10, corrected) and showed no correlation with patient age, seizure onset, or duration of epilepsy. The exclusion of bilateral interindividual variance through the calculation of the hemispheric difference of the diffusion metrics by the symmetric variant of tract-based spatial statistics allows for a sensitive differentiation of LTLE and RTLE with unilateral hippocampal sclerosis.
EVALuna2:34910

Synaptic dysfunction and extracellular matrix dysregulation in dopaminergic neurons from sporadic and E326K-GBA1 Parkinson’s disease patients - Rosh, Idan; Tripathi, Utkarsh; Hussein, Yara; Rike, Wote Amelo; Djamus, Jose; Shklyar, Boris; Manole, Andreea; Houlden, Henry; Winkler, Jürgen; Gage, Fred H.; Stern, Shani (npj Parkinson’s Disease, 2024)
Parkinson’s disease (PD) is a neurodegenerative disease with both genetic and sporadic origins. In this study, we investigated the electrophysiological properties, synaptic activity, and gene expression differences in dopaminergic (DA) neurons derived from induced pluripotent stem cells (iPSCs) of healthy controls, sporadic PD (sPD) patients, and PD patients with E326K-GBA1 mutations. Our results demonstrate reduced sodium currents and synaptic activity in DA neurons derived from PD patients with E326K-GBA1 mutations, suggesting a potential contribution to PD pathophysiology. We also observed distinct electrophysiological alterations in sPD DA neurons, which included a decrease in synaptic currents. RNA sequencing analysis revealed unique dysregulated pathways in sPD neurons and E326K-GBA1 neurons, further supporting the notion that molecular mechanisms driving PD may differ between PD patients. In agreement with our previous reports, Extracellular matrix and Focal adhesion pathways were among the top dysregulated pathways in DA neurons from sPD patients and from patients with E326K-GBA1 mutations. Overall, our study further confirms that impaired synaptic activity is a convergent functional phenotype in DA neurons derived from PD patients across multiple genetic mutations as well as sPD. At the transcriptome level, we find that the brain extracellular matrix is highly involved in PD pathology across multiple PD-associated mutations as well as sPD.
CRIS-Team Scopus Importer:2024-03-01

Synchronized sensor insoles for clinical gait analysis in home-monitoring applications - Roth, Nils; Martindale, Christine; Gaßner, Heiko; Kohl, Zacharias; Klucken, Jochen; Eskofier, Björn (Walter de Gruyter GmbH, 2018)
Wearable sensor systems are of increasing interest in clinical gait analysis. However, little information about gait dynamics of patients under free living conditions is available, due to the challenges of integrating such systems unobtrusively into a patient’s everyday live. To address this limitation, new, fully integrated low power sensor insoles are proposed, to target applications particularly in home-monitoring scenarios. The insoles combine inertial as well as pressure sensors and feature wireless synchronization to acquire biomechanical data of both feet with a mean timing offset of 15.0 μs. The proposed system was evaluated on 15 patients with mild to severe gait disorders against the GAITRite® system as reference. Gait events based on the insoles’ pressure sensors were manually extracted to calculate temporal gait features such as double support time and double support. Compared to the reference system a mean error of 0.06 s ±0.06 s and 3.89 % ±2.61 % was achieved, respectively. The proposed insoles proved their ability to acquire synchronized gait parameters and address the requirements for home-monitoring scenarios, pushing the boundaries of clinical gait analysi
Keywords: Double support; Home-monitoring; Gait; Synchronization; Insole

?-Synuclein impairs oligodendrocyte progenitor maturation in multiple system atrophy - May, Verena Elisabeth Luise; Ettle, Benjamin; Pöhler, Anne-Maria; Nuber, Silke; Ubhi, Kiren; Rockenstein, Edward; Winner, Beate; Wegner, Michael; Masliah, Eliezer; Winkler, Jürgen (Neurobiology of Aging, 2014)
Multiple system atrophy (MSA), an atypical parkinsonian disorder, is characterized by ?-synuclein (?-syn(+)) cytoplasmatic inclusions in mature oligodendrocytes. Oligodendrocyte progenitor cells (OPCs) represent a distinct cell population with the potential to replace dysfunctional oligodendrocytes. However, the role of OPCs in MSA and their potential to replace mature oligodendrocytes is still unclear. A postmortem analysis in MSA patients revealed ?-syn within OPCs and an increased number of striatal OPCs. In an MSA mouse model, an age-dependent increase of dividing OPCs within the striatum and the cortex was detected. Despite of myelin loss, there was no reduction of mature oligodendrocytes in the corpus callosum or the striatum. Dissecting the underlying molecular mechanisms an oligodendroglial cell line expressing human ?-syn revealed that ?-syn delays OPC maturation by severely downregulating myelin-gene regulatory factor and myelin basic protein. Brain-derived neurotrophic factor was reduced in MSA models and its in vitro supplementation partially restored the phenotype. Taken together, efficacious induction of OPC maturation may open the window to restore glial and neuronal function in MSA.
EVALuna2:4963

?-Synuclein-induced myelination deficit defines a novel interventional target for multiple system atrophy - Ettle, Benjamin; Kerman, Bilal E.; Valera, Elvira; Gillmann, Clarissa; Schlachetzki, Johannes; Reiprich, Simone; Büttner, Christian; Ekici, Arif Bülent; Reis, André; Wegner, Michael; Bäuerle, Tobias; Riemenschneider, Markus J.; et al. (Acta Neuropathologica, 2016)
Multiple system atrophy (MSA) is a rare atypical parkinsonian disorder characterized by a rapidly progressing clinical course and at present without any efficient therapy. Neuropathologically, myelin loss and neurodegeneration are associated with ?-synuclein accumulation in oligodendrocytes, but underlying pathomechanisms are poorly understood. Here, we analyzed the impact of oligodendrocytic ?-synuclein on the formation of myelin sheaths to define a potential interventional target for MSA. Post-mortem analyses of MSA patients and controls were performed to quantify myelin and oligodendrocyte numbers. As pre-clinical models, we used transgenic MSA mice, a myelinating stem cell-derived oligodendrocyte-neuron co-culture, and primary oligodendrocytes to determine functional consequences of oligodendrocytic ?-synuclein overexpression on myelination. We detected myelin loss accompanied by preserved or even increased numbers of oligodendrocytes in post-mortem MSA brains or transgenic mouse forebrains, respectively, indicating an oligodendrocytic dysfunction in myelin formation. Corroborating this observation, overexpression of ?-synuclein in primary and stem cell-derived oligodendrocytes severely impaired myelin formation, defining a novel ?-synuclein-linked pathomechanism in MSA. We used the pro-myelinating activity of the muscarinic acetylcholine receptor antagonist benztropine to analyze the reversibility of the myelination deficit. Transcriptome profiling of primary pre-myelinating oligodendrocytes demonstrated that benztropine readjusts myelination-related processes such as cholesterol and membrane biogenesis, being compromised by oligodendrocytic ?-synuclein. Additionally, benztropine restored the ?-synuclein-induced myelination deficit of stem cell-derived oligodendrocytes. Strikingly, benztropine also ameliorated the myelin deficit in transgenic MSA mice, resulting in a prevention of neuronal cell loss. In conclusion, this study defines the ?-synuclein-induced myelination deficit as a novel and crucial pathomechanism in MSA. Importantly, the reversible nature of this oligodendrocytic dysfunction opens a novel avenue for an intervention in MSA.
EVALuna2:4991

Systematic comparison of donor chimerism in peripheral blood and bone marrow after hematopoietic stem cell transplantation - Bach, Christian; Steffen, M.; Rösler, Wolf; Winkler, Jürgen; Mackensen, Andreas; Stachel, Daniel; Metzler, Markus; Spriewald, B. M. (Blood Cancer Journal, 2017)
EVALuna2:13436

Systematic comparison of the effects of alpha-synuclein mutations on its oligomerization and aggregation - Lazaro, Diana F.; Rodrigues, Eva F.; Langohr, Ramona; Shahpasandzadeh, Hedieh; Ribeiro, Thales; Guerreiro, Patricia; Gerhardt, Ellen; Kröhnert, Katharina; Klucken, Jochen; Pereira, Marcos D.; Popova, Blagovesta; Kruse, Niels; et al. (PLoS Genetics, 2014)
Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies.
EVALuna2:25327

Systematic data analysis and data mining in CatWalk gait analysis by heat mapping exemplified in rodent models for neurodegenerative diseases - Timotius, Ivanna; Canneva, Fabio; Minakaki, Georgia; Moceri, Sandra; Plank, Anne-Christine; Casadei, Nicolas; Riess, Olaf; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn; von Hörsten, Stephan (Journal of Neuroscience Methods, 2019)
Background Motor impairment appears as a characteristic symptom of several diseases and injuries. Therefore, tests for analyzing motor dysfunction are widely applied across preclinical models and disease stages. Among those, gait analysis tests are commonly used, but they generate a huge number of gait parameters. Thus, complications in data analysis and reporting raise, which often leads to premature parameter selection. New methods In order to avoid arbitrary parameter selection, we present here a systematic initial data analysis by utilizing heat-maps for data reporting. We exemplified this approach within an intervention study, as well as applied it to two longitudinal studies in rodent models related to Parkinson’s disease (PD) and Huntington disease (HD). Results The systematic initial data analysis (IDA) is feasible for exploring gait parameters, both in experimental and longitudinal studies. The resulting heat maps provided a visualization of gait parameters within a single chart, highlighting important clusters of differences. Comparison with existing method Often, premature parameter selection is practiced, lacking comprehensiveness. Researchers often use multiple separated graphs on distinct gait parameters for reporting. Additionally, negative results are often not reported. Conclusions Heat mapping utilized in initial data analysis is advantageous for reporting clustered gait parameter differences in one single chart and improves data mining.
Keywords: Gait analysis; CatWalk system; Heat map; Parkinson’s disease; Huntington disease; Rodent models

Systematic Data Analysis and Data Mining in Gait Analysis by Heat Mapping - Timotius, Ivanna; Canneva, Fabio; Minakaki, Georgia; Moceri, Sandra; Casadei, Nicolas; Riess, Olaf; Winkler, Jürgen; von Hörsten, Stephan; Eskofier, Björn; Klucken, Jochen (Measuring Behavior 2018, 2018)
Motor impairment appears as a characteristic of several diseases and injuries. Therefore, tests for analyzing motor dysfunction are widely applied across preclinical models and disease stages. The standard analysis addresses an extensive number of gait parameters which raises complication and often lead to premature parameter pre-selection. The parameter selection process was typically based on the previous research or the expert presumption, which sometimes leaves a question about the importance of the unselected parameters. Instead of manual parameter selection, here we propose a data mining technique using a systematic approach of initial data analysis (IDA) using a cluster heat map for data visualization. We exemplify our approach by applying it to a classical before-intervention-after-intervention design. This IDA is useful especially for exploratory research investigating gait abnormality and has the prospect to be applied in selecting parameters for a multivariate data analysi
Keywords: systematic approach; initial data analysis; heat map; cluster; gait analysis; CatWalk assay; gait parameters

Systemic inflammatory response syndrome and long-term outcome after intracerebral hemorrhage - Hagen, Manuel; Sembill, Jochen; Sprügel, Maximilian; Gerner, Stefan; Madžar, Dominik; Lücking, Hannes; Hölter, Philip; Schwab, Stefan; Huttner, Hagen; Kuramatsu, Joji (Neurology, Neuroimmunology and Neuroinflammation, 2019)
ObjectiveTo investigate whether the systemic inflammatory response syndrome (SIRS) without infection as surrogate of a systemic immune response is associated with poor long-term functional outcome in patients with spontaneous intracerebral hemorrhage (ICH).MethodsWe analyzed consecutive patients with spontaneous ICH from our prospective cohort study (2018-2015). SIRS was defined according to standard criteria: i.e., 2 or more of the following parameters during hospitalization: body temperature <36°C or >38°C, respiratory rate >20 per minute, heart rate >90 per minute, or white blood cell count <4,000/L or >12,000/L in the absence of infection. The primary outcome consisted of the modified Rankin Scale (mRS) at 3 and 12 months investigated by adjusted ordinal shift analyses. Bias and confounding were addressed by propensity score matching and multivariable regression models.ResultsOf 780 patients with ICH, 21.8% (n = 170) developed SIRS during hospitalization. Patients with SIRS showed more severe ICH compared with those without; i.e., larger ICH volumes (18.3 cm3, interquartile range [IQR 4.6-47.2 cm3] vs 7.4 cm3, IQR [2.4-18.6 cm3]; p < 0.01), increased intraventricular hemorrhage (57.6%, n = 98/170 vs 24.8%, n = 79/319; p < 0.01), and poorer neurologic admission status (NIH Stroke Scale score 16, IQR [7-30] vs 6, IQR [3-12]; p < 0.01). ICH severity-adjusted analyses revealed an independent association of SIRS with poorer functional outcome after 3 (OR 1.80, 95% CI [1.08-3.00]; p = 0.025) and 12 months (OR 1.76, 95% CI [1.04-2.96]; p = 0.034). Increased ICH volumes on follow-up imaging (OR 1.38, 95% CI [1.01-1.89]; p = 0.05) and previous liver dysfunction (OR 3.01, 95% CI [1.03-10.19]; p = 0.04) were associated with SIRS.ConclusionsIn patients with ICH, we identified SIRS to be predictive of poorer long-term functional outcome over the entire range of mRS estimates. Clinically relevant associations with SIRS were documented for previous liver dysfunction and hematoma enlargement.
CRIS-Team Scopus Importer:2019-10-29

T2-sequence with contrast inversion: diagnostic value in the investigation of gray matter heterotopias - Rösch, Julie; Mennecke, Angelika; Knott, Michael; Hamer, Hajo; Dörfler, Arnd; Engelhorn, Tobias Martin (NeuroReport, 2020)
To compare the diagnostic value of T1-inversion recovery sequence (T1 IR) to that of a T2-sequence with contrast inversion (T2 CI) in the investigation of heterotopias. In this study, we processed a contrast-inverted copy of our coronal T2-sequence of 21 patients with subependymal and subcortical heterotopias on an online picture archiving and communication system workstation. The diagnostic performance of these images was compared with the T1 IR of the same patients by quantitative and qualitative assessments regarding signal-to-noise ratio (SNR), lesion-to-white matter contrast-to-noise ratio (CNR), lesion conspicuity, level of artifacts, overall image quality as well as diagnostic content. SNR values of the T2 CI were significantly higher than those of the T1 IR. CNR values of both sequences were similar. No relevant difference was found for lesion conspicuity and level of artifacts. Overall image quality of the T2 CI was rated slightly better by one reader. Both readers voted the images to have the same diagnostic content. Beside the exact depiction of the hippocampus in the high resoluted T2-sequence, its contrast-inverted copy (T2 CI) is also useful in the detection of heterotopias. In conjunction with the MPRAGE or MP2RAGE as a three-dimensional sequence, it could offer an equivalent and time-saving alternative to the T1 IR in the investigation of this type of malformation of cortical development.
CRIS-Team Scopus Importer:2020-05-29

Targeted Temperature Management: Peltier's Element-Based Focal Brain Cooling Protects Penumbra Neurons from Progressive Damage in Experimental Cerebral Ischemia - Tauchi, Miyuki; De Rink, Maria Mercedes Tejada; Fujioka, Hiroshi; Okayama, Satoko; Nakamura, Kei-Ichiro; Dietel, Barbara; Achenbach, Stephan; Kollmar, Rainer; Schwab, Stefan; Ushijima, Kazuo; Harada, Hideki (Therapeutic Hypothermia and Temperature Management, 2018)
Targeted temperature management (TTM), or therapeutic hypothermia, is one of the most potent neuroprotective approaches after ischemic and traumatic brain injuries. TTM has been applied clinically with various methods, but effective achievement and maintenance of the target temperature remain challenging. Furthermore, timing of cooling and target body and brain temperature to optimize effectiveness for neuroprotection and to minimize side effects are yet to be standardized. Focal brain cooling is a potential strategy to minimize adverse effects of systemic TTM. In this study, we report on a focal brain cooling device for animals and its effectiveness of focal cooling in several animal models of ischemic cerebral stroke. A focal brain cooling device was constructed using a Peltier's element, a thermoelectric heat pump. The device was validated for its cooling ability, and optimal settings to induce an effective intracranial temperature were determined using male Sprague-Dawley rats. Transient and permanent middle cerebral artery occlusions were experimentally induced, and focal brain cooling was applied using the device varying the timing and duration of cooling. The stroke-induced infarct and edema volumes were evaluated from Nissl-stained cryosections. The focal brain cooling device was able to decrease and subsequently maintained cerebral hypothermia in free-moving rats without altering the core temperature. The device with validated intracranial temperatures produced neuroprotective effects in the acute phase of ischemic neural death, reperfusion injury, progressing damage to the penumbra, and edema formation. In conclusion, our validated focal cooling device enabled rapid and accurate cerebral TTM in rats. Using this device, we were able to test the neuroprotective effect of focal TTM in several pathological stages of cerebral ischemia, which warrants further studies to develop clinically feasible TTM procedures for patients with cerebral stroke.
EVALuna2:36338

Targeted transgene expression in neuronal precursors: watching young neurons in the old brain. - Winner, Beate; Bogdahn, Ulrich; Winkler, Jürgen; et al. (European Journal of Neuroscience, 2006)
Progress in the field of neurogenesis is limited by the lack of animal models allowing direct detection and analysis of living cells participating in neurogenesis. We engineered a transgenic mouse model that expresses the fluorescent reporter proteins enhanced green fluorescent protein or Discoma sp. reef coral red fluorescent protein under the control of the doublecortin (DCX) promoter, a gene specifically and transiently active in neuronal precursors and young neurons. The expression of the reporter proteins correlated with expression of the endogenous DCX protein, and with developmental and adult neurogenesis. Neurogenesis was unaffected by the presence of the fluorescent proteins. The transgenic mice allowed direct identification of the very few newly generated neurons present in the aged brain. We performed electrophysiological analysis and established that newly generated hippocampal granule cells in aged and young mice shared identical physiological properties. Hence, although the rate of neurogenesis tapers with ageing, a population of highly excitable young neurons indistinguishable to those found in younger animals is continuously generated. Therefore, maintenance of the fundamental properties of neuronal precursors even at advanced age suggests that stimulation of neurogenesis may constitute a valid strategy to counteract age-related neuronal loss and cognitive declines.

