(23)Na MRI reveals persistent sodium accumulation in tumefactive MS lesions - Huhn, Konstantin; Mennecke, Angelika; Linz, Peter; Tschunko, Franz; Kästle, Nicola; Nagel, Armin Michael; Uder, Michael; Dörfler, Arnd; Linker, Ralf; Engelhorn, Tobias (Journal of the Neurological Sciences, 2017)
Chronic inflammatory demyelinating diseases of the CNS typically show a limited lesion size. However, extended lesions may appear with an atypical configuration. Large lesions with a diameter>2cm accompanied by tumor-like edema are entitled "tumefactive" and may occur in multiple sclerosis (MS) and other demyelinating diseases. Historically, differential diagnosis often requires histological analysis. Therefore, advanced imaging techniques are warranted to allow for a precise non-invasive diagnosis. Cerebral sodium ((23)Na) MRI was recently described as a new method to investigate in vivo sodium accumulation. Indicating extended sodium levels in MS lesions, (23)Na MRI is a promising differential diagnostic tool further elucidating the role of sodium in demyelinating lesions.Repetitive (23)Na MRI measurements in a MS patient with a tumefactive demyelinating lesion providing insight into the medium-term course of cerebral sodium levels.(23)Na MRI depicts persistent lesional sodium accumulation after anti-inflammatory treatment and provides the opportunity of a non-invasive, in vivo analysis of sodium levels in inflammatory CNS lesions without need for contrast enhancing media. As a result of the extended dimension, tumefactive lesions may have an appropriate size for the analysis of inflammatory demyelination by (23)Na MRI with sufficient resolution.
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3D Body Twin: Improving Human Gait Visualizations Using Personalized Avatars - Zieger, Daniel; Güthlein, Florian; Henningson, Jann-Ole; Jakob, Verena; Gaßner, Heiko; Shanbhag, Julian; Fleischmann, Sophie; Miehling, Jörg; Wartzack, Sandro; Eskofier, Björn; Winkler, Jürgen; Egger, Bernhard; et al. (ShapeMI 2024, 2024)
We propose an interactive visualization and reconstruction system for gait pattern analysis that creates a more realistic visualization of the patient than contemporary stick figure-like representations. It supports thorough gait pattern analysis, and enables unbiased inter- and intra-patient comparisons as well as longitudinal studies. Our system takes as input 3D motion capture data, but can be further constrained using readily available metadata or layman-accessible measurements. A statistical shape model is then fitted to the motion capture and personal metadata. The result is an immediate and interactive visualization of an animated 3D twin. Our system handles different marker setups and can thus be applied to already existing data. We further show that we can infer realistic body models with only a few of markers. A survey with medical experts confirms the clinical applicability of our method. <br

3T-MRI in patients with pharmacoresistant epilepsy and a vagus nerve stimulator: a pilot study - Roesch, Julie; Hamer, Hajo; Mennecke, Angelika; Kasper, Burkhard; Engelhorn, Tobias; Dörfler, Arnd; Graf, Wolfgang (Epilepsy Research, 2015)
For safe 3T-MRI of patients with VNS (vagus nerve stimulator), specific conditions are mandatory. However, application of these conditions can lead to a loss of image quality. In this work, we evaluated the diagnostic value of 3T-MRI in VNS patients with pharmacoresistant epilepsy.Using a transmit-and-receive head coil and adapting our sequences to allow for low SAR (specific absorption rate), we examined 15 patients with pharmacoresistant epilepsy. Diagnostic quality was assessed by comparison of the SNR (signal to noise ratio) and CNR (contrast to noise ratio) of the hippocampus, the grey-white matter contrast and epileptogenic lesions to images of patients without VNS acquired with our routine 3T-MRI protocol and the 32-channel head coil.3T-MRI is feasible in VNS-patients. Image quality is adequate for detection and follow-up of epileptogenic lesions such as ganglioglioma or PNH (periventricular nodular heterotopia). Due to a significant reduction of SNR and CNR, the diagnostic value for subtle lesions may be decreased. Overall, the feasibility of 3T-MRI is beneficial in the diagnostic workup and follow-up of epilepsy-patients with VNS.
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47 patients with FLNA associated periventricular nodular heterotopia - Lange, Max; Kasper, Burkhard; Bohring, Axel; Rutsch, Frank; Kluger, Gerhard; Hoffjan, Sabine; Spranger, Stephanie; Behnecke, Anne; Ferbert, Andreas; Hahn, Andreas; Oehl-Jaschkowitz, Barbara; Graul-Neumann, Luitgard; et al. (Orphanet Journal of Rare Diseases, 2015)
Heterozygous loss of function mutations within the Filamin A gene in Xq28 are the most frequent cause of bilateral neuronal periventricular nodular heterotopia (PVNH). Most affected females are reported to initially present with difficult to treat seizures at variable age of onset. Psychomotor development and cognition may be normal or mildly to moderately impaired. Distinct associated extracerebral findings have been observed and may help to establish the diagnosis including patent ductus arteriosus Botalli, progressive dystrophic cardiac valve disease and aortic dissection, chronic obstructive lung disease or chronic constipation. Genotype-phenotype correlations could not yet be established.Sanger sequencing and MLPA was performed for a large cohort of 47 patients with Filamin A associated PVNH (age range 1 to 65 years). For 34 patients more detailed clinical information was available from a structured questionnaire and medical charts on family history, development, epileptologic findings, neurological examination, cognition and associated clinical findings. Available detailed cerebral MR imaging was assessed for 20 patients.Thirty-nine different FLNA mutations were observed, they are mainly truncating (37/39) and distributed throughout the entire coding region. No obvious correlation between the number and extend of PVNH and the severity of the individual clinical manifestation was observed. 10 of the mutation carriers so far are without seizures at a median age of 19.7 years. 22 of 24 patients with available educational data were able to attend regular school and obtain professional education according to age.We report the clinical and mutation spectrum as well as MR imaging for a large cohort of 47 patients with Filamin A associated PVNH including two adult males. Our data are reassuring in regard to psychomotor and cognitive development, which is within normal range for the majority of patients. However, a concerning median diagnostic latency of 17 to 20 years was noted between seizure onset and the genetic diagnosis, intensely delaying appropriate medical surveillance for potentially life threatening cardiovascular complications as well as genetic risk assessment and counseling prior to family planning for this X-linked dominant inherited disorder with high perinatal lethality in hemizygous males.
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7 Tesla Hippocampal Subfield Analyses In Patients With Medically Refractory Epilepsy And Hippocampal Sclerosis - Roessler, K.; Roesch, Johannes; Coras, R.; Blümcke, Ingmar; Hamer, Hajo; Buchfelder, Michael; Rampp, Stefan; Mennecke, Angelika (EPILEPSIA, 2019)
CRIS-Team WoS Importer:2019-11-15