Taylor’s focal cortical dysplasia revisited: History, original specimens and impact - Kasper, Burkhard S. (Free Neuropathology, 2021)
50 years ago back in 1971, David C. Taylor and colleagues from England reported on a small series of surgical epilepsy cases proposing a new type of tissue lesion as a cause of difficult-to-treat focal epilepsy: a localized malformation of cerebral cortex. The lesion is now known as focal cortical dysplasia (FCD) Type II or Taylor’s cortical dysplasia. FCD II is not rare, and today is a frequent finding in neurosurgical epilepsy specimens. Medical progress has been achieved in that the majority of FCD II is diagnosed non-invasively by magnetic resonance imaging today. Detailed studies on FCD revealed that the lesion belongs to a spectrum of mTOR-o-pathies, thereby confirming the authors´ initial hypothesis of a relationship to tuberous sclerosis. Here, selected original materials from Taylor´s series are presented as virtual slides, supplemented by original clinical records, in order to give a first-hand impression of this milestone finding in neuropathology of epilepsy.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Dysplasia; Epilepsy; FCD; History; Taylor

Teaching Video NeuroImages: Facial myokymia and myorhythmia in anti-IgLON5 disease: The bitten lip - Vetter, Elena; Olmes, David G.; Linker, Ralf; Seifert, Frank (Neurology, 2018)
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Technical Modification of Amygdalo-Hippocampectomy in Temporal Lobe Epilepsy Surgery to Further Reduce Severe Neurological Complications: A Clinical-Anatomical Study - Roessler, Karl; Kasper, Burkhard; Coras, Roland; Arinrad, Soheil; Scholz, Michael; Hamer, Hajo; Blümcke, Ingmar; Buchfelder, Michael (World Neurosurgery, 2018)
BACKGROUND: Temporal lobe resection (TLR) including amygdalohippocampectomy (AHE) is the most frequent performed procedure in epilepsy surgery. Owing to the close anatomic relationship of the mesial temporal structures and the midbrain and choroidal fissure, the incidence of severe complications, such as postoperative stroke, is as high as 2.5%. METHODS: We developed a modification of the classical technique for AHE that involves entering the choroidal fissure early via the anterior part of the frontomesial temporal horn cleft to identify the crus cerebri, posterior cerebri artery, and oculomotor nerve. In a second step, after visualization of the cleavage plane between the midbrain and middle cerebral artery, the uncus and amygdala are removed. RESULTS: A total of 81 patients (47 females and 34 males; mean age at surgery, 40 years) underwent TLR including AHE with our surgical modification to treat heterogeneous pathologies. The cohort included 45 patients with hippocampal sclerosis, 11 with ganglioglioma, 2 with dysembryoplastic neuroepithelioma, 2 with diffuse glioma, and 21 with other pathologies, including cavernoma, scar tissue, and mild cortical dysplasia, among others. In all patients, anterior temporal resection was performed via AHE using our modified technique. Seizure outcome was favorable after a mean follow-up of 27 months (range, 3-56 months); 64% of the patients were completely seizure-free (Engel class 1A), and 75% had an Engel class 1 outcome. There was no mortality or permanent severe neurologic complications, and the rate of surgical complications was 3.7%. CONCLUSIONS: Our modified AHE technique is associated with a low rate of complications in TLR for medically refractory temporal lobe epilepsy, and helps avoid permanent severe neurologic complications.
EVALuna2:34587

Technical Validation of an Automated Mobile Gait Analysis System for Hereditary Spastic Paraplegia Patients - Martindale, Christine; Roth, Nils; Gaßner, Heiko; List, Julia; Regensburger, Martin; Eskofier, Björn; Kohl, Zacharias (IEEE Journal of Biomedical and Health Informatics, 2019)
Hereditary spastic paraplegias (HSP) represents a group of orphan neurodegenerative diseases with gait disturbance as the predominant clinical feature. Due to its rarity, research within this field is still limited. Aside from clinical analysis using established scales, gait analysis has been employed to enhance the understanding of the mechanisms behind the disease. However, state of the art gait analysis systems are often large, immobile and expensive. To overcome these limitations, this paper presents the first clinically relevant mobile gait analysis system for HSP patients. We propose an unsupervised model based on local cyclicity estimation and hierarchical hidden Markov models (LCE-hHMM). The system provides stride time, swing time, stance time, swing duration and cadence. These parameters are validated against a GAITRite® system and manual sensor data labelling using a cohort of 24 patients within 2 separate studies. The proposed system achieves a stride time error of -0.00 ± 0.09 s (correlation coefficient, r = 1.00) and a swing duration error of -0.67 ± 3.27 % (correlation coefficient, r = 0.93) with respect to the GAITRite® system. We show that these parameters are also correlated to the clinical spastic paraplegia rating scale (SPRS) in a similar manner to other state of the art gait analysis systems, as well as to supervised and general versions of the proposed model. Finally, we show a proof of concept for this system to be used to analyse alterations in the gait of individual patients. Thus, with further clinical studies, due to its automated approach and mobility, this system could be used to determine treatment effects in future clinical trials.<br
Keywords: Hidden Markov models; Diseases; Legged locomotion; Foot; Informatics; Estimation; Mobile gait analysis; hereditary spastic paraplegia; hidden Markov model; semi-supervised learning; cyclicity

Tele-EEG: Current Applications, Challenges, and Technical Solutions - Rosenow, Felix; Audebert, Heinrich J.; Hamer, Hajo; Hinrichs, Hermann; Kessler-Uberti, Stephanie; Kluge, Tilmann; Noachtar, Soheyl; Remi, Jan; Sotoodeh, Ali; Strzelczyk, Adam; Weber, Joachim E.; Zoellner, Johann Philipp (Klinische Neurophysiologie, 2018)
Telemedicine for people with epilepsy aims to facilitate a thorough diagnosis and therapy regardless of regional constraints. In Germany, this is especially important in rural regions. This review aims to outline current tele-epileptological applications, with a special regard to the individual frameworks, demands, challenges and technical solutions. The requirements of pediatric tele-epileptology are explored. Special considerations are given to the technical and diagnosis guidelines required to review tele-EEG. Projects conducted in the recent past demonstrate positive results in patient care.
EVALuna2:201946

Telemedicine in epilepsy care: doc-to-doc applications Part I: State of the art, challenges, and perspectives - Mues, Sigrid; Hamer, Hajo; Von Podewils, Felix; Sotoodeh, Ali; Rosenow, Felix; Wellmer, Joerg; Zoellner, Johann Philipp (Zeitschrift für Epileptologie, 2021)
Telemedical doc-to-doc applications in epilepsy care can help to provide the special expertise of adult or pediatric epileptologists area wide, as they make it possible to provide medical services across spatial distances. Various solutions are being developed both nationally and internationally for this purpose; however, there are organizational, technical, legal and economic challenges. The long-term perspective of the various current approaches is unclear. Ultimately, business models will have to be developed in which all players (consultation providers and requesting physician, patients, health insurers, operators of telemedical platforms and, if necessary, the respective professional associations) weigh up the specific benefits and risks.
CRIS-Team WoS Importer:2021-07-23

Telemedicine in epilepsy care: doc-to-doc applications: Part I: State of the art, challenges, and perspectives Telemedizin in der Epilepsieversorgung: Arzt-zu-Arzt-Anwendungen: Teil I: State-of-the-Art, Herausforderungen, Perspektiven - Mues, Sigrid; Hamer, Hajo; Von Podewils, Felix; Sotoodeh, Ali; Rosenow, Felix; Wellmer, Joerg; Zoellner, Johann Philipp (Zeitschrift für Epileptologie, 2021)
Telemedical doc-to-doc applications in epilepsy care can help to provide the special expertise of adult or pediatric epileptologists area wide, as they make it possible to provide medical services across spatial distances. Various solutions are being developed both nationally and internationally for this purpose; however, there are organizational, technical, legal and economic challenges. The long-term perspective of the various current approaches is unclear. Ultimately, business models will have to be developed in which all players (consultation providers and requesting physician, patients, health insurers, operators of telemedical platforms and, if necessary, the respective professional associations) weigh up the specific benefits and risks.
CRIS-Team Scopus Importer:2021-08-13
Keywords: Clinical competence; Communication; Digitalization; Funding; Tele-EEG

Telemedicine in General Neurology: Interrater Reliability of Clinical Neurological Examination Via Audio-Visual Telemedicine - Awadallah, Mohamed; Janssen, Frank; Koerber, Barbara; Breuer, Lorenz; Scibor, Mateusz; Handschu, Rene (European neurology, 2018)
Introduction: While there are several studies on reliability of telemedicine in assessing stroke scales, little is known about the validity of a general neurological examination performed via telemedicine. Therefore, we sought to test the agreement between bedside and remote examination in acute patients of the emergency room. Methods: Acute patients at the emergency room of a 450-bed academic teaching hospital were included in this study. A clinical neurological examination consisting of 22 items was performed at bedside and also remotely via an audio-visual link by a different neurologist; both were experienced clinicians at the consultant level. Kappa statistics were calculated for each item of the examination. Results: Forty three patients completed both examinations (mean age 58.3 years, 56% female). Patients were seen between 8 and 72 min after admission (mean 36.3 min). Total time for remote examination was 12.6 min (8-21 min) and 8.9 min (5-18 min) for bedside examination. K-coefficients ranged from 0.32 (muscle tone) - 0.82 (language) indicating a fair to excellent agreement in most items. Conclusions: Remote examination via an audio-visual link produces comparable results to bedside performance even in acute patients of the emergency room. Compared to the scarce data available, inter-observer agreement is about the same as that between 2 examiners at bedside. However, more studies on reliability and validity of clinical neurological examination are required. (c) 2019 S. Karger AG, Basel
CRIS-Team WoS Importer:2019-04-25

Telemedicine in general neurology: use of audiovisual consultation for on call back-up service in an acute care hospital - Janssen, Frank; Awadallah, Mohammed; Alhalabi, Awed; Koerber, Barbara; Lang, Reinhard; Scibor, Mateusz; Handschu, Rene (Journal of Neurology, 2018)
OBJECTIVE: While telemedicine is in expanding use in acute stroke care, little is known about its use in general neurology, especially in acute care. We sought to investigate the feasibility and possible effects of a telemedicine device within the neurological back-up service of an acute care hospital. METHODS: In a 450 bed academic teaching hospital an experienced neurologist (EN) is on call to support the junior doctor at the hospital. Support was possible whether by standard telephone advice (TA) or by audiovisual consultations (AVC). In AVC the expert used a mobile telemedicine device and so he could establish audiovisual contact from his home to the emergency room and examine newly admitted patients. Technical and patient details including timing and diagnosis were recorded. Video and audio quality as well as impact of AVC on diagnosis was rated by the EN. RESULTS: Out of about 1200 cases in off peak times, during the study period, 164 AVC including remote video examination were done (13.6%). Also 48 cases were documented by pure TA. Video quality was rated to a medium of 1.7, audio quality to 2.1. In 36 cases the audiovisual consultation was influenced by technical issues leading to cessation of AVC in 8 cases. Duration of teleconsultation was 17.3 min in AVC compared to 8.7 min for TA. The consultation diagnosis in AVC was confirmed in 74.4% of all cases compared to 57.7% in TA. AVC was rated as a valuable contribution to the diagnostic workup in 74.3% of all cases seen. In about 40% of all cases AVC was not possible due to technical or organizational reasons. CONCLUSIONS: Audiovisual consultation seems to be a feasible and useful support in routine neurology back-up service of an acute care hospital. Better mobility of devices and flexibility of service is needed to improve availability and quality of this valuable tool.
EVALuna2:36429

Telemedicine in stroke-pertinent to stroke care in Germany - Barlinn, J.; Winzer, S.; Worthmann, H.; Urbanek, C.; Haeusler, K. G.; Guenther, A.; Erdur, H.; Goertler, M.; Busetto, L.; Wojciechowski, C.; Schmitt, J.; Shah, Y.; et al. (Der Nervenarzt, 2021)
Background and objective Telemedical stroke networks improve stroke care and provide access to time-dependent acute stroke treatment in predominantly rural regions. The aim is a presentation of data on its utility and regional distribution. Methods The working group on telemedical stroke care of the German Stroke Society performed a survey study among all telestroke networks. Results Currently, 22 telemedical stroke networks including 43 centers (per network: median 1.5, interquartile range, IQR, 1-3) as well as 225 cooperating hospitals (per network: median 9, IQR 4-17) operate in Germany and contribute to acute stroke care delivery to 48 million people. In 2018, 38,211 teleconsultations (per network: median 1340, IQR 319-2758) were performed. The thrombolysis rate was 14.1% (95% confidence interval 13.6-14.7%) and transfer for thrombectomy was initiated in 7.9% (95% confidence interval 7.5-8.4%) of ischemic stroke patients. Financial reimbursement differs regionally with compensation for telemedical stroke care in only three federal states. Conclusion Telemedical stroke care is utilized in about 1 out of 10 stroke patients in Germany. Telemedical stroke networks achieve similar rates of thrombolysis and transfer for thrombectomy compared with neurological stroke units and contribute to stroke care in rural regions. Standardization of network structures, financial assurance and uniform quality measurements may further strengthen the importance of telestroke networks in the future.
CRIS-Team WoS Importer:2021-06-11

Telemedicine networks for acute stroke: An analysis of global coverage, gaps, and opportunities - Tunkl, Christine; Agarwal, Ayush; Ramage, Emily; Velez, Faddi Saleh; Roushdy, Tamer; Ullberg, Teresa; Li, Linxin; Carbonera, Leonardo A.; Yusof Khan, Abdul Hanif Khan; Ciopleias, Bogdan; Law, Zhe Kang; Katsanos, Aristeidis H.; et al. (International Journal of Stroke, 2024)
Background: Despite the proven efficacy of telestroke in improving clinical outcomes by providing access to specialized expertise and allowing rapid expert hyperacute stroke management and decision-making, detailed operational evidence is scarce, especially for less developed or lower income regions. Aim: We aimed to map the global telestroke landscape and characterize existing networks. Methods: We employed a four-tiered approach to comprehensively identify telestroke networks, primarily involving engagement with national stroke experts, stroke societies, and international stroke authorities. A carefully designed questionnaire was then distributed to the leaders of all identified networks to assess these networks’ structures, processes, and outcomes. Results: We identified 254 telestroke networks distributed across 67 countries. High-income countries (HICs) concentrated 175 (69%) of the networks. No evidence of telestroke services was found in 58 (30%) countries. From the identified networks, 88 (34%) completed the survey, being 61 (71%) located in HICs. Network setup was highly heterogeneous, ranging from 17 (22%) networks with more than 20 affiliated hospitals, providing thousands of annual consultations using purpose-built highly specialized technology, to 11 (13%) networks with fewer than 120 consultations annually using generic videoconferencing equipment. Real-time video and image transfer was employed in 64 (75%) networks, while 62 (74%) conducting quality monitoring. Most networks established in the past 3 years were located in low- and middle-income countries (LMICs). Conclusion: This comprehensive global survey of telestroke networks found significant variation in network coverage, setup, and technology use. Most services are in HICs, and a few services are in LMICs, although an emerging trend of new networks in these regions marks a pivotal moment in global telestroke care. The wide variation in quality monitoring practices across networks, with many failing to report key performance metrics, underscores the urgent need for standardized, resource-appropriate, quality assurance measures that can be adapted to diverse settings.
CRIS-Team Scopus Importer:2024-12-06
Keywords: guidelines; healthcare implementation; networks; stroke; Telestroke

Teleneurology in stroke management: costs of service in different organizational models - Handschu, Rene; Scibor, Mateusz; Nueckel, Martin; Asshoff, Dirk; Willaczek, Barbara; Erbguth, Frank; Schwab, Stefan; Daumann, Frank (Journal of Neurology, 2014)
Telemedicine is in increasing use in clinical neuroscience such as acute stroke care, especially by applying remote audiovisual communication for patient evaluation. However, telephone consultation was also used linking stroke centres to smaller hospitals. We compared costs of telestroke services using audiovisual and telephone communication in different organizational models. Within a small network in Northern Bavaria video-based teleconsultation (VTC) and telephone advice (TA) was provided for evaluation of acute stroke patients on a weekly rotation. The costs of the admissions process with or without one of both methods of telemedicine were calculated and compared from the perspective of the spoke hospital. Different levels of service and network size were modelled and costs of transfers as well as loss of revenues were calculated. Yearly total labour costs were 415,000 EUR for an on-site service VTC-service compared to 61,000 EUR in an on-call service. Additional costs for one teleconsultation were 109.55 EUR in VTC and 49.82 EUR in TA (VTC/TA ratio 2.2). The ratio decreased to 0.8 when accounting for costs of transfer and loss of reimbursement for all patients transferred as transfer of patients to the stroke centre was more frequent after TA (9.1 vs. 14.9%full-time on-site ser). Costs of one QALY gained by using VTC instead of TA ranged from 115.00 EUR to 515.86 EUR depending on the different models. In the first view TA looks like the less expensive method as it is easy to access and works without additional costs. When accounting for all disadvantages TA becomes slightly more expensive. In telestroke care VTC should be recommended as the method of choice also from an economic perspective.
EVALuna2:22264

Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration - Massa, Megan G.; David, Christina; Joerg, Stefanie; Berg, Johannes; Gisevius, Barbara; Hirschberg, Sarah; Linker, Ralf; Gold, Ralf; Haghikia, Aiden (American Journal of Pathology, 2017)
The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.
EVALuna2:22495

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease - Sommer, Annika; Marxreiter, Franz; Krach, Florian; Fadler, Tanja; Grosch, Janina; Maroni, Michele; Gräf, Daniela; Eberhardt, Esther; Riemenschneider, Markus J.; Yeo, Gene W.; Kohl, Zacharias; Xiang, Wei; et al. (Cell Stem Cell, 2019)
EVALuna2:203042

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease - Sommer, Annika; Maxreiter, Franz; Krach, Florian; Fadler, Tanja; Grosch, Janina; Maroni, Michele; Graef, Daniela; Eberhardt, Esther; Riemenschneider, Markus J.; Yeo, Gene W.; Kohl, Zacharias; Xiang, Wei; et al. (Cell Stem Cell, 2018)
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NF kappa B activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD.
EVALuna2:35782

The Acute Care of Stroke Patients in German Stroke Units-an Analysis of DRG Data From 2021 and 2022. - Neumann-Haefelin, Tobias; Bartig, Dirk; Faiss, Jürgen; Schwab, Stefan; Nabavi, Darius (Deutsches Ärzteblatt international, 2024)
EVALuna2:581207

The age and genomic integrity of neurons after cortical stroke in humans - Huttner, Hagen B.; Bergmann, Olaf; Salehpour, Mehran; Racz, Attila; Tatarishvili, Jemal; Lindgren, Emma; Csonka, Tamas; Csiba, Laszlo; Hortobagyi, Tibor; Mehes, Gabor; Englund, Elisabet; Solnestam, Beata Werne; et al. (Nature Neuroscience, 2014)
It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.
EVALuna2:22305

The anesthetic approach for endovascular recanalization therapy depends on the lesion site in acute ischemic stroke - Fröhlich, Kilian; Siedler, Gabriela; Stoll, Svenja; Macha, Kosmas; Kinfe, Thomas Mehari; Dörfler, Arnd; Eisenhut, Felix; Engelhorn, Tobias; Hölter, Philip; Lang, Stefan; Mühlen, Iris; Schmidt, Manuel; et al. (Neuroradiology, 2021)
Purpose Endovascular therapy (EVT) of large-vessel occlusion in acute ischemic stroke (AIS) may be performed in general anesthesia (GA) or conscious sedation (CS). We intended to determine the contribution of ischemic cerebral lesion sites on the physician's decision between GA and CS using voxel-based lesion symptom mapping (VLSM). Methods In a prospective local database, we sought patients with documented AIS and EVT. Age, stroke severity, lesion volume, vigilance, and aphasia scores were compared between EVT patients with GA and CS. The ischemic lesions were analyzed on CT or MRI scans and transformed into stereotaxic space. We determined the lesion overlap and assessed whether GA or CS is associated with specific cerebral lesion sites using the voxel-wise Liebermeister test. Results One hundred seventy-nine patients with AIS and EVT were included in the analysis. The VLSM analysis yielded associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas. Stroke severity and lesion volume were significantly higher in the GA group. The prevalence of aphasia and aphasia severity was significantly higher and parameters of vigilance lower in the GA group. Conclusions The VLSM analysis showed associations between GA and ischemic lesions in the left hemispheric middle cerebral artery territory and posterior circulation areas including the thalamus that are known to cause neurologic deficits, such as aphasia or compromised vigilance, in AIS-patients with EVT. Our data suggest that higher disability, clinical impairment due to neurological deficits like aphasia, or reduced alertness of affected patients may influence the physician's decision on using GA in EVT.
CRIS-Team WoS Importer:2021-07-23

The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology - Linnerbauer, Mathias; Lößlein, Lena; Vandrey, Oliver; Peter, Anne; Han, Yanan; Tsaktanis, Thanos; Wogram, Emile; Needhamsen, Maria; Kular, Lara; Nagel, Lisa; Zißler, Julia; Andert, Marie; et al. (Nature Immunology, 2024)
Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
CRIS-Team Scopus Importer:2024-03-08

The Bidirectional Interplay of α-Synuclein with Lipids in the Central Nervous System and Its Implications for the Pathogenesis of Parkinson’s Disease - Battis, Kristina; Xiang, Wei; Winkler, Jürgen (International Journal of Molecular Sciences, 2023)
The alteration and aggregation of alpha-synuclein (α-syn) play a crucial role in neurodegenerative diseases collectively termed as synucleinopathies, including Parkinson’s disease (PD). The bidirectional interaction of α-syn with lipids and biomembranes impacts not only α-syn aggregation but also lipid homeostasis. Indeed, lipid composition and metabolism are severely perturbed in PD. One explanation for lipid-associated alterations may involve structural changes in α-syn, caused, for example, by missense mutations in the lipid-binding region of α-syn as well as post-translational modifications such as phosphorylation, acetylation, nitration, ubiquitination, truncation, glycosylation, and glycation. Notably, different strategies targeting the α-syn-lipid interaction have been identified and are able to reduce α-syn pathology. These approaches include the modulation of post-translational modifications aiming to reduce the aggregation of α-syn and modify its binding properties to lipid membranes. Furthermore, targeting enzymes involved in various steps of lipid metabolism and exploring the neuroprotective potential of lipids themselves have emerged as novel therapeutic approaches. Taken together, this review focuses on the bidirectional crosstalk of α-syn and lipids and how alterations of this interaction affect PD and thereby open a window for therapeutic interventions.
CRIS-Team Scopus Importer:2023-09-15
Keywords: lipids; Parkinson’s disease; post-translational modification; α-synuclein

The Ca2+ sensor protein swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons - Purohit, Pavitra; Perez-Branguli, Francesc; Prots, Iryna; Borger, Eva; Gunn-Moore, Frank; Welzel, Oliver; Loy, Kristina; Wenzel, Eva Maria; Groemer, Teja W.; Brachs, Sebastian; Holzer, Max; Buslei, Rolf; et al. (PLoS ONE, 2014)
Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2-/- neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2-/- primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.
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The comorbidity and co-medication profile of patients with progressive supranuclear palsy - Greten, Stephan; Wegner, Florian; Jensen, Ida; Krey, Lea; Rogozinski, Sophia; Fehring, Meret; Heine, Johanne; Doll-Lee, Johanna; Pötter-Nerger, Monika; Zeitzschel, Molly; Hagena, Keno; Pedrosa, David J.; et al. (Journal of Neurology, 2023)
Background: Progressive supranuclear palsy (PSP) is usually diagnosed in elderly. Currently, little is known about comorbidities and the co-medication in these patients. Objectives: To explore the pattern of comorbidities and co-medication in PSP patients according to the known different phenotypes and in comparison with patients without neurodegenerative disease. Methods: Cross-sectional data of PSP and patients without neurodegenerative diseases (non-ND) were collected from three German multicenter observational studies (DescribePSP, ProPSP and DANCER). The prevalence of comorbidities according to WHO ICD-10 classification and the prevalence of drugs administered according to WHO ATC system were analyzed. Potential drug–drug interactions were evaluated using AiDKlinik®. Results: In total, 335 PSP and 275 non-ND patients were included in this analysis. The prevalence of diseases of the circulatory and the nervous system was higher in PSP at first level of ICD-10. Dorsopathies, diabetes mellitus, other nutritional deficiencies and polyneuropathies were more frequent in PSP at second level of ICD-10. In particular, the summed prevalence of cardiovascular and cerebrovascular diseases was higher in PSP patients. More drugs were administered in the PSP group leading to a greater percentage of patients with polypharmacy. Accordingly, the prevalence of potential drug–drug interactions was higher in PSP patients, especially severe and moderate interactions. Conclusions: PSP patients possess a characteristic profile of comorbidities, particularly diabetes and cardiovascular diseases. The eminent burden of comorbidities and resulting polypharmacy should be carefully considered when treating PSP patients.
CRIS-Team Scopus Importer:2023-12-01
Keywords: Comorbidities; Drug–drug interactions; Polypharmacy; Progressive supranuclear palsy

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts - Friščić, Jasna; Böttcher, Martin; Reinwald, Christiane; Bruns, Heiko; Wirth, Benjamin; Popp, Sebastian; Walker, Kellie Irene; Ackermann, Jochen A.; Chen, Xi; Turner, Jason; Zhu, Honglin; Seyler, Lisa; et al. (Immunity, 2021)
Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.
CRIS-Team Scopus Importer:2021-04-19
Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity

The course of tumor-related epilepsy in glioblastoma patients: A retrospective analysis - Stritzelberger, Jenny; Gesmann, Anna; Fuhrmann, Imke; Uhl, Martin; Brandner, Sebastian; Welte, Tamara; Schembs, Leah; Dörfler, Arnd; Coras, Roland; Adler, Werner; Schwab, Stefan; Putz, Florian; et al. (Epilepsy and Behavior, 2024)
Purpose: Many patients with glioblastoma suffer from tumor-related seizures. However, there is limited data on the characteristics of tumor-related epilepsy achieving seizure freedom. The aim of this study was to characterize the course of epilepsy in patients with glioblastoma and the factors that influence it. Methods: We retrospectively analyzed the medical records of glioblastoma patients treated at the University Hospital Erlangen between 01/2006 and 01/2020. Results: In the final cohort of patients with glioblastoma (n = 520), 292 patients (56.2 %) suffered from tumor-related epilepsy (persons with epilepsy, PWE). Levetiracetam was the most commonly used first-line antiseizure medication (n = 245, 83.9 % of PWE). The onset of epilepsy was preoperative in 154/292 patients (52.7 %). 136 PWE (46.6 %) experienced only one single seizure while 27/292 PWE (9.2 %) developed drug-resistant epilepsy. Status epilepticus occurred in 48/292 patients (16.4 %). Early postoperative onset (within 30 days of surgery) of epilepsy and total gross resection (compared with debulking) were independently associated with a lower risk of further seizures. We did not detect dose-dependent pro- or antiseizure effects of radiochemotherapy. Conclusion: Tumor-related epilepsy occurred in more than 50% of our cohort, but drug-resistant epilepsy developed in less than 10% of cases. Epilepsy usually started before tumor surgery.
CRIS-Team Scopus Importer:2024-07-19
Keywords: Glioblastoma; Radiochemotherapy; Surgery; Tumor-related epilepsy

The debate: Treatment after the first seizure-The PRO - Olmes, David G.; Hamer, Hajo (Seizure-European Journal of Epilepsy, 2017)
According to current diagnosis criteria, first seizures constitute beginning epilepsy when they carry recurrence risks of >=60% over the next 10 years. This is frequently the case and warrants AED treatment. Evidence argues against deferring treatment when provoking factors such as sleep deprivation are reported. There are several characteristics of first seizures which markedly increase recurrence risk but not clearly beyond 60%. This includes status epilepticus or seizure flurries at first manifestation or focal semiology indicating focal epilepsy. In this situation, there are still various medical, social and individual aspects supporting early initiation of AED. Modern AED allow this safely and at low dosages.
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The delta between postoperative seizure freedom and persistence: Automatically detected focal slow waves after epilepsy surgery - Schoenherr, Margit; Stefan, Hermann; Hamer, Hajo; Roessler, Karl; Buchfelder, Michael; Rampp, Stefan (NeuroImage: Clinical, 2017)
In this study, we use a novel automated method for localization and quantitative comparison of magnetoencephalographic (MEG) delta activity in patients with and without recurrent seizures after epilepsy surgery as well as healthy controls.We identified the generators of delta activity by source location in frequency domain between 1 and 4 Hz in spontaneous MEG data. Comparison with healthy control subjects by z-transform emphasized relative changes of activation in patients. The individual results were compared to spike localizations and statistical group analysis was performed. Additionally, MEG results were compared to 1-4 Hz activity in invasive EEG (iEEG) in two patients, in whom this data was available.Patients with recurrent seizures exhibited significantly increased focal MEG delta activity both in comparison to healthy controls and seizure free patients. This slow activity showed a correlation to interictal epileptic activity and was not explained by consequences of the resection alone. In two patients with iEEG, iEEG analysis was concordant with the MEG findings.The quantity of delta activity could be used as a diagnostic marker for recurrent seizures. The close relation to epileptic spike localizations and the resection volume of patients with successful second surgery imply involvement in seizure recurrence. This initial evidence suggests a potential application in the planning of second epilepsy surgery.
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The Diagnostic Scope of Sensor-Based Gait Analysis in Atypical Parkinsonism: Further Observations - Gaßner, Heiko; Raccagni, Cecilia; Eskofier, Björn; Klucken, Jochen; Wenning, Gregor K. (Frontiers in Neurology, 2019)
Background: Differentiating idiopathic Parkinson's disease (IPD) from atypical Parkinsonian disorders (APD) is challenging, especially in early disease stages. Postural instability and gait difficulty (PIGD) are substantial motor impairments of IPD and APD. Clinical evidence implies that patients with APD have larger PIGD impairment than IPD patients. Sensor-based gait analysis as instrumented bedside test revealed more gait deficits in APD compared to IPD. However, the diagnostic value of instrumented bedside tests compared to clinical assessments in differentiating APD from IPD patients have not been evaluated so far. Objective: The objectives were (a) to evaluate whether sensor-based gait parameters provide additional information to validated clinical scores in differentiating APD from matched IPD patients, and (b) to investigate if objective, instrumented gait assessments have comparable discriminative power to clinical scores. Methods: In a previous study we have recorded instrumented gait parameters in patients with APD (Multiple System Atrophy and Progressive Supranuclear Palsy). Here, we compared gait parameters to those of retrospectively pairwise disease duration-, age-, and gender-matched IPD patients in order to address this new research questions. To this aim, the PIGD score was calculated as sum of the MDS-UPDRS-3-items "gait," "postural stability," "arising from chair," and "posture." Gait characteristics were evaluated in standardized gait tests using an instrumented, sensor-based gait analysis system. Machine learning algorithms were used to extract spatio-temporal gait parameters. Receiver Operating Characteristic analysis was performed in order to detect the discriminative power of the instrumented vs. the clinical bedside tests in differentiating IPD from APD. Results: Sensor-based stride length, gait velocity, toe off angle, and parameters representing gait variability significantly differed between IPD and APD groups. ROC analysis revealed a high Area Under the Curve (AUC) for PIGD score (0.919), and UPDRS-3 (0.848). Particularly, the objective parameters stance time variability (0.841), swing time variability (0.834), stride time variability (0.821), and stride length variability (0.804) reached high AUC's as well. Conclusions: PIGD symptoms showed high discriminative power in differentiating IPD from APD supporting gait disorders as substantial diagnostic target. Sensor-based gait variability parameters provide metric, objective added value, and serve as complementary outcomes supporting clinical diagnostics and long-term home-monitoring concepts.
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The Effect of Climatic Factors on the Provocation of Epileptic Seizures - Treib, Philipp; Treib, Sebastian; Adler, Werner; Hamer, Hajo; Schwab, Stefan; Stefan, Hermann; Hammen, Thilo; Treib, Johannes (Deutsches Ärzteblatt international, 2021)
CRIS-Team WoS Importer:2022-03-04

The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease - A systematic literature review by a European panel of experts. - Germain, Dominique P.; Arad, Michael; Burlina, Alessandro; Elliott, Perry M.; Falissard, Bruno; Feldt-Rasmussen, Ulla; Hilz, Max-Josef; Hughes, Derralynn A.; Ortiz, Alberto; Wanner, Christoph; Weidemann, Frank; Spada, Marco (Molecular Genetics and Metabolism, 2019)
BACKGROUND: Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. METHODS: A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. RESULTS: Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. CONCLUSIONS: This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results.
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The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts. - Germain, Dominique P.; Elliott, Perry M.; Falissard, Bruno; Fomin, Victor V.; Hilz, Max-Josef; Jovanovic, Ana; Kantola, Ilkka; Linhart, Ales; Mignani, Renzo; Namdar, Mehdi; Nowak, Albina; Oliveira, Joao-Paulo; et al. (Molecular Genetics and Metabolism Reports, 2019)
Background: Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods: We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results: Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions: ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.
EVALuna2:206759

The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease - A systematic literature review by a European panel of experts - Spada, Marco; Baron, Ralf; Elliott, Perry M.; Falissard, Bruno; Hilz, Max-Josef; Monserrat, Lorenzo; Tondel, Camilla; Tylki-Szymariska, Anna; Wanner, Christoph; Germain, Dominique P. (Molecular Genetics and Metabolism, 2019)
Background: Fabry disease is caused by a deficiency of the lysosomal enzyme alpha-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human alpha-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease.
CRIS-Team WoS Importer:2019-04-18