7T MRI features in control human hippocampus and hippocampal sclerosis: An ex vivo study with histologic correlations - Coras, Roland; Milesi, Gloria; Zucca, Ileana; Mastropietro, Alfonso; Scotti, Alessandro; Figini, Matteo; Muehlebner, Angelika; Heß, Andreas; Graf, Wolfgang; Tringali, Giovanni; Blümcke, Ingmar; Villani, Flavio; et al. (Epilepsia, 2014)
Hippocampal sclerosis (HS) is the major structural brain lesion in patients with temporal lobe epilepsy (TLE). However, its internal anatomic structure remains difficult to recognize at 1.5 or 3 Tesla (T) magnetic resonance imaging (MRI), which allows neither identification of specific pathology patterns nor their proposed value to predict postsurgical outcome, cognitive impairment, or underlying etiologies. We aimed to identify specific HS subtypes in resected surgical TLE samples on 7T MRI by juxtaposition with corresponding histologic sections.Fifteen nonsclerotic and 18 sclerotic hippocampi were studied ex vivo using an experimental 7T MRI scanner. T2 -weighted images (T2wi) and diffusion tensor imaging (DTI) data were acquired and validated using a systematic histologic analysis of same specimens along the anterior-posterior axis of the hippocampus.In nonsclerotic hippocampi, differences in MR intensity could be assigned to seven clearly recognizable layers and anatomic boundaries as confirmed by histology. All hippocampal subfields could be visualized also in the hippocampal head with three-dimensional imaging and angulated coronal planes. Only four discernible layers were identified in specimens with histopathologically confirmed HS. All sclerotic hippocampi showed a significant atrophy and increased signal intensity along the pyramidal cell layer. Changes in DTI parameters such as an increased mean diffusivity, allowed to distinguish International League Against Epilepsy (ILAE) HS type 1 from type 2. Whereas the increase in T2wi signal intensities could not be attributed to a distinct specific histopathologic substrate, that is, decreased neuronal or increased glial cell densities, intrahippocampal projections and fiber tracts were distorted in HS specimens suggesting a complex disorganization of the cellular composition, fiber networks, as well as its extracellular matrix.Our data further advocate high-resolution MRI as a helpful and promising diagnostic tool for the investigation of hippocampal pathology along the anterior-posterior extent in TLE, as well as in other neurologic and neurodegenerative disorder
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7 tricks for 7 T CEST: Improving the reproducibility of multipool evaluation provides insights into the effects of age and the early stages of Parkinson's disease - Mennecke, Angelika; Khakzar, Katrin M.; German, Alexander; Herz, Kai; Fabian, Moritz; Liebert, Andrzej; Blümcke, Ingmar; Kasper, Burkhard; Nagel, Armin Michael; Laun, Frederik Bernd; Schmidt, Manuel; Winkler, Jürgen; et al. (NMR in Biomedicine, 2022)
The objective of the current study was to optimize the postprocessing pipeline of 7 T chemical exchange saturation transfer (CEST) imaging for reproducibility and to prove this optimization for the detection of age differences and differences between patients with Parkinson's disease versus normal subjects. The following 7 T CEST MRI experiments were analyzed: repeated measurements of a healthy subject, subjects of two age cohorts (14 older, seven younger subjects), and measurements of 12 patients with Parkinson's disease. A slab-selective, (Formula presented.) -homogeneous parallel transmit protocol was used. The postprocessing, consisting of motion correction, smoothing, (Formula presented.) -correction, normalization, denoising, (Formula presented.) -correction and Lorentzian fitting, was optimized regarding the intrasubject and intersubject coefficient of variation (CoV) of the amplitudes of the amide pool and the aliphatic relayed nuclear Overhauser effect (rNOE) pool within the brain. Seven “tricks” for postprocessing accomplished an improvement of the mean voxel CoV of the amide pool and the aliphatic rNOE pool amplitudes of less than 5% and 3%, respectively. These postprocessing steps are: motion correction with interpolation of the motion of low-signal offsets (1) using the amide pool frequency offset image as reference (2), normalization of the Z-spectrum using the outermost saturated measurements (3), (Formula presented.) correction of the Z-spectrum with moderate spline smoothing (4), denoising using principal component analysis preserving the 11 highest intensity components (5), (Formula presented.) correction using a linear fit (6) and Lorentzian fitting using the five-pool fit model (7). With the optimized postprocessing pipeline, a significant age effect in the amide pool can be detected. Additionally, for the first time, an aliphatic rNOE contrast between subjects with Parkinson's disease and age-matched healthy controls in the substantia nigra is detected. We propose an optimized postprocessing pipeline for CEST multipool evaluation. It is shown that by the use of these seven “tricks”, the reproducibility and, thus, the statistical power of a CEST measurement, can be greatly improved and subtle changes can be detected.
CRIS-Team Scopus Importer:2022-03-25
Keywords: 7 T; age; amide; CEST; Lorentzian fitting; Parkinson; rNOE; standardization

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis - Krach, Florian; Wheeler, Emily C.; Regensburger, Martin; Börstler, Tom; Wend, Holger; Vu, Anthony Q.; Wang, Ruth; Reischl, Stephanie; Boldt, Karsten; Batra, Ranjan; Aigner, Stefan; Ravits, John; et al. (Acta Neuropathologica, 2022)
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.
CRIS-Team WoS Importer:2022-07-08

Abrogating Native α-Synuclein Tetramers in Mice Causes a L-DOPA-Responsive Motor Syndrome Closely Resembling Parkinson's Disease - Nuber, Silke; Rajsombath, Molly; Minakaki, Georgia; Winkler, Jürgen; Müller, Christian P.; Ericsson, Maria; Caldarone, Barbara; Dettmer, Ulf; Selkoe, Dennis J. (Neuron, 2018)
α-Synuclein (αS) regulates vesicle exocytosis but forms insoluble deposits in Parkinson's disease (PD). Developing disease-modifying therapies requires animal models that reproduce cardinal features of PD. We recently described a previously unrecognized physiological form of αS, α-helical tetramers, and showed that familial PD-causing missense mutations shift tetramers to aggregation-prone monomers. Here, we generated mice expressing the fPD E46K mutation plus 2 homologous E→K mutations in adjacent KTKEGV motifs. This tetramer-abrogating mutant causes phenotypes similar to PD. αS monomers accumulate at membranes and form vesicle-rich inclusions. αS becomes insoluble, proteinase K-resistant, Ser129-phosphorylated, and C-terminally truncated, as in PD. These changes affect regions controlling motor behavior, including a decrease in nigrostriatal dopaminergic neurons. The outcome is a progressive motor syndrome including tremor and gait and limb deficits partially responsive to L-DOPA. This fully penetrant phenotype indicates that tetramers are required for normal αS homeostasis and that chronically shifting tetramers to monomers may result in PD, with attendant therapeutic implications.
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Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data - Al-Shahi Salman, Rustam; Frantzias, Joseph; Lee, Robert J.; Battey, Thomas W.K.; Ayres, Alison M.; Goldstein, Joshua N.; Mayer, Stephan A.; Steiner, Thorsten; Wang, Xia; Arima, Hisatomi; Hasegawa, Hitoshi; Oishi, Makoto; et al. (Lancet Neurology, 2018)
BACKGROUND: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. METHODS: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. FINDINGS: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07). INTERPRETATION: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. FUNDING: UK Medical Research Council and British Heart Foundation.
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Abstract: Automatic Dementia Screening and Scoring by Applying Deep Learning on Clock-drawing Tests - Chen, Shuqing; Stromer, Daniel; Alnasser Alabdalrahim, Harb; Schwab, Stefan; Weih, Markus; Maier, Andreas (Informatik aktuell, 2021)
CRIS-Team Scopus Importer:2021-04-09

A Case Report of Severe Delirium after Amantadine Withdrawal - Marxreiter, Franz; Winkler, Jürgen; Uhl, Martin; Madzar, Dominik (Case Reports in Neurology, 2017)
Amantadine is frequently used in addition to dopaminergic substances like dopamine agonists or L-Dopa in advanced Parkinson disease (PD). However, adverse effects like hallucinations limit its use. PD patients developing severe psychotic symptoms upon treatment with either dopaminergic substances and/or amantadine need to stop intake of any psychotropic substance. Here, we report the case of a 71-year-old PD patient without previously known cognitive impairment. He presented with drug-induced psychotic symptoms due to changes in his therapeutic regimen (increase in COMT inhibitors, newly introduced MAO B inhibitors). Also, amantadine had been part of his long-term medication for more than 2 years. The severity of his psychotic symptoms required a L-Dopa monotherapy. After changing his medication, the patient developed severe delirium that resolved rapidly after i.v. amantadine infusion, suggesting an amantadine withdrawal syndrome. Amantadine withdrawal syndrome is a rare adverse event that may present even in PD patients without cognitive impairment. This case report highlights the need for a gradual withdrawal of amantadine even if acute and severe psychotic symptoms are present. Moreover, this is the first report of a cognitively unimpaired patient developing an amantadine withdrawal syndrome.
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Accumulation of alpha-synuclein within the liver, potential role in the clearance of brain pathology associated with Parkinson's disease - Reyes, Juan F.; Ekmark-Lewen, Sara; Perdiki, Marina; Klingstedt, Therese; Hoffmann, Alana; Wiechec, Emilia; Nilsson, Per; Nilsson, K. Peter R.; Alafuzoff, Irina; Ingelsson, Martin; Hallbeck, Martin (Acta Neuropathologica Communications, 2021)
Alpha-synuclein (alpha-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that alpha-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that alpha-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification. We further demonstrate that cultured human hepatocytes readily internalize oligomeric alpha-syn assemblies mediated, at least in part, by the gap junction protein connexin-32 (Cx32). Moreover, we identified a time-dependent accumulation of alpha-syn within the liver of three different transgenic (tg) mouse models expressing human alpha-syn under CNS-specific promoters, despite the lack of alpha-syn mRNA expression within the liver. Such a brain-to-liver transmission route could be further corroborated by detection of alpha-syn pathology within the liver of wild type mice one month after a single striatal alpha-syn injection. In contrast to the synucleinopathy models, aged mice modeling AD rarely show any amyloid-beta (Ass) deposition within the liver. In human post-mortem liver tissue, we identified cases with neuropathologically confirmed alpha-syn pathology containing alpha-syn within hepatocellular structures to a higher degree (75%) than control subjects without alpha-syn accumulation in the brain (57%). Our results reveal that alpha-syn accumulates within the liver and may be derived from the brain or other peripheral sources. Collectively, our findings indicate that the liver may play a role in the clearance and detoxification of pathological proteins in PD and related synucleinopathies.
CRIS-Team WoS Importer:2021-04-02

Accumulation of Iron Oxide-Based Contrast Agents in Rabbit Atherosclerotic Plaques in Relation to Plaque Age and Vulnerability Features - Sekita, Alexander; Unterweger, Harald; Berg, Sonja; Ohlmeyer, Sabine; Bäuerle, Tobias; Zheng, Kang H.; Coolen, Bram F.; Nederveen, Aart J.; Cabella, Claudia; Rossi, Silvia; Stroes, Erik S.G.; Alexiou, Christoph; et al. (International Journal of Nanomedicine, 2024)
Purpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI). Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats. Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg. Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.
CRIS-Team Scopus Importer:2024-03-08
Keywords: atherosclerosis; histology; macrophages; plaque vulnerability; rabbit model; SPION-enhanced MRI; tissue iron

Accumulation of oligomer-prone ?-synuclein exacerbates synaptic and neuronal degeneration in vivo - Rockenstein, Edward; Nuber, Silke; Overk, Cassia R.; Ubhi, Kiren; Mante, Michael; Patrick, Christina; Adame, Anthony; Trejo-Morales, Margarita; Gerez, Juan; Picotti, Paola; Jensen, Poul H.; Campioni, Silvia; et al. (Brain, 2014)
In Parkinson's disease and dementia with Lewy bodies, ?-synuclein aggregates to form oligomers and fibrils; however, the precise nature of the toxic ?-synuclein species remains unclear. A number of synthetic ?-synuclein mutations were recently created (E57K and E35K) that produce species of ?-synuclein that preferentially form oligomers and increase ?-synuclein-mediated toxicity. We have shown that acute lentiviral expression of ?-synuclein E57K leads to the degeneration of dopaminergic neurons; however, the effects of chronic expression of oligomer-prone ?-synuclein in synapses throughout the brain have not been investigated. Such a study could provide insight into the possible mechanism(s) through which accumulation of ?-synuclein oligomers in the synapse leads to neurodegeneration. For this purpose, we compared the patterns of neurodegeneration and synaptic damage between a newly generated mThy-1 ?-synuclein E57K transgenic mouse model that is prone to forming oligomers and the mThy-1 ?-synuclein wild-type mouse model (Line 61), which accumulates various forms of ?-synuclein. Three lines of ?-synuclein E57K (Lines 9, 16 and 54) were generated and compared with the wild-type. The ?-synuclein E57K Lines 9 and 16 were higher expressings of ?-synuclein, similar to ?-synuclein wild-type Line 61, and Line 54 was a low expressing of ?-synuclein compared to Line 61. By immunoblot analysis, the higher-expressing ?-synuclein E57K transgenic mice showed abundant oligomeric, but not fibrillar, ?-synuclein whereas lower-expressing mice accumulated monomeric ?-synuclein. Monomers, oligomers, and fibrils were present in ?-synuclein wild-type Line 61. Immunohistochemical and ultrastructural analyses demonstrated that ?-synuclein accumulated in the synapses but not in the neuronal cells bodies, which was different from the ?-synuclein wild-type Line 61, which accumulates ?-synuclein in the soma. Compared to non-transgenic and lower-expressing mice, the higher-expressing ?-synuclein E57K mice displayed synaptic and dendritic loss, reduced levels of synapsin 1 and synaptic vesicles, and behavioural deficits. Similar alterations, but to a lesser extent, were seen in the ?-synuclein wild-type mice. Moreover, although the oligomer-prone ?-synuclein mice displayed neurodegeneration in the frontal cortex and hippocampus, the ?-synuclein wild-type only displayed neuronal loss in the hippocampus. These results support the hypothesis that accumulating oligomeric ?-synuclein may mediate early synaptic pathology in Parkinson's disease and dementia with Lewy bodies by disrupting synaptic vesicles. This oligomer-prone model might be useful for evaluating therapies directed at oligomer reduction.
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Accuracy of Dose-Saving Artificial-Intelligence-Based 3D Angiography (3DA) for Grading of Intracranial Artery Stenoses: Preliminary Findings - Lang, Stefan; Hölter, Philip; Schmidt, Manuel; Mrochen, Anne; Kuramatsu, Joji; Kaethner, Christian; Roser, Philipp; Kowarschik, Markus; Dörfler, Arnd (Diagnostics, 2023)
Background and purpose: Based on artificial intelligence (AI), 3D angiography (3DA) is a novel postprocessing algorithm for “DSA-like” 3D imaging of cerebral vasculature. Because 3DA requires neither mask runs nor digital subtraction as the current standard 3D-DSA does, it has the potential to cut the patient dose by 50%. The object was to evaluate 3DA’s diagnostic value for visualization of intracranial artery stenoses (IAS) compared to 3D-DSA. Materials and methods: 3D-DSA datasets of IAS (nIAS = 10) were postprocessed using conventional and prototype software (Siemens Healthineers AG, Erlangen, Germany). Matching reconstructions were assessed by two experienced neuroradiologists in consensus reading, considering image quality (IQ), vessel diameters (VD1/2), vessel-geometry index (VGI = VD1/VD2), and specific qualitative/quantitative parameters of IAS (e.g., location, visual IAS grading [low-/medium-/high-grade] and intra-/poststenotic diameters [dintra-/poststenotic in mm]). Using the NASCET criteria, the percentual degree of luminal restriction was calculated. Results: In total, 20 angiographic 3D volumes (n3DA = 10; n3D-DSA = 10) were successfully reconstructed with equivalent IQ. Assessment of the vessel geometry in 3DA datasets did not differ significantly from 3D-DSA (VD1: r = 0.994, p = 0.0001; VD2:r = 0.994, p = 0.0001; VGI: r = 0.899, p = 0.0001). Qualitative analysis of IAS location (3DA/3D-DSA:nICA/C4 = 1, nICA/C7 = 1, nMCA/M1 = 4, nVA/V4 = 2, nBA = 2) and the visual IAS grading (3DA/3D-DSA:nlow-grade = 3, nmedium-grade = 5, nhigh-grade = 2) revealed identical results for 3DA and 3D-DSA, respectively. Quantitative IAS assessment showed a strong correlation regarding intra-/poststenotic diameters (rdintrastenotic = 0.995, pdintrastenotic = 0.0001; rdpoststenotic = 0.995, pdpoststenotic = 0.0001) and the percentual degree of luminal restriction (rNASCET 3DA = 0.981; pNASCET 3DA = 0.0001). Conclusions: The AI-based 3DA is a resilient algorithm for the visualization of IAS and shows comparable results to 3D-DSA. Hence, 3DA is a promising new method that allows a considerable patient-dose reduction, and its clinical implementation would be highly desirable.
CRIS-Team Scopus Importer:2023-03-10
Keywords: 3D angiography; artificial intelligence; deep learning; dose reduction; flat-detector computed tomography (FD-CT); innovative postprocessing; intracranial artery stenosis