The effect of rotating random dot motion on visuospatial line orientation in patients with right-sided stroke - Schaadt, A. K.; Reinhart, S.; Keller, I.; Hildebrandt, H.; Kerkhoff, G.; Utz, K. S. (Neuropsychologia, 2016)
Spatial deficits are frequent after brain damage, particularly right hemisphere stroke. Visual judgments of line orientation (LINE) are often impaired after right parietal lesions. Perception of line orientation is an important visuoperceptual component of visuoconstructive capacities. Yet, little is known about modulating factors in LINE and effective treatments are rare for this disorder. Studies in patients with spatial neglect show that horizontal random dot motion (RDM) significantly modulates horizontal spatial disorders, both transiently and permanently after treatment. In the current study, we investigated whether rotational RDM modulates judgements in an oblique LINE task in 20 patients with right-hemispheric first ever stroke (10 of them with a disorder in LINE and 10 without such a disorder), and 10 healthy, age-matched subjects. Subjects were tested under three experimental conditions: (1) with a static background of small white dots, (2) with slow clockwise or (3) counterclockwise circular RDM of these background stimuli, while they performed the LINE task. In the baseline condition with static background, the impaired patient group showed a significant counterclockwise tilt. Clockwise rotating RDM normalized this deficit transiently but completely, while counterclockwise rotating RDM slightly aggravated it, though not significantly. Tilts in the LINE task were significantly correlated with left visuospatial neglect. Similar but much smaller effects were obtained in the spatially unimpaired patients and the normal controls. These results show that rotational RDM modulates deficits of line orientation in patients with right-sided stroke, possibly by influencing higher spatial representations devoted to the perception of oblique lines.
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The Effects of an Individualized Smartphone-Based Exercise Program on Self-defined Motor Tasks in Parkinson Disease: Pilot Interventional Study. - Gaßner, Heiko; Friedrich, Jana; Masuch, Alisa; Jukic, Jelena; Stallforth, Sabine; Regensburger, Martin; Marxreiter, Franz; Winkler, Jürgen; Klucken, Jochen (JMIR Rehabilitation and Assistive Technologies, 2022)
BACKGROUND: Bradykinesia and rigidity are prototypical motor impairments of Parkinson disease (PD) highly influencing everyday life. Exercise training is an effective treatment alternative for motor symptoms, complementing dopaminergic medication. High frequency training is necessary to yield clinically relevant improvements. Exercise programs need to be tailored to individual symptoms and integrated in patients' everyday life. Due to the COVID-19 pandemic, exercise groups in outpatient setting were largely reduced. Developing remotely supervised solutions is therefore of significant importance. OBJECTIVE: This pilot study aimed to evaluate the feasibility of a digital, home-based, high-frequency exercise program for patients with PD. METHODS: In this pilot interventional study, patients diagnosed with PD received 4 weeks of personalized exercise at home using a smartphone app, remotely supervised by specialized therapists. Exercises were chosen based on the patient-defined motor impairment and depending on the patients' individual capacity (therapists defined 3-5 short training sequences for each participant). In a first education session, the tailored exercise program was explained and demonstrated to each participant and they were thoroughly introduced to the smartphone app. Intervention effects were evaluated using the Unified Parkinson Disease Rating Scale, part III; standardized sensor-based gait analysis; Timed Up and Go Test; 2-minute walk test; quality of life assessed by the Parkinson Disease Questionnaire; and patient-defined motor tasks of daily living. Usability of the smartphone app was assessed by the System Usability Scale. All participants gave written informed consent before initiation of the study. RESULTS: In total, 15 individuals with PD completed the intervention phase without any withdrawals or dropouts. The System Usability Scale reached an average score of 72.2 (SD 6.5) indicating good usability of the smartphone app. Patient-defined motor tasks of daily living significantly improved by 40% on average in 87% (13/15) of the patients. There was no significant impact on the quality of life as assessed by the Parkinson Disease Questionnaire (but the subsections regarding mobility and social support improved by 14% from 25 to 21 and 19% from 15 to 13, respectively). Motor symptoms rated by Unified Parkinson Disease Rating Scale, part III, did not improve significantly but a descriptive improvement of 14% from 18 to 16 could be observed. Clinically relevant changes in Timed Up and Go test, 2-minute walk test, and sensor-based gait parameters or functional gait tests were not observed. CONCLUSIONS: This pilot interventional study presented that a tailored, digital, home-based, and high-frequency exercise program over 4 weeks was feasible and improved patient-defined motor activities of daily life based on a self-developed patient-defined impairment score indicating that digital exercise concepts may have the potential to beneficially impact motor symptoms of daily living. Future studies should investigate sustainability effects in controlled study designs conducted over a longer period.
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The effects of an individualized smartphone-based exercise program on self-defined motor tasks in Parkinson's disease: a long-term feasibility study - Lützow, Lisa; Teckenburg, Isabelle Berenice; Koch, Veronika; Marxreiter, Franz; Jukic, Jelena; Stallforth, Sabine; Regensburger, Martin; Winkler, Jürgen; Klucken, Jochen; Gaßner, Heiko (Journal of Patient-Reported Outcomes, 2023)
BACKGROUND: Exercise therapy is considered effective for the treatment of motor impairment in patients with Parkinson's disease (PD). During the COVID-19 pandemic, training sessions were cancelled and the implementation of telerehabilitation concepts became a promising solution. The aim of this controlled interventional feasibility study was to evaluate the long-term acceptance and to explore initial effectiveness of a digital, home-based, high-frequency exercise program for PD patients. Training effects were assessed using patient-reported outcome measures combined with sensor-based and clinical scores. METHODS: 16 PD patients (smartphone group, SG) completed a home-based, individualized training program over 6-8 months using a smartphone app, remotely supervised by a therapist, and tailored to the patient's motor impairments and capacity. A control group (CG, n = 16) received medical treatment without participating in digital exercise training. The usability of the app was validated using System Usability Scale (SUS) and User Version of the Mobile Application Rating Scale (uMARS). Outcome measures included among others Unified Parkinson Disease Rating Scale, part III (UPDRS-III), sensor-based gait parameters derived from standardized gait tests, Parkinson's Disease Questionnaire (PDQ-39), and patient-defined motor activities of daily life (M-ADL). RESULTS: Exercise frequency of 74.5% demonstrated high adherence in this cohort. The application obtained 84% in SUS and more than 3.5/5 points in each subcategory of uMARS, indicating excellent usability. The individually assessed additional benefit showed at least 6 out of 10 points (Mean = 8.2 ± 1.3). From a clinical perspective, patient-defined M-ADL improved for 10 out of 16 patients by 15.5% after the training period. The results of the UPDRS-III remained stable in the SG while worsening in the CG by 3.1 points (24%). The PDQ-39 score worsened over 6-8 months by 83% (SG) and 59% (CG) but the subsection mobility showed a smaller decline in the SG (3%) compared to the CG (77%) without reaching significance level for all outcomes. Sensor-based gait parameters remained constant in both groups. CONCLUSIONS: Long-term training over 6-8 months with the app is considered feasible and acceptable, representing a cost-effective, individualized approach to complement dopaminergic treatment. This study indicates that personalized, digital, high-frequency training leads to benefits in motor sections of ADL and Quality of Life.
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The first detailed study and illustration of Ammon’s horn sclerosis in epilepsy and the men behind it: Emil Bratz (1868–1934) and Otto Hebold (1856–1945) Erste detaillierte Studie und Darstellung einer Ammonshornsklerose bei Epilepsie und die Männer dahinter: Emil Bratz (1868–1934) und Otto Hebold (1856–1945) - Kasper, Burkhard S.; Hebold, M.; Stockmann, J. P. (Clinical Epileptology, 2025)
Ammon’s horn sclerosis (AHS) is a frequent, important, and intriguing central nervous lesion in human epilepsy. As early as 200 years ago in 1825, AHS was recognized and described macroscopically first, but its significance was debated. After an initial microscopic report from postmortem brain tissue in 1880 made by Wilhelm Sommer, it was Emil Bratz (1868–1934) who published the first systematic investigation of AHS in epilepsy in Europe, performed under the directorship of Otto Hebold (1856–1945) at Wuhlgarten, an early German institution built for the care of patients with epilepsy in Berlin. In 1899, a paper published by Bratz contained a precise illustration of AHS tissue characteristics: a beautiful woodcarving. The picture as well as Bratz’s writings encompasses all the hallmarks of AHS. Here, we revisit this milestone paper of epilepsy pathology in a historical context including several aspects so far unknown or not readily available. Bratz, supported by Hebold, recognized the pathognomonic histological pattern of AHS, as seen in certain cases of epilepsy, at a time when epilepsy and its anatomical correlates were still poorly understood. As shown here, this contribution was widely recognized at the time, represented a seed point for many researchers to come, remains cited to this day, and is worth being remembered along with the two men behind it.
CRIS-Team Scopus Importer:2025-03-21
Keywords: Ammon’s horn; Hippocampal sclerosis; Histology; Historical aspects; Pathology

The footprint of orthostatic hypotension in parkinsonian syndromes - Raccagni, Cecilia; Sidoroff, Victoria; Goebel, Georg; Granata, Roberta; Leys, Fabian; Klucken, Jochen; Eskofier, Björn; Richer, Robert; Seppi, Klaus; Wenning, Gregor K.; Fanciulli, Alessandra (Parkinsonism & Related Disorders, 2020)
•Orthostatic hypotension may worsen gait performance in Parkinson's disease and multiple system atrophy. •Gait impairment correlates with the fall in blood pressure upon standing. •Wearable sensors detect the impact of orthostatic hypotension on gai
Keywords: Parkinson's disease; Multiple system atrophy; Orthostatic hypotension; Gait analysis

The fumaric acid ester BG-12: a new option in MS therapy - Lee, De-Hyung; Stangel, Martin; Gold, Ralf; Linker, Ralf (Expert review of neurotherapeutics, 2013)
In March 2013, BG-12 was approved by the US FDA and EMA for the treatment of relapsing-remitting multiple sclerosis (RRMS) after meeting the primary and most secondary end points in two global phase III trials (CONFIM and DEFINE). From these data, the optimal BG-12 dosage for the treatment of RRMS is 240 mg twice daily. In the DEFINE and CONFIRM trials, the relative reduction of annual relapse rates were 53 and 44% in the approval-relevant dosages, respectively. Moreover, in the DEFINE trial, progression of disability was significantly ameliorated with a relative risk reduction of 38%. In both studies, administration of BG-12 was generally well-tolerated and safe. Most common adverse events were flushing and gastrointestinal events, including diarrhea, nausea and upper abdominal pain, which were particularly common in the early phases of treatment. At present, the introduction of BG-12 into the European market and its position among current MS treatment regimens is awaited with great interest.
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The genomic landscape across 474 surgically accessible epileptogenic human brain lesions - A López-Rivera, Javier; Leu, Costin; Macnee, Marie; Khoury, Jean; Hoffmann, Lucas; Coras, Roland; Kobow, Katja; Bhattarai, Nisha; Pérez-Palma, Eduardo; Hamer, Hajo; Brandner, Sebastian; Rössler, Karl; et al. (Brain, 2022)
Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT; 7.92 ± 5.65 SNV) than in brain tissue from malformations of cortical development (MCD; 6.11 ± 4 SNV) or hippocampal sclerosis (HS; 5.1 ± 3.04 SNV). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical genetic analyses showed that the numbers of somatic SNV across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with LEAT. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening, and guides future directions for clinical implementation of epilepsy surgery genetics.<br
Keywords: epilepsy; malformation of cortical development; low-grade epilepsy-associated tumor; hippocampal sclerosis; genetics

The gut-brain axis in inflammatory bowel disease—current and future perspectives - Günther, Claudia; Rothhammer, Veit; Karow, Marisa; Neurath, Markus; Winner, Beate (International Journal of Molecular Sciences, 2021)
The gut–brain axis is a bidirectional communication system driven by neural, hormonal, metabolic, immunological, and microbial signals. Signaling events from the gut can modulate brain function and recent evidence suggests that the gut–brain axis may play a pivotal role in linking gastrointestinal and neurological diseases. Accordingly, accumulating evidence has suggested a link between inflammatory bowel diseases (IBDs) and neurodegenerative, as well as neuroinflammatory diseases. In this context, clinical, epidemiological and experimental data have demonstrated that IBD predisposes a person to pathologies of the central nervous system (CNS). Likewise, a number of neurological disorders are associated with changes in the intestinal environment, which are indicative for disease-mediated gut–brain inter-organ communication. Although this axis was identified more than 20 years ago, the sequence of events and underlying molecular mechanisms are poorly defined. The emergence of precision medicine has uncovered the need to take into account non-intestinal symptoms in the context of IBD that could offer the opportunity to tailor therapies to individual patients. The aim of this review is to highlight recent findings supporting the clinical and biological link between the gut and brain, as well as its clinical significance for IBD as well as neurodegeneration and neuroinflammation. Finally, we focus on novel human-specific preclinical models that will help uncover disease mechanisms to better understand and modulate the function of this complex system.
CRIS-Team Scopus Importer:2021-08-27
Keywords: Ex vivo organ models; Gut-brain axis; IBD; MS; PD

The Gut–Immune–Brain Axis: An Important Route for Neuropsychiatric Morbidity in Inflammatory Bowel Disease - Masanetz, Rebecca Katharina; Winkler, Jürgen; Winner, Beate; Günther, Claudia; Süß, Patrick (International Journal of Molecular Sciences, 2022)
Inflammatory bowel disease (IBD) comprises Crohn’s disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD. We present a stepwise cascade along a gut–immune–brain axis initiated by evasion of chronic intestinal inflammation to pass the epithelial and vascular barrier in the gut and cause systemic inflammation. We then summarize different anatomical transmission routes of gut-derived peripheral inflammation into the central nervous system (CNS) and highlight the current knowledge on neuroinflammatory changes in the CNS of preclinical IBD mouse models with a focus on microglia, the brain-resident macrophages. Subsequently, we discuss how neuroinflammation in IBD can alter neuronal circuitry to trigger symptoms like depression and anxiety. Finally, the role of intestinal microbiota in the gut–immune–brain axis in IBD will be reviewed. A more comprehensive understanding of the interaction between the gastrointestinal tract, the immune system and the CNS accounting for the similarities and differences between UC and CD will pave the path for improved prediction and treatment of neuropsychiatric comorbidities in IBD and other inflammatory diseases.
Created from Fastlane, Scopus look-up
Keywords: Crohn’s disease; depression; gut microbiota; gut-brain axis; inflammatory bowel disease; neuroinflammation; systemic inflammation; ulcerative colitis

The hedonics of olfactory induced memories - a new model for the analyses of emotional blunting - Thürauf, Norbert; Sollmann, Manuel; Fuchs, Michael; Jäger, Jakob; Mettang, Melissa; Reich, Karin; Kornhuber, Johannes; Sperling, Wolgang; Freiherr, Jessica (CHEMICAL SENSES, 2020)
CRIS-Team WoS Importer:2020-06-23

The hyperintense acute reperfusion marker on fluid-attenuated inversion recovery magnetic resonance imaging is caused by gadolinium in the cerebrospinal fluid - Köhrmann, Martin; Struffert, Tobias; Frenzel, Thomas; Schwab, Stefan; Dörfler, Arnd (Stroke, 2012)
Background and PurposeS-: The hyperintense acute reperfusion marker (HARM) on fluid-attenuated inversion recovery MRI is believed to be caused by gadolinium-based contrast agents crossing a disrupted blood-brain barrier. However, this hypothesis has never been directly verified in humans. Methods-: In this study, we analyzed cerebrospinal fluid samples of patients with HARM on imaging regarding the presence and concentration of gadolinium-based contrast agents. Results-: Gadobutrol was found in concentrations of approximately 50 μmol/L. Using phantom MRI experiments, we demonstrate that the detected concentrations are consistent with the observed HARM imaging pattern. Conclusions-: Our study yields first direct evidence in humans that the imaging phenomenon HARM is indeed caused by leakage of gadolinium-based contrast agents into the cerebrospinal fluid. © 2011 American Heart Association. All rights reserved.
CRIS-Team Scopus Importer:2022-08-05
Keywords: FLAIR; hyperintensive acute reperfusion marker; MRI

The Impact of Burst Motor Cortex Stimulation on Cardiovascular Autonomic Modulation in Chronic Pain: A Feasibility Study for a New Approach to Objectively Monitor Therapeutic Effects - Borutta, Matthias; Köhn, Julia; Souza de Oliveira, Daniela; Del Vecchio, Alessandro; Engelhorn, Tobias; Schwab, Stefan; Buchfelder, Michael; Kinfe, Thomas Mehari (Pain and Therapy, 2023)
Introduction: Chronic refractory pain of various origin occurs in 30–45% of pain patients, and a considerable proportion remains resistant to pharmacological and behavioral therapies, requiring adjunctive neurostimulation therapies. Chronic pain is known to stimulate sympathetic outflow, yet the impact of burst motor cortex stimulation (burstMCS) on objectifiable autonomic cardiovascular parameters in chronic pain remains largely unknown. Methods: In three patients with chronic pain (2 facial pain/1 post-stroke pain), we compared pain intensity using a visual analog scale (VAS 1–10) and parameters of autonomic cardiovascular modulation at supine rest, during parasympathetic challenge with six cycles per minute of metronomic deep breathing, and during sympathetic challenge (active standing) at baseline and after 4 months of burstMCS compared to age-/gender-matched healthy controls. Results: While two out of three patients were responsive after 4 months of adjunctive burstMCS (defined as pain reduction of > 30%), no differences were found in any of the three patients regarding the R-R intervals of adjacent QRS complexes (RRI, 642 vs. 676 ms) and blood pressure (BP, 139/88 vs. 141/90 mmHg). Under resting conditions, parameters of parasympathetic tone [normalized units of high-frequency oscillations of RRI (RRI-HFnu power) 0.24 vs. 0.38, root-mean-square differences of successive RRI (RRI-RMSSD) 7.7 vs. 14.7 ms], total autonomic cardiac modulation [RRI total power 129.3 vs. 406.2 ms2, standard deviation of RRI (RRI-SD) 11.6 vs. 18.5 ms, coefficient of variation of RRI (RRI-CV) 1.9 vs. 3.7%], and baroreceptor reflex sensitivity (BRS, 1.9 vs. 2.3 ms/mmHg) increased, and parameters of sympathetic tone [normalized units of low-frequency oscillations of RRI (RRI-LFnu power) 0.76 vs. 0.62] and sympatho-vagal balance [ratio of RR-LF to RRI-HF power (RRI-LF/HF ratio) 3.4 vs. 1.9] decreased after 4 months of burstMCS. Low-frequency oscillations of systolic blood pressure (SBP-LF power), a parameter of sympathetic cardiovascular modulation, increased slightly (17.6 vs. 20.4 mmHg2). During parasympathetic stimulation, the expiratory–inspiratory ratio (E/I ratio) increased slightly, while upon sympathetic stimulation, the ratio between the shortest RRI around the 15th heartbeat and the longest RRI around the 30th heartbeat after standing up (RRI 30/15 ratio) remained unchanged. Conclusion: Four months of adjunctive burstMCS was associated with an increase in parameters reflecting both total and parasympathetic autonomic modulation and baroreceptor reflex sensitivity. In contrast, sympathetic tone declined in our three patients, suggesting stimulation-associated improvement not only in subjectively perceived VAS pain scores, but also in objectifiable parameters of autonomic cardiovascular modulation.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Autonomic cardiovascular modulation; Burst motor cortex stimulation; Chronic post stroke pain; Objective outcome measures