Acid sphingomyelinase controls dopamine activity and responses to appetitive stimuli in mice - Kalinichenko, Liubov; Hammad, Lara; Reichel, Martin; Kohl, Zacharias; Gulbins, Erich; Kornhuber, Johannes; Müller, Christian P. (Brain Research Bulletin, 2019)
Alcohol use disorder and depression show a high comorbidity at clinical level with no treatment available selectively for this condition. A hyperfunction of acid sphingomyelinase (ASM) and resulting ceramide overload were recently identified as one pathway into this comorbidity. Here we analyzed the involvement of ASM, one of the main enzymes involved in ceramide synthesis, in the molecular control of monoaminergic systems in their basal activity and in response to pharmacological and natural reinforcers. The effects of alcohol and a palatable food on the extracellular levels of dopamine (DA), serotonin (5-HT), and noradrenaline (NE) were measured by in-vivo microdialysis in ASM overexpressing mice (tgASM). We found reduced basal extracellular DA levels in the nucleus accumbens (Nac) and dorsal hippocampus (DH) of tgASM mice with little effect on 5-HT and NE levels. In contrast, ASM overexpression potentiated the DA response to alcohol (2 g/kg, i.p.) in the DH and Nac, but reduced NE responses. DA and NE responses to a food stimulus were not altered in tgASM mice, but the Nac 5-HT response was enhanced.
CRIS-Team WoS Importer:2019-03-15

A common SCN1A splice-site polymorphism modifies the effect of carbamazepine on cortical excitability–a pharmacogenetic transcranial magnetic stimulation study - Menzler, Katja; Hermsen, Anke; Balkenhol, Katharina; Duddek, Caroline; Bugiel, Hannes; Bauer, Sebastian; Schorge, Stephanie; Reif, Philipp S.; Klein, Karl Martin; Haag, Anja; Oertel, Wolfgang H.; Hamer, Hajo; et al. (Epilepsia, 2014)
SCN1A encodes the alpha subunit of the voltage-gated sodium channel and plays a crucial role in several epilepsy syndromes. The common SCN1A splice-site polymorphism rs3812718 (IVS5N+5 G>A) might contribute to the pathophysiology underlying genetic generalized epilepsies and is associated with electrophysiologic properties of the channel and the effect of sodium-channel blocking antiepileptic drugs. We assessed the effects of the rs3812718 genotype on cortical excitability at baseline and after administration of carbamazepine in order to investigate the mechanism of this association.Paired-pulse transcranial magnetic stimulation (TMS) was applied in 92 healthy volunteers with the homozygous genotypes AA or GG of rs3812718 at baseline and after application of 400 mg of carbamazepine or placebo in a double-blind, randomized, crossover design. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), and cortical silent period (CSP) were determined.At baseline there was no significant difference in any TMS parameter. Genotype GG was associated with a higher carbamazepine-induced increase in CSP duration as compared to AA (multivariate analysis of covariance [MANCOVA], p = 0.013). An expected significant increase in RMT was genotype independent.We found that the rs3812718 genotype modifies the effect of carbamazepine on CSP duration (mainly reflecting modulation of ?-aminobutyric acid (GABA)ergic inhibition), but not on RMT (mainly reflecting modulation of voltage-gated sodium channels). This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons. Our results also confirm that TMS is useful to investigate the effect of genetic variants on cortical excitability and pharmacoresponse.
EVALuna2:7257

A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ) p.Thr124Met mutation shares the Belgian haplotype - Leal, Alejandro; Berghoff, Corinna; Berghoff, Martin; Rojas-Araya, Melissa; Ortiz, Carolina; Heuss, Dieter; Del Valle, Gerardo; Rautenstrauß, Bernd (Revista De Biologia Tropical, 2014)
The p.Thr124Met mutation in the myelin protein zero (MPZ) causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers' sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch), the founder effect hypothesis for this allele migration is suggestive.
EVALuna2:22390

Activation and Purification of ß-Glucocerebrosidase by Exploiting its Transporter LIMP-2 – Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease - Dobert, Jan; Bub, Simon; Mächtel, Rebecca; Januliene, Dovile; Steger, Lisa; Regensburger, Martin; Wilfling, Sibylle; Chen, Jia Xuan; Dejung, Mario; Plötz, Sonja; Hehr, Ute; Moeller, Arne; et al. (Advanced Science, 2024)
Genetic variants of GBA1 can cause the lysosomal storage disorder Gaucher disease and are among the highest genetic risk factors for Parkinson's disease (PD). GBA1 encodes the lysosomal enzyme beta-glucocerebrosidase (GCase), which orchestrates the degradation of glucosylceramide (GluCer) in the lysosome. Recent studies have shown that GluCer accelerates α-synuclein aggregation, exposing GCase deficiency as a major risk factor in PD pathology and as a promising target for treatment. This study investigates the interaction of GCase and three disease-associated variants (p.E326K, p.N370S, p.L444P) with their transporter, the lysosomal integral membrane protein 2 (LIMP-2). Overexpression of LIMP-2 in HEK 293T cells boosts lysosomal abundance of wt, E326K, and N370S GCase and increases/rescues enzymatic activity of the wt and E326K variant. Using a novel purification approach, co-purification of untagged wt, E326K, and N370S GCase in complex with His-tagged LIMP-2 from cell supernatant of HEK 293F cells is achieved, confirming functional binding and trafficking for these variants. Furthermore, a single helix in the LIMP-2 ectodomain is exploited to design a lysosome-targeted peptide that enhances lysosomal GCase activity in PD patient-derived and control fibroblasts. These findings reveal LIMP-2 as an allosteric activator of GCase, suggesting a possible therapeutic potential of targeting this interaction.
CRIS-Team Scopus Importer:2024-05-03
Keywords: Gaucher's disease (GD); GCase; LIMP-2; lysosomes; Parkinson's disease (PD); protein purification; β-glucocerebrosidase

Acute care and secondary prevention of stroke with newly detected versus known atrial fibrillation - Wang, Ruihao; Macha, Kosmas; Haupenthal, David; Gaßmann, Luise; Siedler, Gabriela; Stoll, Svenja; Fröhlich, Kilian; Köhn, Julia; Schwab, Stefan; Kallmünzer, Bernd (European Journal of Neurology, 2022)
Background and purpose: Atrial fibrillation (AF) in stroke patients can be classified as either “known AF” (KAF), defined as AF confirmed before stroke onset, or “AF detected after stroke” (AFDAS), defined as AF diagnosed after stroke onset. While KAF is considered primarily cardiogenic, AFDAS includes patients with stroke-triggered neurogenic arrhythmias. This study aimed to investigate the clinical course of stroke, functional outcomes and the value of oral anticoagulation (OAC) for secondary prevention according to AF subtype. Methods: Acute ischemic stroke patients were consecutively enrolled and AF was classified as AFDAS or KAF. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and 3-month functional outcomes were measured on the modified Rankin scale. Inverse probability weighting was applied to adjust for baseline confounders in patients with AFDAS and KAF. Multivariate logistic regression models were calculated to investigate the value of OAC for secondary prevention. Results: A total of 822 stroke patients with AF were included, of whom 234 patients (28.5%) had AFDAS. AFDAS patients had a lower prevalence of coronary artery disease, heart failure, and sustained AF, but higher rates of large vessel occlusion compared to KAF patients. NIHSS scores were lower in patients on pre-stroke anticoagulation. OAC for secondary prevention was associated with favorable 3-month functional outcome (odds ratio 7.60, 95% confidence interval 3.42–16.88) independently of AF subtype. The rate of stroke recurrence did not differ significantly. Conclusions: Clinical characteristics suggest that AFDAS might comprise a distinct pathophysiological and clinical entity among stroke patients with AF. The benefit of anticoagulation for secondary prevention was not affected by AF subtype.
CRIS-Team Scopus Importer:2022-04-22
Keywords: acute ischemic stroke; atrial fibrillation detected after stroke; known atrial fibrillation; modified Rankin scale; oral anticoagulation; stroke recurrence

Acute effects of a novel treadmill device on gait and postural control in patients with Parkinson’s disease - Klamroth, Sarah; Steib, Simon; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus (ISPGR World Congress, 2015)

Acute effects of perturbation treadmill training on gait and postural control in patients with Parkinson’s disease - Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Goßler, Julia; Eskofier, Björn; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Crossing borders through sport science. ECSS - Book of Abstracts, 2016)

Acute exercise following skill practice promotes motor memory consolidation in Parkinson's disease - Wanner, Philipp; Winterholler, Martin; Gaßner, Heiko; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus; Steib, Simon (Neurobiology of Learning and Memory, 2021)
Acute cardiovascular exercise has shown to promote neuroplastic processes supporting the consolidation of newly acquired motor skills in healthy adults. First results suggest that this concept may be transferred to populations with motor and cognitive dysfunctions. In this context, Parkinson's disease (PD) is highly relevant since patients demonstrate deficits in motor learning. Hence, in the present study we sought to explore the effect of a single post-practice exercise bout on motor memory consolidation in PD. For this purpose, 17 patients with PD (Hoehn and Yahr: 1 – 2.5, age: 60.1 ± 7.9 y) practiced a whole-body skill followed by either (i) a moderate-intense bout of cycling, or (ii) seated rest for a total of 30 min. The motor skill required the participants to balance on a tiltable platform (stabilometer) for 30 s. During skill practice, participants performed 15 trials followed by a retention test 1 day and 7 days later. We calculated time in balance (platform within ± 5° from horizontal) for each trial and within- and between-group differences in memory consolidation (i.e. offline learning = skill change from last acquisition block to retention tests) were analyzed. Groups revealed similar improvements during skill practice (F4,60 = 0.316, p = 0.866), but showed differences in offline learning, which were only evident after 7 days (F1,14 = 5.602, p = 0.033). Our results suggest that a single post-practice exercise bout is effective in enhancing long-term motor memory consolidation in a population with motor learning impairments. This may point at unique promoting effects of exercise on dopamine neurotransmission involved in memory formation. Future studies should investigate the potential role of exercise-induced effects on the dopaminergic system.
CRIS-Team Scopus Importer:2021-01-22
Keywords: Cardiovascular exercise; Motor learning; Neuroplasticity; Neurorehabilitation; Offline learning; Parkinsonism

Acute ischemic stroke and transient ischemic attack: an update on recent practically relevant clinical trials - Staykov, Dimitre; Schwab, Stefan (Neurohospitalist, 2014)
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Acute Neuromuscular Adaptations in the Postural Control of Patients with Parkinson’s disease after Perturbed Walking - Pasluosta, Cristian Federico; Steib, Simon; Klamroth, Sarah; Gaßner, Heiko; Goßler, Julia; Hannink, Julius; Von Tscharner, Vinzenz; Pfeifer, Klaus; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (Frontiers in Aging Neuroscience, 2017)

Acute right insular ischaemic lesions and poststroke left ventricular dysfunction - Winder, Klemens; Villegas Millar, Carolina; Siedler, Gabriela; Knott, Michael; Dörfler, Arnd; Engel, Anna; Achenbach, Stephan; Hilz, Max-Josef; Kallmünzer, Bernd; Schwab, Stefan; Seifert, Frank; Fröhlich, Kilian (Stroke and Vascular Neurology, 2023)
IntroductionMyocardial injury related to acute ischaemic stroke is common even without primary cardiac disease. We intended to determine associations between values of left ventricular ejection fraction (LVEF) and ischaemic stroke lesion sites. MethodsOf a local database, patients with acute first-ever ischaemic stroke confirmed by brain imaging but without pre-existing heart disease were included. The cardiac morphology and LVEF were obtained from transthoracic or transesophageal echocardiography, and impaired LVEF was categorised as mild (35%-50%), moderate (34%-25%) and severe (<25%). Patient age, stroke severity, ischaemic lesion volume, prevalence of troponin I increase (>0.1 ng/mL), atrial fibrillation and cardiac wall motion abnormalities were assessed and compared between patients with and without impaired LVEF after stroke (significance: p<0.05). A multivariate voxelwise lesion analysis correlated LVEF after stroke with sites of ischaemic lesions. ResultsOf 1209 patients who had a stroke, 231 (mean age 66.3 +/- 14.0 years) met the inclusion criteria; 40 patients (17.3%) had an impaired LVEF after stroke. Patients with impaired LVEF had higher infarct volumes (53.8 mL vs 30.0 mL, p=0.042), a higher prevalence of troponin increase (17.5% vs 4.2%, p=0.006), cardiac wall motion abnormalities (42.5% vs 5.2%, p<0.001) and atrial fibrillation (60.0% vs 26.2%, p<0.001) than patients with LVEF of >50%. The multivariate voxelwise lesion analysis yielded associations between decreased LVEF and damaged voxels in the insula, amygdala and operculum of the right hemisphere. ConclusionOur imaging analysis unveils a prominent role of the right hemispheric central autonomic network, especially of the insular cortex, in the brain-heart axis. Our results support preliminary evidence that acute ischaemic stroke in distinct brain regions of the central autonomic network may directly impair cardiac function and thus further supports the concept of a distinct stroke-heart syndrome.
CRIS-Team WoS Importer:2023-02-24