The impact of the coronavirus disease (COVID-19) pandemic on outpatient epilepsy care: An analysis of physician practices in Germany - Müller, Tamara; Kostev, Karel; Gollwitzer, Stephanie; Lang, Johannes; Stritzelberger, Jenny; Westermayer, Vivien; Reindl, Caroline; Hamer, Hajo (Epilepsy & Behavior, 2021)
Objective: To gain insight into epilepsy care during coronavirus disease (COVID-19) pandemic, we analyzed prescription data of a large cohort of persons with epilepsy (PWE) during lockdown in Germany. Methods: Information was obtained from the Disease Analyzer database, which collects anonymous demographic and medical data from practice computer systems of general practitioners (GP) and neurologists (NL) throughout Germany. We retrospectively compared prescription data for anti-seizure medication (ASM) and physicians’ notes of “known” and “new” PWE from January 2020 until May 2020 with the corresponding months in the three preceding years 2017–2019. Adherence was estimated by calculating the proportion of patients with follow-up prescriptions within 90 days after initial prescriptions in January or February. We additionally analyzed hospital referrals of PWE. The significance level was set to 0.01 to adjust for multiple comparisons. Results: A total of 52,844 PWE were included. Anti-seizure medication prescriptions for known PWE increased in March 2020 (GP + 36%, NL + 29%; P < 0.01). By contrast, a decrease in prescriptions to known and new PWE was observed in April and significantly in May 2020 ranging from −16% to −29% (P < 0.01). The proportion of PWE receiving follow-up prescriptions was slightly higher in 2020 (73.5%) than in 2017–2019 (70.7%, P = 0.001). General practitioners and NL referred fewer PWE to hospitals in March 2020 (GP: −30%, P < 0.01; NL: −12%), April 2020 (GP: −29%, P < 0.01; NL: −37%), and May 2020 (GP: −24%, P < 0.01; NL: −16%). Conclusion: Adherence of known PWE to ASM treatment appeared to remain stable during lockdown in Germany. However, this study revealed findings which point to reduced care for newly diagnosed PWE as well as fewer hospital admissions. These elements may warrant consideration during future lockdown situations.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Anti-seizure drugs; COVID-19; Epilepsy care

The impact of the DWI-FLAIR-mismatch in the ECASS-4 trial – A post hoc analysis - Pfaff, Johannes A. R.; Bendszus, Martin; Donnan, Geoffrey; Molina, Carlos; Leys, Didier; Schellinger, Peter D.; Schwab, Stefan; Toni, Danilo; Wahlgren, Nils; Hacke, Werner; Ringleb, Peter Arthur (European Stroke Journal, 2020)
Introduction: To investigate the impact of a mismatch between diffusion-weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) on functional outcome in patients with acute stroke in a prolonged time window or unknown time of symptom onset randomized to intravenous thrombolysis or placebo. Patients and Methods: We performed a post-hoc analysis of the European Cooperative Acute Stroke Study-4 (ECASS-4) trial. ECASS-4 was an investigator driven, phase 3, multi-center, double-blind, placebo-controlled study which randomized ischemic stroke patients presenting within 4.5 and 9h of stroke onset or unknown time-window to either rt-PA or placebo after MR-imaging. Two subgroups “no mismatch” (nMM) and “any mismatch” (aMM) were created by applying a DWI-FLAIR-mismatch criterion. We calculated frequency of nMM and aMM and performed a univariate analysis (Fisher's Test) for excellent clinical outcome (mRS 0-1) and mortality (mRS=6). Results: MR-Imaging of n=111/119 (93.2%) patients was suitable for this analysis. DWI-FLAIR mismatch was found in 49 patients (44.1%). Proportions of mismatch nMM and aMM were comparable in treatment-groups (aMM: Placebo 46.3%, Alteplase 42.1%; p=0.70). Patients with nMM showed no benefit of rt-PA-treatment (OR (95%CI) mRS 0-1: 0.95 (0.29-3.17)). Patients with aMM showed a point estimate of the odds ratio in favour of a treatment benefit of rt-PA (mRS 0-1: OR (95%CI) 2.62 (0.68-11.1)). Mortality within 90 days was not different in patients treated with rt-PA if nMM (15.2%) or aMM (12.5%) was present. Discussion: In this analysis no significant evidence, but subtle indication towards patients treated with rt-PA in a prolonged time window reaching an excellent clinical outcome if a DWI-FLAIR-mismatch is present on initial stroke MR-imaging. Conclusion: A DWI-FLAIR mismatch in the region of ischemia as imaging based surrogate parameter for patient selection for i.v. rt-PA should be strongly pursued.
CRIS-Team Scopus Importer:2020-05-08
Keywords: acute ischemic stroke; diffusion-weighted imaging; DWI-FLAIR-mismatch; European Cooperative Acute Stroke Study-4; fluid-attenuated inversion recovery; magnetic resonance imaging; Thrombolysis

The Influence of Climatic Factors on the Provocation of Epileptic Seizures - Hammen, Thilo; Treib, Sebastian; Treib, Philipp; Stefan, Hermann; Hamer, Hajo; Landwehr, Ralf; Lohmann, Lynn; Koch, Sebastian; Treib, Johannes; Adler, Werner (Journal of Clinical Medicine, 2024)
Background/Objectives: Recent studies provide the first indications of the impact of climate factors on human health, especially with individuals already grappling with internal and neurological conditions being particularly vulnerable. In the face of escalating climate change, our research delves into the specific influence of a spectrum of climatic factors and seasonal variations on the hospital admissions of patients receiving treatment for epileptic seizures at our clinic in Kaiserslautern. Methods: Our study encompassed data from 9366 epilepsy patients who were admitted to hospital due to epileptic seizures. We considered seven climate parameters that Germany’s National Meteorological Service made available. We employed the Kruskal–Wallis test to examine the correlation between the frequency of admittance to our hospital in the mentioned patient group and seasons. Furthermore, we used conditional Poisson regression and distributed lag linear models (DLMs) to scrutinize the coherence of the frequency of patient admittance and the investigated climate parameters. The mentioned parameters were also analyzed in a subgroup analysis regarding the gender and age of patients and the classification of seizures according to ILAE 2017. Results: Our results demonstrate that climatic factors, such as precipitation and air pressure, can increase the frequency of hospital admissions for seizures in patients with general-onset epilepsy. In contrast, patients with focal seizures are less prone to climatic changes. Consequently, admittance to the hospital for seizures is less affected by climatic factors in the latter patient group. Conclusions: The present study demonstrated that climatic factors are possible trigger factors for the provocation of seizures, particularly in patients with generalized seizures. This was determined indirectly by analyzing the frequency of seizure-related emergency admissions and their relation to prevailing climate factors. Our study is consistent with other studies showing that climate factors, such as cerebral infarcts or cerebral hemorrhages, influence patients’ health.
CRIS-Team Scopus Importer:2024-07-12
Keywords: climatic factors; epilepsy; seasonal variation; seizures; trigger factors

The influence of liver dysfunction (LD) on functional outcome in intracerebral hemorrhage - Beuscher, Vanessa; Sprügel, Maximilian; Mrochen, Anne; Hölter, Philip; Lang, Stefan; Kuramatsu, Joji; Huttner, Hagen (Journal für Anasthesie und Intensivbehandlung, 2021)
CRIS-Team Scopus Importer:2024-12-16

The influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome - Lenk, Christian; Meßbacher, Maria-Elena; Abel, Judith; Müller, Sarina Katrin; Mantsopoulos, Konstantinos; Gostian, Antoniu-Oreste; Sievert, Matti; Wirtz, Stefan; Marxreiter, Franz; Winkler, Jürgen; Iro, Heinrich; Traxdorf, Maximilian (European Review for Medical and Pharmacological Sciences, 2023)
OBJECTIVE: The aim of this study was to investigate the influence of obstructive sleep apnea and continuous positive airway pressure on the nasal microbiome. PATIENTS AND METHODS: Endonasal swabs from the olfactory groove of 22 patients with moderate and severe obstructive sleep apnea (OSA) and a control group of 17 healthy controls were obtained at the Department of Otorhinolaryngology of the Friedrich-Alexander-Universität Erlangen-Nürnberg. 16S rRNA gene sequencing was performed to further evaluate the endonasal microbiome. In a second step, the longitudinal influence of continuous positive airway pressure (CPAP) therapy on the nasal microbiome was investigated (3-6 and 6-9 months). RESULTS: Analysis of the bacterial load and β-diversity showed no significant differences between the groups, although patients with severe OSA showed increased α-diversity compared to the control group, while those with moderate OSA showed decreased α-diversity. The evaluation of longitudinal changes in the nasal microbiota during CPAP treatment showed no significant difference in α- or β-diversity. However, the number of bacteria for which a significant difference between moderate and severe OSA was found in the linear discriminant analysis decreased during CPAP treatment. CONCLUSIONS: Long-term CPAP treatment showed an alignment of the composition of the nasal microbiome in patients with moderate and severe OSA as well as an alignment of biodiversity with that of the healthy control group. This change in the composition of the microbiome could be both part of the therapeutic effect in CPAP therapy and a promoting factor of the adverse side effects of the therapy. Further studies are needed to investigate whether the endonasal microbiome is related to CPAP compliance and whether CPAP compliance can be positively influenced in the future by therapeutic modification of the microbiome.
CRIS-Team WoS Importer:2023-05-26

The innate immune system in Parkinson's disease: a novel target promoting endogenous neuroregeneration - Schlachetzki, Johannes; Winkler, Jürgen (Neural Regeneration Research, 2015)
EVALuna2:25344

The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain - Süß, Patrick; Rothe, Tobias; Hoffmann, Alana; Schlachetzki, Johannes C. M.; Winkler, Jürgen (Frontiers in Immunology, 2020)
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases.
CRIS-Team WoS Importer:2021-01-08

The long-term course of temporal lobe epilepsy: From unilateral to bilateral interictal epileptiform discharges in repeated video-EEG monitorings - Gollwitzer, Stephanie; Scott, Catherine A.; Farrell, Fiona; Bell, Gail S.; De Tisi, Jane; Walker, Matthew C.; Wehner, Tim; Sander, Josemir W.; Hamer, Hajo; Diehl, Beate (Epilepsy and Behavior, 2017)
Bilateral interictal epileptiform discharges (IED) and ictal patterns are common in temporal lobe epilepsy (TLE) and have been associated with decreased chances of seizure freedom after epilepsy surgery. It is unclear whether secondary epileptogenesis, although demonstrated in experimental models, exists in humans and may account for progression of epilepsy.We reviewed consecutive video-EEG recordings from 1992 to 2014 repeated at least two years apart (mean interval 6.14years) in 100 people diagnosed with TLE.Ictal EEG patterns and IED remained restricted to one hemisphere in 36 people (group 1), 46 exhibited bilateral abnormalities from the first recording (group 2), 18 progressed from unilateral to bilateral EEG pathology over time (group 3). No significant differences between the three groups were seen with respect to age at epilepsy onset, duration, or underlying pathology. Extra-temporal IED during the first EEG recording were associated with an increased risk of developing bilateral epileptiform changes over time (hazard ratio 3.67; 95% CI 1.4, 9.4).Our findings provide some support of progression in TLE and raise the possibility of secondary epileptogenesis in humans. The development of an independent contra-lateral epileptogenic focus is known to be associated with a less favorable surgical outcome. We defined reliable EEG markers for an increased risk of progression to more widespread or independent bitemporal epileptogenicity at an early stage, thus allowing for individualized pre-surgical counselling.
EVALuna2:22487

The Luxembourg Parkinson's Study: A Comprehensive Approach for Stratification and Early Diagnosis - Hipp, Geraldine; Vaillant, Michel; Diederich, Nico J.; Roomp, Kirsten; Satagopam, Venkata P.; Banda, Peter; Sandt, Estelle; Mommaerts, Kathleen; Schmitz, Sabine K.; Longhino, Laura; Schweicher, Alexandra; Hanff, Anne-Marie; et al. (Frontiers in Aging Neuroscience, 2018)
While genetic advances have successfully defined part of the complexity in Parkinson's disease (PD), the clinical characterization of phenotypes remains challenging. Therapeutic trials and cohort studies typically include patients with earlier disease stages and exclude comorbidities, thus ignoring a substantial part of the real-world PD population. To account for these limitations, we implemented the Luxembourg PD study as a comprehensive clinical, molecular and device-based approach including patients with typical PD and atypical parkinsonism, irrespective of their disease stage, age, comorbidities, or linguistic background. To provide a large, longitudinally followed, and deeply phenotyped set of patients and controls for clinical and fundamental research on PD, we implemented an open-source digital platform that can be harmonized with international PD cohort studies. Our interests also reflect Luxembourg-specific areas of PD research, including vision, gait, and cognition. This effort is flanked by comprehensive biosampling efforts assuring high quality and sustained availability of body liquids and tissue biopsies. We provide evidence for the feasibility of such a cohort program with deep phenotyping and high quality biosampling on parkinsonism in an environment with structural specificities and alert the international research community to our willingness to collaborate with other centers. The combination of advanced clinical phenotyping approaches including device-based assessment will create a comprehensive assessment of the disease and its variants, its interaction with comorbidities and its progression. We envision the Luxembourg Parkinson's study as an important research platform for defining early diagnosis and progression markers that translate into stratified treatment approaches.
EVALuna2:50530

The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis - Hammer, Anna; Waschbisch, Anne; Kuhbandner, Kristina; Bayas, Antonios; Lee, De-Hyung; Duscha, Alexander; Haghikia, Aiden; Gold, Ralf; Linker, Ralf (Annals of Clinical and Translational Neurology, 2018)
Objective: Immunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate (DMF) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing-remitting multiple sclerosis (MS) patients. Methods: We explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy. Results: Gene expression analysis proved activation of NRF2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3+ regulatory T cells, CD56bright natural killer cells, plasmacytoid dendritic cells, and a decrease in CD8+ T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) 4-6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO1 induction further correlated with patient age. Interpretation: We demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF2 pathway as potential biomarker for DMF treatment in MS.
EVALuna2:35516

The Parkinson's disease e-diary: Developing a clinical and research tool for the digital age - Vizcarra, Joaquin A.; Sánchez-Ferro, Álvaro; Maetzler, Walter; Marsili, Luca; Zavala, Lucia; Lang, Anthony E.; Martinez-Martin, Pablo; Mestre, Tiago A.; Reilmann, Ralf; Hausdorff, Jeffrey M.; Dorsey, E. Ray; Paul, Serene S.; et al. (Movement Disorders, 2019)
CRIS-Team Scopus Importer:2019-05-21

The Quest for Anti-α-Synuclein Antibody Specificity—Lessons Learnt From Flow Cytometry Analysis - Leupold, Lukas; Sigutova, Veronika; Gerasimova, Elizaveta; Regensburger, Martin; Zundler, Sebastian; Zunke, Friederike; Xiang, Wei; Winner, Beate; Prots, Iryna (Frontiers in Neurology, 2022)
The accumulation of alpha-synuclein (aSyn) is the hallmark of a group of neurodegenerative conditions termed synucleopathies. Physiological functions of aSyn, including those outside of the CNS, remain elusive. However, a reliable and reproducible evaluation of aSyn protein expression in different cell types and especially in low-expressing cells is impeded by the existence of a huge variety of poorly characterized anti-aSyn antibodies and a lack of a routinely used sensitive detection methods. Here, we developed a robust flow cytometry-based workflow for aSyn detection and antibody validation. We test our workflow using three commercially available antibodies (MJFR1, LB509, and 2A7) in a variety of human cell types, including induced pluripotent stem cells, T lymphocytes, and fibroblasts, and provide a cell- and antibody-specific map for aSyn expression. Strikingly, we demonstrate a previously unobserved unspecificity of the LB509 antibody, while the MJFR1 clone revealed specific aSyn binding however with low sensitivity. On the other hand, we identified an aSyn-specific antibody clone 2A7 with an optimal sensitivity for detecting aSyn in a range of cell types, including those with low aSyn expression. We further utilize our workflow to demonstrate the ability of the 2A7 antibody to distinguish between physiological differences in aSyn expression in neuronal and non-neuronal cells from the cortical organoids, and in neural progenitors and midbrain dopaminergic neurons from healthy controls and in patients with Parkinson's disease who have aSyn gene locus duplication. Our results provide a proof of principle for the use of high-throughput flow cytometry-based analysis of aSyn and highlight the necessity of rigorous aSyn antibody validation to facilitate the research of aSyn physiology and patholog
Keywords: alpha-synuclein; antibodies; synuclein antibodies; T cell; antibody specificity; flow cytometry; α-synuclein expression