Acute Stroke in Times of the COVID-19 Pandemic: A Multicenter Study - Hoyer, Carolin; Ebert, Anne; Huttner, Hagen; Puetz, Volker; Kallmünzer, Bernd; Barlinn, Kristian; Haverkamp, Christian; Harloff, Andreas; Brich, Jochen; Platten, Michael; Szabo, Kristina (Stroke, 2020)
Background and Purpose: This study aims to assess the number of patients with acute ischemic cerebrovascular events seeking in-patient medical emergency care since the implementation of social distancing measures in the coronavirus disease 2019 (COVID-19) pandemic. Methods: In this retrospective multicenter study, data on the number of hospital admissions due to acute ischemic stroke or transient ischemic attack and numbers of reperfusion therapies performed in weeks 1 to 15 of 2020 and 2019 were collected in 4 German academic stroke centers. Poisson regression was used to test for a change in admission rates before and after the implementation of extensive social distancing measures in week 12 of 2020. The analysis of anonymized regional mobility data allowed for correlations between changes in public mobility as measured by the number and length of trips taken and hospital admission for stroke/transient ischemic attack. Results: Only little variation of admission rates was observed before and after week 11 in 2019 and between the weeks 1 and 11 of 2019 and 2020. However, reflecting the impact of the COVID-19 pandemic, a significant decrease in the number of admissions for transient ischemic attack was observed (-85%, -46%, -42%) in 3 of 4 centers, while in 2 of 4 centers, stroke admission rates decreased significantly by 40% and 46% after week 12 in 2020. A relevant effect on reperfusion therapies was found for 1 center only (thrombolysis, -60%; thrombectomy, -61%). Positive correlations between number of ischemic events and mobility measures in the corresponding cities were identified for 3 of 4 centers. Conclusions: These data demonstrate and quantify decreasing hospital admissions due to ischemic cerebrovascular events and suggest that this may be a consequence of social distancing measures, in particular because hospital resources for acute stroke care were not limited during this period. Hence, raising public awareness is necessary to avoid serious healthcare and economic consequences of undiagnosed and untreated strokes and transient ischemic attacks.
CRIS-Team Scopus Importer:2020-07-10
Keywords: brain ischemia; pandemics; reperfusion; stroke; thrombectomy

Acute Stroke With Large Vessel Occlusion and Minor Clinical Deficits: Prognostic Factors and Therapeutic Implications - Volbers, Bastian; Gröger, Rebecca; Engelhorn, Tobias; Marsch, Armin; Macha, Kosmas; Schwab, Stefan; Dörfler, Arnd; Lang, Stefan; Kallmünzer, Bernd (Frontiers in Neurology, 2021)
Background and Purpose: The optimal acute management of patients with large vessel occlusion (LVO) and minor clinical deficits on admission [National Institutes of Health Stroke Scale (NIHSS) <= 4] remains to be elucidated. The aim of the present study was to investigate the prognostic factors and therapeutic management of those patients.
CRIS-Team WoS Importer:2021-11-19

Acute treatment of intracerebral hemorrhage Akutbehandlung der intrazerebralen Blutung - Sembill, Jochen; Kuramatsu, J. B. (Medizinische Klinik - Intensivmedizin und Notfallmedizin, 2019)
Background: Intracerebral hemorrhage (ICH) represents one of the most severe forms of stroke with high morbidity and mortality; however, effective treatment options to significantly improve patient outcome do not exist so far. Objective: This review article evaluates the most recent developments in acute ICH treatment. Material and methods: Analysis and interpretation of currently available evidence regarding ICH treatment, focusing on the most important studies from the last 3 years. Results: Hematoma enlargement, perhaps the most important prognostic factor, should be counteracted by aggressive blood pressure management (targeted systolic pressure 140 mm Hg). In cases of ICH under oral anticoagulation, inhibition of coagulation must be immediately antagonized: vitamin K antagonists with prothrombin complex concentrates (PCC), idarucizumab for dabigatran and andexanet if available or high-dose PCC for factor Xa inhibitors. Currently, surgical treatment strategies, both open and minimally invasive, to evacuate the hematoma can currently not be routinely recommended. In patients with intraventricular ICH, treatment with intraventricular fibrinolysis with or without additional lumbar drainage represents a promising treatment option. Conclusion: In recent years, several randomized controlled and observational studies have generated robust evidence regarding ICH treatment; however, there is still no single breakthrough intervention, which significantly improves patient functional outcome. Nevertheless, the sum of various, possibly interacting treatment concepts may potentially improve outcome after ICH.
CRIS-Team Scopus Importer:2019-10-22
Keywords: Anticoagulants; oral; Blood pressure; Drainage; lumbar; Fibrinolysis; intraventricular; Intracerebral hemorrhage; treatment outcome

Adaptive Immune Response to and Survival Effect of Temozolomide- and Valproic Acid-induced Autophagy in Glioblastoma - Proske, Judith; Walter, Lisa; Bumes, Elisabeth; Hutterer, Markus; Vollmann-Zwerenz, Arabel; Eyüpoglu, Ilker Yasin; Savaskan, Nicolai E.; Seliger, Corinna; Hau, Peter; Uhl, Martin; Walter, Lisa (Anticancer Research, 2016)
The combination of radiotherapy, temozolomide and valproic acid (VPA) has shown some promise in retrospective analyses of patients with glioblastoma, although their mechanisms of action remain unknown.We investigated the in vitro and in vivo effects of pretreating glioma cells with temozolomide and VPA as an immunization strategy to boost an adaptive immune response in a syngeneic mouse model.Temozolomide and VPA induced autophagy in GL261 glioma cells, and caused tumor antigen-specific T-cells to become activated effector T-cells. Mice with a pre-existing glioma showed no improvement in clinical outcome when immunized with temozolomide- and VPA-treated glioma cells.Although temozolomide and VPA treatment of glioma cells can boost the adaptive immune response, in the context of a vaccine therapy, additional factors are necessary to eradicate the tumor and improve survival.
EVALuna2:22525

A deep learning-based histopathology classifier for Focal Cortical Dysplasia - Vorndran, Jörg; Neuner, Christoph; Coras, Roland; Hoffmann, Lucas; Geffers, Simon; Honke, Jonas; Herms, Jochen; Roeber, Sigrun; Hamer, Hajo; Brandner, Sebastian; Hartlieb, Till; Pieper, Tom; et al. (Neural Computing & Applications, 2023)
A light microscopy-based histopathology diagnosis of human brain specimens obtained from epilepsy surgery remains the gold standard to confirm the underlying cause of a patient’s focal epilepsy and further inform postsurgical patient management. The differential diagnosis of neocortical specimens in the realm of epilepsy surgery remains, however, challenging. Herein, we developed an open access, deep learning-based classifier to histopathologically assess whole slide microscopy images (WSI) and to automatically recognize various subtypes of Focal Cortical Dysplasia (FCD), according to the ILAE consensus classification update of 2022. We trained a convolutional neuronal network (CNN) with fully digitalized WSI of hematoxylin–eosin stainings obtained from 125 patients covering the spectrum of mild malformation of cortical development (mMCD), mMCD with oligodendroglial hyperplasia in epilepsy (MOGHE), FCD ILAE Type 1a, 2a and 2b using 414 formalin-fixed and paraffin-embedded archival tissue blocks. An additional series of 198 postmortem tissue blocks from 59 patients without neurological disorders served as control to train the CNN for homotypic frontal, temporal and occipital areas and heterotypic Brodmann areas 4 and 17, entorhinal cortex and dentate gyrus. Special stains and immunohistochemical reactions were used to comprehensively annotate the region of interest. We then programmed a novel tile extraction pipeline and graphical dashboard to visualize all areas on the WSI recognized by the CNN. Our deep learning-based classifier is able to compute 1000 × 1000 µm large tiles and recognizes 25 anatomical regions and FCD categories with an accuracy of 98.8% (F1 score = 0.82). Microscopic review of regions predicted by the network confirmed these results. This deep learning-based classifier will be made available as online web application to support the differential histopathology diagnosis in neocortical human brain specimens obtained from epilepsy surgery. It will also serve as blueprint to build a digital histopathology slide suite addressing all major brain diseases encountered in patients with surgically amenable focal epilepsy.
CRIS-Team Scopus Importer:2023-03-17
Keywords: Classification; Convolutional neuronal network; Cortex; Deep learning; Digital pathology; Epilepsy; FCD1; FCD2; mMCD; MOGHE

Adherence to antiepileptic drugs in children and adolescents: A retrospective study in primary care settings in Germany - Jacob, Louis; Hamer, Hajo; Kostev, Karel (Epilepsy and Behavior, 2017)
The goal of this study was to analyze adherence to antiepileptic drugs (AED) in children and adolescents treated in pediatric practices in Germany.The present study included patients aged between 2 and 17years who were diagnosed with epilepsy (ICD-10: G40) and had received at least two prescriptions of AED between January 2006 and December 2015 in 243 pediatric practices in Germany. The medication possession ratio (MPR) was used to estimate adherence, and patients with a MPR greater than 80% were considered adherent. The impact of patient and drug characteristics on adherence was analyzed using a multivariate logistic regression model.A total of 5214 patients were included. Mean age was 10.9years (SD=4.9years). The overall MPR was 88.8% (SD=34.1%), and 68.9% of patients were considered adherent. Children aged 5years or younger were more adherent to AED than those aged between 14 and 17years (OR=1.22, 95% CI: 1.07-1.39). Individuals living in western Germany were also found to be more adherent than those living in eastern Germany (OR=1.71, 95% CI: 1.55-1.88). Asthma as a comorbidity (OR=1.59, 95% CI: 1.29-1.96) was positively and attention-deficit hyperactivity disorder (OR=0.81, 95% CI: 0.71-0.93) negatively associated with treatment adherence. Finally, no significant association was found between adherence and the type of AED.Two-thirds of children and adolescents suffering from epilepsy in Germany were adherent to AED. Age, place of residence, and comorbidities were significantly associated with adherence.
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Adherence to oral anticoagulation in secondary stroke prevention - the first year of direct oral anticoagulants - Sauer, Rolf; Sauer, Eva-Maria; Bobinger, Tobias; Blinzler, Christian; Huttner, Hagen; Schwab, Stefan; Köhrmann, Martin (Journal of Stroke and Cerebrovascular Diseases, 2015)
Patients with ischemic stroke caused by atrial fibrillation (AF) have a high risk of recurrence without adequate secondary prevention with oral anticoagulation (OAC). We investigated adherence to OAC in the first year after introduction of direct oral anticoagulants.In 284 appropriate patients, the rate of anticoagulation (AC) at discharge, adherence at 90 days and 1 year, changes between substances, and predictors for adherence to AC were analyzed. Functional outcome was assessed using the modified Rankin Scale score.AC was initiated in 70.3% of survivors before discharge. In these patients, only 8.6% and 9.9% discontinued AC after 90 days and 1 year, respectively. In 22.1%, AC was recommended but not started before discharge. Only 53.2% of them received AC at 90 days, increasing to 67.5% at 1 year. A total of 7.6% of patients were deemed unsuitable for AC, none of them subsequently received AC. Overall, 85.4% of patients suitable for AC were treated at 1-year follow-up. No independent predictors for withholding AC were identified. Switching of medication occurred in only a minority of patients within the first year.AC is feasible in more than 90% patients with acute ischemic stroke and AF. When initiated during the acute hospital stay, AC is discontinued in only a minority of patients. However, if AC is recommended but not started during initial hospitalization the rate of AC treatment at 90 days and 1 year is much lower. Therefore, AC should be initiated within the acute hospital stay whenever possible.
EVALuna2:22269

Adjunctive retigabine in refractory focal epilepsy: Postmarketing experience at four tertiary epilepsy care centers in Germany - Nass, R. D.; Kurth, C.; Kull, A.; Graf, Wolfgang; Kasper, Burkhard; Hamer, Hajo; Strzelczyk, Adam; Elger, C. E.; Steinhoff, B. J.; Surges, R.; Rosenow, F. (Epilepsy and Behavior, 2016)
Retigabine (RTG, ezogabine) is the first potassium channel-opening anticonvulsant drug approved for adjunctive treatment of focal epilepsies. We report on the postmarketing clinical efficacy, adverse events, and retention rates of RTG in adult patients with refractory focal epilepsy.Clinical features before and during RTG treatment were retrospectively collected from patients treated at four German epilepsy centers in 2011 and 2012.A total of 195 patients were included. Daily RTG doses ranged from 100 to 1500 mg. Retigabine reduced seizure frequency or severity for 24.6% and led to seizure-freedom in 2.1% of the patients but had no apparent effect in 43.1% of the patients. Seizure aggravation occurred in 14.9%. The one-, two-, and three-year retention rates amounted to 32.6%, 7.2%, and 5.7%, respectively. Adverse events were reported by 76% of the patients and were mostly CNS-related. Blue discolorations were noted in three long-term responders. Three possible SUDEP cases occurred during the observation period, equalling an incidence rate of about 20 per 1000 patient years.Our results are similar to other pivotal trials with respect to the long-term, open-label extensions and recent postmarketing studies. Despite the limitations of the retrospective design, our observational study suggests that RTG leads to good seizure control in a small number of patients with treatment-refractory seizures. However, because of the rather high percentage of patients who experienced significant adverse events, we consider RTG as a drug of reserve.
EVALuna2:22452

A dual role for UCMA in osteoarthritis-Inhibition of aggrecanases and promotion of bone turnover - Stock, Michael; Menges, Stefanie; Eitzinger, Nicole; Gesslein, Maria; Botschner, Renate; Wormser, Laura; Distler, Alfiya; Schlötzer-Schrehardt, Ursula; Dietel, Katharina; Distler, Jörg; Beyer, Christian; Gelse, Kolja; et al. (Arthritis and Rheumatology, 2017)
Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. How these processes are interlinked is however incompletely understood to date. Here, we investigate the mechanistic role of the cartilage-derived protein UCMA in osteoarthritis-related cartilage and bone changes.UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. DMM-induced osteoarthritis was performed in WT and Ucma-deficient mice analysing cartilage and bone changes. UCMA-collagen interactions, effect of UCMA on aggrecanase activity and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro.UCMA was found overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes were aggravated in Ucma-deficient mice compared to WT littermates, showing increased structural damage, proteoglycan loss and chondrocyte cell death indicating chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis-related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro.UCMA links cartilage with bone changes in osteoarthritis, supporting cartilage integrity as an endogenous inhibitor of aggrecanases on the one hand, and promoting osteoclastogenesis and subchondral bone turnover on the other hand. Hence, UCMA represents an important link between cartilage and bone in osteoarthritis. This article is protected by copyright. All rights reserved.
EVALuna2:10230