Therapeutic goals in Fabry disease: Recommendations of a European expert panel, based on current clinical evidence with enzyme replacement therapy - Wanner, Christoph; Gerrnain, Dominique P.; Hilz, Max-Josef; Spada, Marco; Falissard, Bruno; Elliott, Perry M. (Molecular Genetics and Metabolism, 2019)
CRIS-Team WoS Importer:2019-04-18

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial - Van Der Worp, H. Bart; Macleod, Malcolm R.; Bath, Philip M. W.; Bathula, Raj; Christensen, Hanne; Colam, Bridget; Cordonnier, Charlotte; Demotes-Mainard, Jacques; Durand-Zaleski, Isabelle; Gluud, Christian; Jakobsen, Janus Christian; Kallmünzer, Bernd; et al. (European Stroke Journal, 2019)
Introduction We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. Patients and methods In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0 degrees C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. Results The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94; p = 0.52). Discussion In this trial, cooling to a target of 34.0-35.0 degrees C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. Conclusion Before new trials are launched, the feasibility of cooling needs to be improved.
CRIS-Team WoS Importer:2019-10-01

Therapy of intracerebral and subarachnoid hemorrhage Therapie der intrazerebralen und subarachnoidalen Blutung - Sprügel, Maximilian; Huttner, Hagen; Gerner, Stefan (Nervenheilkunde, 2020)
In recent years there have been significant advances in the acute treatment of patients with intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). However, mortality remains high and functional outcome of surviving patients is often severely impaired. While ICH patients often suffer from motor deficits, SAH patients may be limited in daily activities due to concentration disorders, headaches, depression and cognitive impairment. Treatment of ICH focuses on prevention of early hematoma expansion by blood pressure management and hemostasis. Further, novel minimally invasive techniques for hemorrhage evacuation are currently at trial. The management of perihemorrhagic edema, intracranial pressure, ventricular involvement and hydrocephalus as well as long-term antithrombotic therapy remain challenging. In SAH, acute treatment relies on rapid aneurysm closure and hydrocephalus treatment. New aspects have also emerged in the prevention and treatment of vasospasms and secondary cerebral ischemia. Further research areas are optimal drainage management using ventricular and lumbar drains as well as intraventricular fibrinolysis. This review article deals with these relevant topics in acute and long-term treatment of ICH and SAH patients and provides an overview of current evidence and controversies in these treatment fields.
CRIS-Team Scopus Importer:2020-11-13
Keywords: hematoma enlargement; hematoma evacuation; hydrocephalus; Intracerebral hemorrhage; mortality; outcome; subarachnoid hemorrhage; vasospasm

Therapy response prediction of focal cortex stimulation based on clinical parameters: a multicentre, non-interventional study protocol - Kalousios, Sotirios; Hesser, Jürgen; Dümpelmann, Matthias; Baumgartner, Christoph; Hamer, Hajo; Hirsch, Martin; Imbach, Lukas; Kaufmann, Elisabeth; Kegele, Josua; Knake, Susanne; Leonhardt, Georg; Mayer, Thomas; et al. (BMJ Open, 2025)
Introduction A novel focal cortex stimulation (FCS) device has recently received approval in Europe for patients with focal drug-resistant epilepsy (DRE). After 6 months of stimulation, 17 of 32 patients achieved ≥50% reduction in seizure frequency compared with their prestimulation baseline (responders). Currently, there is no established method for predicting FCS treatment response prior to implantation. Methods and analysis This is an ongoing combined retrospective-prospective non-interventional multicentre study. Clinical data of up to 100 patients treated with FCS are collected across 20 collaborating epilepsy centres in four European countries. The key outcome parameters, seizure frequency and severity, are measured along with metrics on cognition, mood and quality of life, both pre-electrode and postelectrode implantation. The data are complemented by demographics, medical history and information on antiseizure medication and FCS treatment parameters during the stimulation period. In addition to clinical data, MRI and electroencephalography registrations are used to gain insights into spatial and electrophysiological aspects of FCS. Multivariate statistical and machine learning analyses are employed to identify key predictive biomarkers associated with patient outcomes (responders vs non-responders). The primary goal is to improve counselling for DRE patients by identifying promising candidates for FCS treatment. Ethics and dissemination This study has received approval from the ethics committee of the University of Freiburg, Germany (23-1540 S1; 23-1183_1-S1-retro). The same approval is applicable for all participating centres in Germany as part of a multicentre study. Ghent University Hospital, Belgium, has received approval for participation in the retrospective arm from their local ethics committee (ONZ-2024-0168). The final approvals for the participating Swiss and Austrian sites are still pending. The results will be made available to the public through peer-reviewed journals and conference presentations.
CRIS-Team Scopus Importer:2025-03-07
Keywords: Electric Stimulation Therapy; Epilepsy; Machine Learning; NEUROLOGY; Patients

The Role of Gut and Oral Microbiota in the Formation and Rupture of Intracranial Aneurysms: A Literature Review. - Joerger, Ann Kathrin; Albrecht, Carolin; Rothhammer, Veit; Neuhaus, Klaus; Wagner, Arthur; Meyer, Bernhard; Wostrack, Maria (International Journal of Molecular Sciences, 2023)
In recent years, there has been a growing interest in the role of the microbiome in cardiovascular and cerebrovascular diseases. Emerging research highlights the potential role of the microbiome in intracranial aneurysm (IA) formation and rupture, particularly in relation to inflammation. In this review, we aim to explore the existing literature regarding the influence of the gut and oral microbiome on IA formation and rupture. In the first section, we provide background information, elucidating the connection between inflammation and aneurysm formation and presenting potential mechanisms of gut-brain interaction. Additionally, we explain the methods for microbiome analysis. The second section reviews existing studies that investigate the relationship between the gut and oral microbiome and IAs. We conclude with a prospective overview, highlighting the extent to which the microbiome is already therapeutically utilized in other fields. Furthermore, we address the challenges associated with the context of IAs that still need to be overcome.
EVALuna2:552389

The role of intrathecal free light chains kappa for the detection of autoimmune encephalitis in subacute onset neuropsychiatric syndromes - Bertram, Dominic; Tsaktanis, Thanos; Berthele, Achim; Korn, Thomas (Scientific Reports, 2023)
Intrathecal synthesis of free light chains kappa (FLCK) is increasingly recognized as a marker of inflammatory CNS pathologies. Here, we tested the performance of FLCK in differentiating autoimmune encephalitis (AIE) from non-inflammatory etiologies in subacute onset neuropsychiatric syndromes. Patients undergoing diagnostic work-up for suspected autoimmune encephalitis at our department between 2015 and 2020 were retrospectively assessed for definitive diagnosis, available CSF and blood samples, as well as complete clinical records. Intrathecal FLCK was measured along with established CSF markers of CNS inflammation. The study cohort consisted of 19 patients with antibody-mediated AIE (AIE+), 18 patients with suspected AIE but without detectable autoantibodies (AIE–), 10 patients with infectious (viral) encephalitis (INE), and 15 patients with degenerative encephalopathies (DGE). 25 age- and sex-matched patients with non-inflammatory neurological diseases (NIND) were used as a control group. All AIE+ patients exhibited intrathecal synthesis of FLCK compared to only 39% of AIE– patients and 81% of patients in the INE group. No intrathecal synthesis of FLCK was found in DGE and NIND patients. While intrathecal FLCK was equally specific for an inflammatory etiology as oligoclonal bands (OCB) in the cerebrospinal fluid (CSF), the sensitivity of intrathecal FLCK for any inflammatory intrathecal process was higher than that of OCB (83% vs. 38%). Intrathecal FLCK synthesis was found to discriminate AIE+ from non-inflammatory encephalopathies and AIE– when the CSF cell count was normal [receiver operating characteristic (ROC) analysis area under the curve (AUC): 0.867, p = 0.002], while it failed to differentiate between AIE+ and INE in the presence of CSF pleocytosis (AUC: 0.561, p = 0.607). In conclusion, in the absence of CSF pleocytosis, intrathecal FLCK discriminated AIE+ from competing diagnoses in our cohort of subacute onset neuropsychiatric syndromes. In addition to established markers of CSF inflammation, intrathecal FLCK might support clinical decision-making and contribute to selecting patients for (repeated) antibody testing.
CRIS-Team Scopus Importer:2023-10-20

The role of lysosomal cathepsins in neurodegeneration: Mechanistic insights, diagnostic potential and therapeutic approaches - Drobny, Alice; Prieto Huarcaya, Susy; Dobert, Jan; Kluge, Annika; Bunk, Josina; Schlothauer, Theresia; Zunke, Friederike (Biochimica Et Biophysica Acta-Molecular Cell Research, 2022)
Lysosomes are ubiquitous organelles with a fundamental role in maintaining cellular homeostasis by mediating degradation and recycling processes. Cathepsins are the most abundant lysosomal hydrolyses and are responsible for the bulk degradation of various substrates. A correct autophagic function is essential for neuronal survival, as most neurons are post-mitotic and thus susceptible to accumulate cellular components. Increasing evidence suggests a crucial role of the lysosome in neurodegeneration as a key regulator of aggregation-prone and disease-associated proteins, such as α-synuclein, β-amyloid and huntingtin. Particularly, alterations in lysosomal cathepsins CTSD, CTSB and CTSL can contribute to the pathogenesis of neurodegenerative diseases as seen for neuronal ceroid lipofuscinosis, synucleinopathies (Parkinson's disease, Dementia with Lewy Body and Multiple System Atrophy) as well as Alzheimer's and Huntington's disease. In this review, we provide an overview of recent evidence implicating CTSD, CTSB and CTSL in neurodegeneration, with a special focus on the role of these enzymes in α-synuclein metabolism. In addition, we summarize the potential role of lysosomal cathepsins as clinical biomarkers in neurodegenerative diseases and discuss potential therapeutic approaches by targeting lysosomal function.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Alzheimer's disease; Cathepsins; Huntington's disease; Lysosome; Neurodegeneration; Neuronal ceroid lipofuscinosis; Parkinson's disease; Synucleinopathies; α-Synuclein

The role of lysosomes in alpha-synucleinopathies: A focus on glial cells - Balta, Denise; Zunke, Friederike (Neural Regeneration Research, 2022)
CRIS-Team Scopus Importer:2022-01-07

The role of midkine in health and disease - Neumaier, Emely; Rothhammer, Veit; Linnerbauer, Mathias (Frontiers in Immunology, 2023)
Midkine (MDK) is a neurotrophic growth factor highly expressed during embryogenesis with important functions related to growth, proliferation, survival, migration, angiogenesis, reproduction, and repair. Recent research has indicated that MDK functions as a key player in autoimmune disorders of the central nervous system (CNS), such as Multiple Sclerosis (MS) and is a promising therapeutic target for the treatment of brain tumors, acute injuries, and other CNS disorders. This review summarizes the modes of action and immunological functions of MDK both in the peripheral immune compartment and in the CNS, particularly in the context of traumatic brain injury, brain tumors, neuroinflammation, and neurodegeneration. Moreover, we discuss the role of MDK as a central mediator of neuro-immune crosstalk, focusing on the interactions between CNS-infiltrating and -resident cells such as astrocytes, microglia, and oligodendrocytes. Finally, we highlight the therapeutic potential of MDK and discuss potential therapeutic approaches for the treatment of neurological disorders.
CRIS-Team Scopus Importer:2023-12-22
Keywords: CNS; inflammation; injury; malignancy; midkine

The role of myelin oligodendrocyte glycoprotein in autoimmune demyelination: a target for multiple sclerosis therapy? - Lee, De-Hyung; Linker, Ralf (Expert Opinion on Therapeutic Targets, 2012)
INTRODUCTION: Myelin oligodendrocyte glycoprotein (MOG) is a myelin antigen at the outer surface of the central nervous system (CNS) myelin sheath, which may trigger T-cell as well as B-cell responses. It therefore constitutes a pivotal target for autoimmune responses, which result in inflammation and also demyelination in the CNS. In particular, it is a major target for auto-antibodies in experimental autoimmune encephalomyelitis (EAE), which mimics many aspects of multiple sclerosis (MS). B-cell responses toward MOG and anti-MOG antibodies have also been demonstrated in patients with demyelinating diseases, such as MS and acute disseminating encephalomyelitis (ADEM). Co-transfer of such anti-MOG antibodies in experimental models results in a distinct lesion pattern with antibody and complement-mediated demyelination, which is also hallmark of some lesion subtypes in MS. AREAS COVERED: A comprehensive literature search on MOG, B cells, MS, and ADEM was performed to outline the role of MOG in autoimmune demyelination in animal models and its relevance for human disease. EXPERT OPINION: Although the definite role of MOG in the pathogenesis of MS still remains to be clarified, innovative therapeutic strategies targeting B cells may reduce pathogenic immune responses against myelin auto-antigens including anti-myelin auto-antibodies.
EVALuna2:36327

The role of triggering receptor expressed on myeloid cells 2 in Parkinson's disease and other neurodegenerative disorders - Schwarz, Hannah; Bässler, Sarah; Balta, Denise; Socher, Eileen; Zunke, Friederike; Arnold, Philipp (Behavioural Brain Research, 2022)
Parkinson's disease (PD) is a progressive neurological disorder marked by cardinal clinical symptoms such as rigor, tremor, and akinesia. Albeit a loss of dopaminergic neurons from the substantia nigra pars compacta is causative for the movement impairments found in patients, molecular reasoning for this loss is still incomplete. In recent years, triggering factor expressed on myeloid cells (TREM2) gained attention in the field of neurodegeneration as it could be associated with different neurodegenerative disorders. Primarily identified as a risk factor in Alzheimer's disease, variants in TREM2 were linked to PD and multiple sclerosis, too. Expressed on phagocytic cells, such as macrophages and microglia, TREM2 puts the focus on inflammation associated conditions in PD and provides a molecular target that could at least partly explain the role of immune cells in PD. Here, we summarize expression patterns and molecular functions of TREM2, recapitulate on its role in inflammation, phagocytosis and cell survival, before turning to neurodegenerative disorders with an emphasis on PD.
CRIS-Team Scopus Importer:2022-07-22
Keywords: Cell signaling; DAP12; Inflammation; Neurodegeneration; Parkinson's disease; TREM2

The roles of astrocyte in the brain pathologies following ischemic stroke - Sun, Linlin; Zhang, Yixuan; Liu, E.; Ma, Qingyi; Anatol, Manaenko; Han, Hongbin; Yan, Junhao (Brain Injury, 2019)
Aim: In this work, we systematically explored the physiological functions of astrocytes and their roles following ischemic stroke, additionally, the potential therapy strategy targeting the astrocytes was also discussed. Methods: This work searched the PubMed database (including MEDLINE) until 14 Feb 2018, and furthermore, the studies were identified through cross-referencing and by consulting the experts in this field. Results: This study indicated that the astrocytes can not only play harmful roles following ischemic stroke through release of inflammatory factors and formation of glial scar but also have protective effects through quenching glutamate excitotoxicity and maintaining the clearance function of glymphatic system in brain. Conclusion: Owing to their important roles in physiological functions of brain and in the pathological conditions following ischemic stroke, the astrocytes might be a potential but promising therapeutic target for treating the ischemic stroke in the future.
CRIS-Team Scopus Importer:2019-06-28
Keywords: aquaporin 4; astrocyte; glymphatic system; Ischemic stroke

The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients - Sachau, Juliane; Bruckmueller, Henrike; Gierthmühlen, Janne; Magerl, Walter; May, Denisa; Binder, Andreas; Forstenpointner, Julia; Koetting, Judith; Maier, Christoph; Tölle, Thomas R.; Treede, Rolf Detlef; Berthele, Achim; et al. (European Journal of Pain, 2020)
Background: The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. Methods: At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G > A (rs6311) and c.102C > T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. Results: There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (−0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p <.001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. −0.34 ± 0.23 p =.002; MPS, +0.66 ± 0.17 vs. −0.09 ± 0.23, p =.009) and ongoing pain was increased by 30%. Conclusions: The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. Significance: This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies.
CRIS-Team Scopus Importer:2020-12-11

The small GTPase Rab11 co-localizes with ?-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity - Chutna, Oldriska; Goncalves, Susana; Villar-Pique, Anna; Guerreiro, Patricia; Marijanovic, Zrinka; Mendes, Tiago; Ramalho, Jose; Emmanouilidou, Evangelia; Ventura, Salvador; Klucken, Jochen; Barral, Duarte C.; Giorgini, Flaviano; et al. (Human Molecular Genetics, 2014)
Alpha-synuclein (aSyn) misfolding and aggregation are pathological features common to several neurodegenerative diseases, including Parkinson's disease (PD). Mounting evidence suggests that aSyn can be secreted and transferred from cell to cell, participating in the propagation and spreading of pathological events. Rab11, a small GTPase, is an important regulator in both endocytic and secretory pathways. Here, we show that Rab11 is involved in regulating aSyn secretion. Rab11 knockdown or overexpression of either Rab11a wild-type (Rab11a WT) or Rab11a GDP-bound mutant (Rab11a S25N) increased secretion of aSyn. Furthermore, we demonstrate that Rab11 interacts with aSyn and is present in intracellular inclusions together with aSyn. Moreover, Rab11 reduces aSyn aggregation and toxicity. Our results suggest that Rab11 is involved in modulating the processes of aSyn secretion and aggregation, both of which are important mechanisms in the progression of aSyn pathology in PD and other synucleinopathies.
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The Subarachnoid Hemorrhage International Trialists (SAHIT) Repository: advancing clinical research in subarachnoid hemorrhage - Jaja, Blessing N. R.; Attalla, Daniel; Macdonald, R. Loch; Schweizer, Tom A.; Cusimano, Michael D.; Etminan, Nima; Hanggi, Daniel; Hasan, David; Johnston, S. Claiborne; Le Roux, Peter; Lo, Benjamin; Louffat-Olivares, Ada; et al. (Neurocritical Care, 2014)
Researchers and other stakeholders continue to express concern about the failure of randomized clinical trials (RCT) in subarachnoid hemorrhage (SAH) to show efficacy of new treatments. Pooled data may be particularly useful to generate hypotheses about causes of poor outcomes and reasons for failure of RCT in SAH, and strategies to improve them. Investigators conducting SAH research collaborated to share data with the intent to develop a large repository of pooled individual patient data for exploratory analysis and testing of new hypotheses relevant to improved trial design and analysis in SAH. This repository currently contains information on 11,443 SAH patients from 14 clinical databases, of which 9 are datasets of recent RCTs and 5 are datasets of prospective observational studies and hospital registries. Most patients were managed in the last 15 years. Data validation and quality checks have been conducted and are satisfactory. Data is available on demographic, clinical, neuroimaging, and laboratory results and various outcome measures. We have compiled the largest known dataset of patients with SAH. The SAHIT repository may be an important resource for advancing clinical research in SAH and will benefit from contributions of additional datasets.
EVALuna2:22319

Theta rhythmicity governs human behavior and hippocampal signals during memory-dependent tasks - Ter Wal, Marije; Linde-Domingo, Juan; Lifanov, Julia; Roux, Frederic; Kolibius, Luca D.; Gollwitzer, Stephanie; Lang, Johannes; Hamer, Hajo; Rollings, David; Sawlani, Vijay; Chelvarajah, Ramesh; Staresina, Bernhard; et al. (Nature Communications, 2021)
Memory formation and reinstatement are thought to lock to the hippocampal theta rhythm, predicting that encoding and retrieval processes appear rhythmic themselves. Here, we show that rhythmicity can be observed in behavioral responses from memory tasks, where participants indicate, using button presses, the timing of encoding and recall of cue-object associative memories. We find no evidence for rhythmicity in button presses for visual tasks using the same stimuli, or for questions about already retrieved objects. The oscillations for correctly remembered trials center in the slow theta frequency range (1-5 Hz). Using intracranial EEG recordings, we show that the memory task induces temporally extended phase consistency in hippocampal local field potentials at slow theta frequencies, but significantly more for remembered than forgotten trials, providing a potential mechanistic underpinning for the theta oscillations found in behavioral responses.
CRIS-Team Scopus Importer:2021-12-17

The temporal expression pattern of alpha-synuclein modulates olfactory neurogenesis in transgenic mice - Schreglmann, Sebastian R.; Regensburger, Martin; Rockenstein, Edward; Masliah, Eliezer; Xiang, Wei; Winkler, Jürgen; Winner, Beate (PLoS ONE, 2015)
Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS) under the murine Thy1 (mThy1) promoter, a model known to have a particularly high tg expression associated with impaired olfaction.Survival of newly generated neurons (NeuN-positive) in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor ? (PDGF) promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex.The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.
EVALuna2:4712

The transcriptional regulator DREAM modulates glial cell proliferation dependent on the regional inflammatory microenvironment - Süß, Patrick; Masanetz, Rebecca Katharina; Baum, Wolfgang; Schett, Georg; Schlachetzki, Johannes; Winkler, Jürgen (JOURNAL OF NEUROCHEMISTRY, 2022)
CRIS-Team WoS Importer:2022-09-09

The Use of Digital Technology and Media in German Parkinson's Disease Patients - Marxreiter, Franz; Buttler, Ulrike; Gaßner, Heiko; Gandor, Florin; Gladow, Till; Eskofier, Björn; Winkler, Jürgen; Ebersbach, Georg; Klucken, Jochen (Journal of Parkinson's Disease, 2020)
BACKGROUND: Parkinson's disease (PD) is an age dependent neurodegenerative disorder with increasing prevalence. Digital technologies like computers and smartphones offer mobile telecommunication, diagnostic and monitoring and may connect the patient continuously with his healthcare team, providing disease related information, and support healthcare. Since the use of these technologies in western civilization is age dependent, possession and usage cannot be regarded as given in PD. In contrast to increasing efforts to implement digital technology into PD patient care, little is known about the use of computers, smartphones, and internet-affinity in PD patients. OBJECTIVE: We evaluated the use of digital technologies in different age groups of PD patients. METHODS: We developed a questionnaire adapted to the annual German microcensus on "use of digital communication technologies", allowing a comparison to the general population in Germany. RESULTS: 190 PD patients completed the questionnaire. About 75% of PD patients access disease related information on the internet. Patients across all age groups used computers and the internet as frequent or more frequently compared to the German population. Use of computers, smartphones, and the internet in PD was age dependent. Advanced PD patients with higher motor impairment used smartphones less often, while mobile phone usage was not reduced. CONCLUSION: The adoption of a digital lifestyle is present in the PD population, apart from smartphone usage, which is impaired by motor symptoms. Thus, future healthcare technologies are not hampered by the inability of PD patients to use the necessary tools, however, fine motor-skill requirements have to be acknowledged.
EVALuna2:213360
Keywords: Smartphones; digital media; Parkinson's disease; movement disorder; digital healthcare

Thigh-Derived Inertial Sensor Metrics to Assess the Sit-to-Stand and Stand-to-Sit Transitions in the Timed Up and Go (TUG) Task for Quantifying Mobility Impairment in Multiple Sclerosis - Witchel, Harry J.; Oberndorfer, Caecilia; Needham, Robert; Healy, Aoife; Westling, Carina E.; Guppy, Joseph H.; Bush, Jake; Barth, Jens; Herberz, Chantal; Roggen, Daniel; Eskofier, Björn; Rashid, Waciar; et al. (Frontiers in Neurology, 2018)
Introduction: Inertial sensors generate objective and sensitive metrics of movement disability that may indicate fall risk in many clinical conditions including multiple sclerosis (MS). The Timed-Up-And-Go (TUG) task is used to assess patient mobility because it incorporates clinically-relevant submovements during standing. Most sensor-based TUG research has focused on the placement of sensors at the spine, hip or ankles; an examination of thigh activity in TUG in multiple sclerosis is wanting. Methods: We used validated sensors (x-IMU by x-io) to derive transparent metrics for the sit-to-stand (SI-ST) transition and the stand-to-sit (ST-SI) transition of TUG, and compared effect sizes for metrics from inertial sensors on the thighs to effect sizes for metrics from a sensor placed at the L3 level of the lumbar spine. Twenty-three healthy volunteers were compared to 17 ambulatory persons with MS (PwMS, HAI ≤ 2). Results: During the SI-ST transition, the metric with the largest effect size comparing healthy volunteers to PwMS was the Area Under the Curve of the thigh angular velocity in the pitch direction-representing both thigh and knee extension; the peak of the spine pitch angular velocity during SI-ST also had a large effect size, as did some temporal measures of duration of SI-ST, although less so. During the ST-SI transition the metric with the largest effect size in PwMS was the peak of the spine angular velocity curve in the roll direction. A regression was performed. Discussion: We propose for PwMS that the diminished peak angular velocity during SI-ST directly represents extensor weakness, while the increased roll during ST-SI represents diminished postural control. Conclusions: During the SI-ST transition of TUG, angular velocities can discriminate between healthy volunteers and ambulatory PwMS better than temporal features. Sensor placement on the thighs provides additional discrimination compared to sensor placement at the lumbar spine.
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Thin corpus callosum and amyotrophy in spastic paraplegia–case report and review of literature. - Winner, Beate; Winkler, Jürgen; Bogdahn, Ulrich; Hehr, Ute; et al. (Clinical Neurology and Neurosurgery, 2006)
We report the clinical, structural, functional and genetic characterization of a 37-year-old Caucasian female, presenting as a sporadic case of complicated spastic paraplegia with thin corpus callosum (CC), cognitive impairment, amyotrophy of the hand muscles and a sensorimotor neuropathy and review the literature for spastic paraplegia with thin CC. Magnetic resonance imaging (MRI) examination revealed a thin CC with fronto-parietal cortical atrophy. 18Fluordesoxyglucose positron emission tomography (FDG-PET) showed reduced cortical and thalamic metabolism. By transcranial magnetic stimulation, we delineated a severe impairment of transcallosal inhibition. Sequence analysis did not reveal disease causing mutations in the genes SLC12A6 (Andermann), Spastin (SPG 4), BSCL2 (SPG 17) and Spartin (SPG 20). We reviewed the literature for HSP with thin CC and found 113 HSP patients with thin CC previously described (35 with linkage to chromosome 15q13-15). Thin CC and peripheral neuropathy often appear together in spastic paraplegia and might be indicative for combined degeneration mechanism of central and peripheral axons.

Thrombocytopenia and Clinical Outcomes in Intracerebral Hemorrhage: A Retrospective Multicenter Cohort Study - Mrochen, Anne; Sprügel, Maximilian; Gerner, Stefan; Sembill, Jochen; Lang, Stefan; Lücking, Hannes; Kuramatsu, Joji; Huttner, Hagen (Stroke, 2021)
BACKGROUND AND PURPOSE: The impact of platelets on hematoma enlargement (HE) of intracerebral hemorrhage (ICH) is not yet sufficiently elucidated. Especially the role of reduced platelet counts on HE and clinical outcomes is still poorly understood. This study investigated the influence of thrombocytopenia on HE, functional outcome, and mortality in patients with ICH with or without prior antiplatelet therapy (APT). METHODS: Individual participant data of multicenter cohort studies (multicenter RETRACE program [German-Wide Multicenter Analysis of Oral Anticoagulation-Associated Intracerebral Hemorrhage] and single-center UKER-ICH registry [Universitätsklinikum Erlangen Cohort of Patients With Spontaneous ICH]) were grouped into APT and non-APT ICH patients according to the platelet count, that is, with or without thrombocytopenia (cells <150×109/L). Of all patients, 51.5% (1124 of 2183) were on vitamin K antagonist. Imbalances in baseline characteristics including proportions of vitamin K antagonist patients were addressed using propensity score matching. Outcome analyses included HE (>33%), as well as mortality and functional outcome, after 3 months using the modified Rankin Scale, dichotomized into favorable (modified Rankin Scale score, 0-3) and unfavorable (modified Rankin Scale score, 4-6). RESULTS: Of overall 2252 ICH patients, 11.4% (52 of 458) under APT and 14.0% (242 of 1725) without APT presented with thrombocytopenia on admission. The proportion of patients with HE was not significantly different between patients with or without thrombocytopenia among APT and non-APT ICH patients after propensity score matching (HE: APT patients: 9 of 40 [22.5%] thrombocytopenia versus 27 of 115 [23.5%] nonthrombocytopenia, P=0.89; non-APT patients: 54 of 174 [31.0%] thrombocytopenia versus 106 of 356 [29.8%] nonthrombocytopenia, P=0.77). In both (APT and non-APT) propensity score matching cohorts, there were no significant differences regarding functional outcome. Mortality after 3 months did not differ among non-APT patients, whereas the mortality rate was significantly higher for APT patients with thrombocytopenia versus APT patients with normal platelet count (APT: 29 of 46 [63.0%] thrombocytopenia versus 58 of 140 [41.4%] nonthrombocytopenia, P=0.01; non-APT: 95 of 227 [41.9%] thrombocytopenia versus 178 of 455 [39.1%] nonthrombocytopenia, P=0.49). CONCLUSIONS: Our study implies that thrombocytopenia does not affect rates of HE and functional outcome among ICH patients, neither in patients with nor without APT. In light of increased mortality, the significance of platelet transfusions for ICH patients with thrombocytopenia and previous APT should be explored in future studies.
CRIS-Team Scopus Importer:2021-04-19
Keywords: cohort studies; hematoma enlargement; intracerebral hemorrhage; platelet count; thrombocytopenia

Thymocyte-derived BDNF influences T-cell maturation at the DN3/DN4 transition stage - Linker, Ralf; Lee, De-Hyung; Flach, Anne-Christine; Litke, Tanja; Van Den Brandt, Jens; Reichardt, Holger M.; Lingner, Thomas; Bommhardt, Ursula; Sendtner, Michael; Gold, Ralf; Fluegel, Alexander; Luehder, Fred (European Journal of Immunology, 2015)
Brain-derived neurotrophic factor (BDNF) promotes neuronal survival, regeneration, and plasticity. Emerging evidence also indicates an essential role for BDNF outside the nervous system, for instance in immune cells. We therefore investigated the impact of BDNF on T cells using BDNF knockout (KO) mice and conditional KO mice lacking BDNF specifically in this lymphoid subset. In both settings, we observed diminished T-cell cellularity in peripheral lymphoid organs and an increase in CD4(+) CD44(+) memory T cells. Analysis of thymocyte development revealed diminished total thymocyte numbers, accompanied by a significant increase in CD4/CD8 double-negative (DN) thymocytes due to a partial block in the transition from the DN3 to the DN4 stage. This was neither due to increased thymocyte apoptosis nor defects in the expression of the TCR-? chain or the pre-TCR. In contrast, pERK but not pAKT levels were diminished in DN3 BDNF-deficient thymocytes. BDNF deficiency in T cells did not result in gross deficits in peripheral acute immune responses nor in changes of the homeostatic proliferation of peripheral T cells. Taken together, our data reveal a critical autocrine and/or paracrine role of T-cell-derived BDNF in thymocyte maturation involving ERK-mediated TCR signaling pathways.
EVALuna2:22336

Tideglusib Rescues Neurite Pathology of SPG11 iPSC Derived Cortical Neurons. - Pozner, Tatyana; Schray, Annika; Regensburger, Martin; Lie, Dieter Chichung; Schlötzer-Schrehardt, Ursula; Winkler, Jürgen; Turan, Sören; Winner, Beate (Frontiers in Neuroscience, 2018)
Mutations in SPG11 cause a complicated autosomal recessive form of hereditary spastic paraplegia (HSP). Mechanistically, there are indications for the dysregulation of the GSK3 beta/beta Cat signaling pathway in SPG11. In this study, we tested the therapeutic potential of the GSK3 beta inhibitor, tideglusib, to rescue neurodegeneration associated characteristics in an induced pluripotent stem cells (iPSCs) derived neuronal model from SPG11 patients and matched healthy controls as well as a CRISPR-Cas9 mediated SPG11 knock-out line and respective control. SPG11-iPSC derived cortical neurons, as well as the genome edited neurons exhibited shorter and less complex neurites than controls. Administration of tideglusib to these lines led to the rescue of neuritic impairments. Moreover, the treatment restored increased cell death and ameliorated the membranous inclusions in iPSC derived SPG11 neurons. Our results provide a first evidence for the rescue of neurite pathology in SPG11-HSP by tideglusib. The current lack of disease-modifying treatments for SPG11 and related types of complicated HSP renders tideglusib a candidate compound for future clinical application.
EVALuna2:35778
Keywords: CRISPR knock-out; GSK3β inhibitor; SPG11; hereditary spastic paraplegia; induced pluripotent stem cell; neuronal culture; tideglusib

Time-dependent risk factors for epileptic seizures in glioblastoma patients: A retrospective analysis of 520 cases - Stritzelberger, Jenny; Gesmann, Anna; Fuhrmann, Imke; Brandner, Sebastian; Welte, Tamara; Balk, Stefanie; Eisenhut, Felix; Dörfler, Arnd; Coras, Roland; Adler, Werner; Schwab, Stefan; Putz, Florian; et al. (Epilepsia, 2023)
Objective: Epilepsy is a common comorbidity of glioblastoma. Seizures may occur in various phases of the disease. We aimed to assess potential risk factors for seizures in accordance with the point in time at which they occurred. Methods: We retrospectively analyzed medical files of adult patients with de novo glioblastoma treated at our institution between January 2006 and January 2020. We categorized seizures as preoperative seizures (POS), early postoperative seizures (EPS; before initiation of radio[chemo]therapy [RCT]), seizures during radiotherapy (SDR; during or <30 days after RCT), and posttherapeutic seizures (PTS; ≥30 days after completion of RCT). We addressed associations between patients' characteristics and their seizures. Results: In the final cohort (N = 520), 292 patients experienced seizures. POS, EPS, SDR, and/or PTS occurred in 29.6% (154/520), 6.0% (31/520), 13.8% (70/509), and 36.1% (152/421) of patients, respectively. POS occurred more frequently in patients with higher Karnofsky Performance Scale scores (odds ratio [OR] = 3.27, p =.001) and tumor location in the temporal lobe (OR = 1.51, p =.034). None of the parameters we analyzed was related to the occurrence of EPS. SDR were independently associated with tumor location (parietal lobe, OR = 1.86, p =.027) and POS, but not EPS, and were independent of RCT. PTS were independently associated with tumor progression (OR = 2.32, p <.001) and with occurrence of SDR (OR = 3.36, p <.001), and negatively correlated with temporal lobe location (OR =.58, p <.014). In patients with tumors exclusively located in the temporal lobe, complete tumor resection was associated with a decreased risk of postoperative seizures. Significance: Seizures in glioblastoma patients have various, time-dependent risk factors. Temporal lobe localization was a risk factor for preoperative seizures; surgery may have had a protective effect in these patients. RCT did not have dose-dependent pro- or anticonvulsive effects. PTS were associated with tumor progression.
CRIS-Team Scopus Importer:2023-07-07
Keywords: glioblastoma; radiochemotherapy; seizures; surgery

Timed Up-and-Go phase segmentation in Parkinson's disease patients using unobtrusive inertial sensors - Hauer, Roland; Eskofier, Björn; Barth, Jens; Klucken, Jochen; Reinfelder, Samuel; Klucken, Jochen (Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBS, 2015)
A widely accepted functional motor test for measuring basic mobility capabilities is the `Timed Up-and-Go' (TUG) test. Although several basic mobility tasks are included, only the total time is used as outcome parameter. It has been shown that timings of sub-phases can be used as relevant clinical parameters for the assessment of Parkinson's disease patients. A variety of systems and methods have been proposed for instrumenting the TUG test, but only limited information has been published regarding phase classification. In this paper an automated TUG phase classification methodology is proposed and validated in a study with 16 Parkinson's disease patients. Statistical, signal energy, chronological and gait features were extracted from acceleration and orientation signals of shoe mounted inertial measurement units. The phases `sit to walk', `walking', `first turn', `second turn' and `turn to sit' were segmented in a two stage classifier approach. Strides were used for a separation of the walking phase and classifiers like NaiveBayes, k-Nearest-Neighbor, Support Vector Machine (SVM) and Random Forest for the final phase segmentation. SVM performed best with a mean sensitivity of 81.80 % over all phases. Additionally, the impact of UPDRS and Hoehn & Yahr ratings on the phase times was assessed. The proposed methodology could be used to analyze gait parameters of sub-phases like stride length, stride time, foot clearance, heel-strike or toe-off angle for an improved assessment of Parkinson's disease patients.
EVALuna2:25339

"Time is brain" in relapsing remitting multiple sclerosis : Current treatment concepts in immunotherapy - Linker, Ralf; Kallmann, B. -A.; Kleinschnitz, C.; Rieckmann, P.; Maeurer, M.; Schwab, Sibylle (Der Nervenarzt, 2015)
Despite highly divergent time scales of disease evolution in multiple sclerosis (MS) and ischemic stroke, clear analogies are apparent that may point the way to optimization of MS treatment. Inflammatory disease activity and neurodegeneration may induce potentially irreversible damage to central nervous system structures and thus lead to permanent disability. For the treatment of MS early detection of disease activity and early immunotherapy or treatment optimization are pivotal determinants of long-term outcomes. Such therapeutic concepts may be described with the catchy phrase "time is brain" as coined for the acute thrombolytic treatment of ischemic stroke.For MS a "time is brain" concept would comprise an early initiation of first line therapy as well as sensitive and structured monitoring of disease activity under therapy in conjunction with a low threshold for timely treatment optimization to achieve sustained freedom from measurable disease activity. This approach may substantially improve the long-term outcome in patients who show insufficient response to platform therapies. The intersectorial collaboration in regional MS care networks involving office-based neurologists and specialized MS centers may facilitate the timely use of highly active therapies with their specific benefit-risk profiles thus supporting sustained stabilization of patient quality of life.
EVALuna2:22369

Time trends in incidence of pathological and etiological stroke subtypes during 16 years: the Erlangen Stroke Project - Kolominsky-Rabas, Peter; Wiedmann, Silke; Weingärtner, Michael; Liman, Thomas G.; Endres, Matthias; Schwab, Stefan; Buchfelder, Michael; Heuschmann, Peter U. (Neuroepidemiology, 2015)
Population-based data, which continuously monitors time trends in stroke epidemiology are limited. We investigated the incidence of pathological and etiological stroke subtypes over a 16 year time period.Data were collected within the Erlangen Stroke Project (ESPro), a prospective, population-based stroke register in Germany covering a total study population of 105,164 inhabitants (2010). Etiology of ischemic stroke was classified according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria.Between January 1995 and December 2010, 3,243 patients with first-ever stroke were documented. The median age was 75 and 55% were females. The total stroke incidence decreased over the 16 year study period in men (Incidence Rate Ratio 1995-1996 vs. 2009-2010 (IRR) 0.78; 95% CI 0.58-0.90) but not in women. Among stroke subtypes, a decrease in ischemic stroke incidence (IRR 0.73; 95% CI 0.57-0.93) and of large artery atherosclerotic stroke (IRR 0.27; 95% CI 0.12-0.59) was found in men and an increase of stroke due to small artery occlusion in women (IRR 2.33; 95% CI 1.39-3.90).Variations in time trends of pathological and etiological stroke subtypes were found between men and women that might be linked to gender differences in the development of major vascular risk factors in the study population.
EVALuna2:22434

Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients - Weishaupt, Jochen H.; Körtvélyessy, Péter; Schumann, Peggy; Valkadinov, Ivan; Weyen, Ute; Hesebeck-Brinckmann, Jasper; Weishaupt, Kanchi; Endres, Matthias; Andersen, Peter M.; Regensburger, Martin; Dreger, Marie; Koch, Jan C.; et al. (Communications Medicine, 2024)
Background: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1D91A in Europe, exceeding 1% in Finno-Scandinavia. Methods: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1D91A allele for up to 16 months with tofersen. Results: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1D91A. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1D91A. The results indicate that both mono- and bi-allelic SOD1D91A are causally relevant targets, with a possibly reduced effect size of SOD1D91Ahet. Conclusions: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.
CRIS-Team Scopus Importer:2024-09-20

"TORNADO" - Theranostic One-Step RNA Detector; microfluidic disc for the direct detection of microRNA-134 in plasma and cerebrospinal fluid - Mcardle, Hazel; Jimenez-Mateos, Eva M.; Raoof, Rana; Carthy, Eadaoin; Boyle, David; Elnaggar, Hany; Delanty, Norman; Hamer, Hajo; Dogan, Muejgdan; Huchtemann, Tessa; Koertvelyessy, Peter; Rosenow, Felix; et al. (Scientific Reports, 2017)
Diagnosis of seizure disorders such as epilepsy currently relies on clinical examination and electroencephalogram recordings and is associated with substantial mis-diagnosis. The miRNA, miR-134 (MIR134 in humans), has been found to be elevated in brain tissue after experimental status epilepticus and in human epilepsy cells and their detection in biofluids may serve as unique biomarkers. miRNAs from unprocessed human plasma and human cerebrospinal fluid samples were used in a novel electrochemical detection based on electrocatalytic platinum nanoparticles inside a centrifugal microfluidic device where the sandwich assay is formed using an event triggered release system, suitable for the rapid point-of-care detection of low abundance biomarkers of disease. The device has the advantage of controlling the rotation speed of the centrifugal device to pump nanoliter volumes of fluid at a set time and manipulate the transfer of liquids within the device. The centrifugal platform improves reaction rates and yields by proposing efficient mixing strategies to overcome diffusion-limited processes and improve mass transport rates, resulting in reduced hybridization times with a limit of detection of 1 pM target concentration. Plasma and cerebrospinal fluid samples (unprocessed) from patients with epilepsy or who experienced status epilepticus were tested and the catalytic response obtained was in range of the calibration plot. This study demonstrates a rapid and simple detection for epilepsy biomarkers in biofluid.
EVALuna2:22536

Towards a multi-sensor system for the diagnosis of neurological disorders - Tenner, Felix; Schramm, Axel; Söhle, Mona; Regensburger, Martin; Wirthmann, Elisa; Zalevsky, Zeev; Schmidt, Michael (2016 IEEE International Conference on Advanced Intelligent Mechatronics (AIM), 2016)

Towards Mobile Gait Analysis: Concurrent Validity and Test-Retest Reliability of an Inertial Measurement System for the Assessment of Spatio-Temporal Gait Parameters - Kluge, Felix; Gaßner, Heiko; Hannink, Julius; Pasluosta, Cristian Federico; Klucken, Jochen; Eskofier, Björn (Sensors, 2017)
EVALuna2:33509

Toxic Metamorphosis-How Changes from Lysosomal to Cytosolic pH Modify the Alpha-Synuclein Aggregation Pattern - Eymsh, Bisher; Drobny, Alice; Heyn, Timon R.; Xiang, Wei; Lucius, Ralph; Schwarz, Karin; Keppler, Julia K.; Zunke, Friederike; Arnold, Philipp (Biomacromolecules, 2020)
Alpha-synuclein (aSyn) is a cytosolic, aggregation-prone protein that is associated with neurodegenerative disorders like Parkinsons disease. Interestingly, the protein can appear in different conformations, including monomeric and oligomeric forms as well as amyloid fibrils. Its individual structural constituents seem to be dependent on various factors and the composition of the respective cellular surroundings. Although under physiological conditions, most aSyn is found in the cytosol and synapses of neurons, aSyn can also be found in lysosomal compartments, where it gets degraded. We here compare the assembly speed, morphology, folding state, and spreading of aSyn at cytosolic pH (pH 7.4) and lysosomal pH (pH 5) using Thioflavin T, transmission electron microscopy, circular dichroism, and Fourier transform infrared spectroscopy. Interestingly, we found substantial differences between aSyn aggregation under neutral and acidic pH conditions, like those present in cytosolic and lysosomal cellular compartments. Also, lysosomal aSyn enriched from an aSyn-overexpressing cell line was able to seed aggregation in a concentration-dependent manner. Moreover, we observed that aSyn aggregates formed under in vitro lysosomal pH (pH 5) conditions were not stable at neutral pH and collapsed into partly soluble aggregates with changed structural characteristics. Our findings have meaningful implications in intracellular toxicity events as well as in lysis procedures for molecular and structural characterization of intracellular aSyn conformers.
CRIS-Team WoS Importer:2021-01-15

Toxic retrobulbar neuritis due to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-based chronic sinusitis in the left sphenoid sinus: a case report - Schapher, Mirco; Brügel, Jacob; Güner, Fabian; Volbers, Bastian; Eichhorn, Philip; Agaimy, Abbas; Berger, Magdalena; Mardin, Christian; Dörfler, Arnd; Hock, Stefan (Journal of Medical Case Reports, 2023)
BACKGROUND: Abrupt visual impairment constitutes a medical urgency, necessitating an interdisciplinary diagnostic and therapeutic approach owing to the broad spectrum of potential etiologies, thereby engaging numerous medical specialties. CASE PRESENTATION: A 21-year-old Mixed White and Asian female patient, with medical history of nonsteroidal antiinflammatory drug-exacerbated respiratory disease necessitating previous sinus surgery, reported sudden monocular vision loss. Unremarkable ophthalmological examination of the fellow eye and hematological parameters, save for a slight elevation in lymphocytes and eosinophils, were observed. Imaging studies indicated recurrence of bilateral chronic rhinosinusitis with nasal polyps and a mucocele in the left sphenoid sinus, accompanied by bony structural deficits. Emergency revision sinus surgery, guided by navigation, was promptly performed. The patient received treatment with methylprednisolone, ceftriaxone, cyanocobalamin, pyridoxine, thiamine, and acetylsalicylic acid. During the hospital stay, she developed steroid-induced glaucoma, which was subsequently managed successfully. Negative microbiological swabs, along with pathohistological evidence of increased tissue eosinophilia and the patient's clinical history, led to the diagnosis of toxic retrobulbar neuritis secondary to recurrent nonsteroidal antiinflammatory drug-exacerbated respiratory disease-associated chronic rhinosinusitis of the left sphenoid sinus. CONCLUSIONS: In cases of acute unilateral vision loss, optic neuritis is a highly probable differential diagnosis and may be induced by pathologies of the paranasal sinuses. Nonsteroidal antiinflammatory drug-exacerbated respiratory disease, a subtype of chronic rhinosinusitis, is associated with type 2 inflammation, which is increasingly recognized for its role in the pathogenesis of bronchial asthma, eosinophilic esophagitis, and atopic eczema. Clinicians should consider chronic rhinosinusitis as a potential differential diagnosis in unilateral visual loss and be cognizant of the rising significance of type 2 inflammations, which are relevant to a variety of diseases.
CRIS-Team Scopus Importer:2023-08-11
Keywords: Blindness; Case report; Inflammation mediators; Neuritis; Optic; Sinusitis

Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry - Röder, Sebastian; Bonnin, Elisa A.; Wu, Ting Di; Guerquin-Kern, Jean Luc; Jabari, Samir; Brandner, Sebastian; Eyüpoglu, Ilker Yasin; Gollwitzer, Stephanie; Hamer, Hajo; Gerner, Stefan; Döppner, Thorsten R.; Rummel, Christoph; et al. (Frontiers in Neuroscience, 2023)
Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.
CRIS-Team Scopus Importer:2023-11-03
Keywords: adult; cell turnover; DNA-labeling; glioblastoma; hippocampus; Nano-SIMS; neurogenesis

Tracking micro-optical resonances for identifying and sensing novel procaspase-3 protein marker released from cell cultures in response to toxins - Chen, Ying-Jen; Xiang, Wei; Klucken, Jochen; Vollmer, Frank; Klucken, Jochen (Nanotechnology, 2016)
The response of cells to toxins is commonly investigated by detecting intracellular markers for cell death, such as caspase proteins. This requires the introduction of labels by the permeabilization or complete lysis of cells. Here we introduce a non-invasive tool for monitoring a caspase protein in the extracellular medium. The tool is based on highly sensitive optical micro-devices, referred to as whispering-gallery mode biosensors (WGMBs). WGMBs are functionalized with antibodies for the specific and label-free detection of procaspase-3 released from human embryonic kidney HEK293 and neuroglioma H4 cells after introducing staurosporine and rotenone toxins, respectively. Additional tests show that the extracellular accumulation of procaspase-3 is concomitant with a decrease in cell viability. The hitherto unknown release of procaspase-3 from cells in response to toxins and its accumulation in the medium is further investigated by Western blot, showing that the extracellular detection of procaspase-3 is interrelated with cytotoxicity of alpha-synuclein protein (aSyn) overexpressed in H4 cells. These studies provide evidence for procaspase-3 as a novel extracellular biomarker for cell death, with applications in cytotoxicity tests. Such WGMBs could be applied to further identify as-yet unknown extracellular biomarkers using established antibodies against intracellular antigens.
EVALuna2:4742

Transcription factor Olig2 is a major downstream effector of histone demethylase Phf8 during oligodendroglial development - Kremp, Marco; Aberle, Tim; Sock, Elisabeth; Bohl, Bettina; Hillgärtner, Simone; Winkler, Jürgen; Wegner, Michael (Glia, 2024)
The plant homeodomain finger protein Phf8 is a histone demethylase implicated by mutation in mice and humans in neural crest defects and neurodevelopmental disturbances. Considering its widespread expression in cell types of the central nervous system, we set out to determine the role of Phf8 in oligodendroglial cells to clarify whether oligodendroglial defects are a possible contributing factor to Phf8-dependent neurodevelopmental disorders. Using loss- and gain-of-function approaches in oligodendroglial cell lines and primary cell cultures, we show that Phf8 promotes the proliferation of rodent oligodendrocyte progenitor cells and impairs their differentiation to oligodendrocytes. Intriguingly, Phf8 has a strong positive impact on Olig2 expression by acting on several regulatory regions of the gene and changing their histone modification profile. Taking the influence of Olig2 levels on oligodendroglial proliferation and differentiation into account, Olig2 likely acts as an important downstream effector of Phf8 in these cells. In line with such an effector function, ectopic Olig2 expression in Phf8-deficient cells rescues the proliferation defect. Additionally, generation of human oligodendrocytes from induced pluripotent stem cells did not require PHF8 in a system that relies on forced expression of Olig2 during oligodendroglial induction. We conclude that Phf8 may impact nervous system development at least in part through its action in oligodendroglial cells.
CRIS-Team Scopus Importer:2024-07-12
Keywords: chromatin; histone demethylase; myelin; oligodendrocyte; Siderius–Hamel syndrome

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS - Krach, Florian; Batra, Ranjan; Wheeler, Emily C.; Vu, Anthony Q.; Wang, Ruth; Hutt, Kasey; Rabin, Stuart J.; Baughn, Michael W.; Libby, Ryan T.; Diaz-Garcia, Sandra; Stauffer, Jennifer; Pirie, Elaine; et al. (Acta Neuropathologica, 2018)
Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched surviving motor neurons (MNs) from lumbar spinal cords of sALS patients with rostral onset and caudal progression. After correcting for immunological background, we discover a highly specific gene expression signature for sALS that is associated with phosphorylated TDP-43 (pTDP-43) pathology. Transcriptome-pathology correlation identified casein kinase 1 epsilon (CSNK1E) mRNA as tightly correlated to levels of pTDP-43 in sALS patients. Enhanced crosslinking and immunoprecipitation in human sALS patient- and healthy control-derived frontal cortex, revealed that TDP-43 binds directly to and regulates the expression of CSNK1E mRNA. Additionally, we were able to show that pTDP-43 itself binds RNA. CK1E, the protein product of CSNK1E, in turn interacts with TDP-43 and promotes cytoplasmic accumulation of pTDP-43 in human stem-cell-derived MNs. Pathological TDP-43 phosphorylation is therefore, reciprocally regulated by CK1E activity and TDP-43 RNA binding. Our framework of transcriptome-pathology correlations identifies candidate genes with relevance to novel mechanisms of neurodegeneration.
EVALuna2:35779