Adult alcohol drinking and emotional tone are mediated by neutral sphingomyelinase during development in males - Kalinichenko, Liubov; Mühle, Christiane; Jia, Tianye; Anderheiden, Felix; Datz, Maria; Eberle, Anna-Lisa; Eulenburg, Volker; Granzow, Jonas; Hofer, Martin Jürgen; Hohenschild, Julia; Huber, Sabine; Kämpf, Stefanie; et al. (Cerebral Cortex, 2022)
Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we report strong sex-dimorphisms for central, but not for peripheral mechanisms of NSM action in mouse models. Reduced NSM activity resulted in enhanced alcohol consumption in males, but delayed conditioned rewarding effects. It enhanced the acute dopamine response to alcohol, but decreased monoaminergic systems adaptations to chronic alcohol. Reduced NSM activity increased depression- and anxiety-like behavior, but was not involved in alcohol use for the self-management of the emotional state. Constitutively reduced NSM activity impaired structural development in the brain and enhanced lipidomic sensitivity to chronic alcohol. While the central effects were mostly opposite to NSM function in females, similar roles in bone-mediated osteocalcin release and its effects on alcohol drinking and emotional behavior were observed. These findings support the view that the NSM and multiple downstream mechanism may be a source of the sex-differences in alcohol use and emotional behavior.
CRIS-Team WoS Importer:2022-04-15
Keywords: neutral sphingomyelinase; osteocalcin; depression; alcohol; anxiety

Adult neural precursor cells unaffected in animal models of DYT1 dystonia - Regensburger, Martin; Kohl, Zacharias; Grundmann, Kathrin; Winner, Beate; Riess, Olaf; Winkler, Jürgen (NeuroReport, 2009)
Hereditary dystonias in humans are frequently related to a specific mutation of the DYT1 gene that encodes torsinA. This mutation has been shown to disrupt neuronal cell migration during development. We compared adult neurogenesis, occurring in the hippocampus and the olfactory bulb, in transgenic mice overexpressing either the wild-type or mutant form of human torsinA. Neurogenesis was assessed by quantification of bromodeoxyuridine-labeled cells. Both transgenic mouse models displayed perinuclear inclusions in the brainstem and in mitral cells of the olfactory bulb, altered striatal dopamine levels, and behavioral abnormalities. However, both hippocampal and olfactory neurogenesis levels were unchanged compared with control animals. We conclude that overexpression of human wild-type or mutant torsinA does not affect the survival of adult newborn neurons. © 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.
CRIS-Team Scopus Importer:2021-08-17
Keywords: Bromodeoxyuridine; Cellular plasticity; Doublecortin; Dystonia; DYT1; Hippocampus; Olfactory bulb; Subventricular zone; TorsinA

Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice - Winner, Beate; Gage, Fred H.; Winkler, Jürgen; et al. (Neurobiology of Disease, 2011)
The generation and maturation of adult neural stem/progenitor cells are impaired in many neurodegenerative diseases, among them is Parkinson's disease (PD). In mammals, including humans, adult neurogenesis is a lifelong feature of cellular brain plasticity in the hippocampal dentate gyrus (DG) and in the subventricular zone (SVZ)/olfactory bulb system. Hyposmia, depression, and anxiety are early non-motor symptoms in PD. There are parallels between brain regions associated with non-motor symptoms in PD and neurogenic regions. In autosomal dominant PD, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent LRRK2 homologs in non-vertebrate systems play an important role in chemotaxis, cell polarity, and neurite arborization. We investigated adult neurogenesis and the neurite development of new neurons in the DG and SVZ/olfactory bulb system in bacterial artificial chromosome (BAC) human Lrrk2 G2019S transgenic mice. We report that mutant human Lrrk2 is highly expressed in the hippocampus in the DG and the SVZ of adult Lrrk2 G2019S mice. Proliferation of newly generated cells is significantly decreased and survival of newly generated neurons in the DG and olfactory bulb is also severely impaired. In addition, after stereotactic injection of a GFP retrovirus, newly generated neurons in the DG of Lrrk2 G2019S mice exhibited reduced dendritic arborization and fewer spines. This loss in mature, developed spines might point towards a decrease in synaptic connectivity. Interestingly, physical activity partially reverses the decrease in neuroblasts observed in Lrrk2 G2010S mice. These data further support a role for Lrrk2 in neuronal morphogenesis and provide new insights into the role of Lrrk2 in adult neurogenesis. Published by Elsevier Inc.
Keywords: Neural progenitor cells; Neurogenesis; Parkinson's disease; Dendrites; Spines; LRRK2

Adult neurogenesis in neurodegenerative diseases - Winner, Beate; Winkler, Jürgen (Cold Spring Harbor Perspectives in Biology, 2015)
Adult neurogenesis is limited to specific brain regions in the mammalian brain, such as the hippocampal dentate gyrus and the subventricular zone/olfactory bulb system. Alterations in adult neurogenesis appear to be a common hallmark in different neurodegenerative diseases including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This is remarkable, because the distinct pathological proteins responsible for the different diseases induce the loss of different neural populations. Impaired adult neurogenesis was shown in numerous animal models of neurodegenerative diseases; however, only few postmortem studies have been performed. We will review concepts related to the interplay between cellular plasticity in regions of adult neurogenesis with a specific focus on cell-autonomous and non-cell-autonomous factors. Furthermore, various strategies aimed to stimulate neuronal plasticity will be discussed within the context of a potential translation into therapeutic approaches for neuropsychiatric symptoms associated with PD, HD, and AD.
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Adult neurogenesis in Parkinson's disease - Marxreiter, Franz; Regensburger, Martin; Winkler, Jürgen (Cellular and Molecular Life Sciences, 2013)
Parkinson's disease (PD), the second most common neurodegenerative disorder, affects 1-2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.
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Adult-Onset Neurodegeneration in Nucleotide Excision Repair Disorders (NERDND): Time to Move Beyond the Skin - Cordts, Isabell; Oender, Demet; Traschuetz, Andreas; Kobeleva, Xenia; Karin, Ivan; Minnerop, Martina; Koertvelyessy, Peter; Biskup, Saskia; Forchhammer, Stephan; Binder, Johannes; Tzschach, Andreas; Meiss, Frank; et al. (Movement Disorders, 2022)
Background Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early-onset neurological degeneration. Adult-onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. Objective The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. Methods In-house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER-related genes. Clinical workup included in-depth neurological and dermatological assessments. Results We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult-onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. Conclusions We introduce NERDND as adult-onset neurodegeneration ((ND)) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
CRIS-Team WoS Importer:2022-06-24

Advances in stroke pharmacology - Zhou, Zhenhua; Lu, Jianfei; Liu, Wen-Wu; Manaenko, Anatol; Hou, Xianhua; Mei, Qiyong; Huang, Jun-Long; Tang, Jiping; Zhang, John H.; Yao, Honghong; Hu, Qin (Pharmacology & Therapeutics, 2018)
Stroke occurs when a cerebral blood vessel is blocked or ruptured, and it is the major cause of death and adult disability worldwide. Various pharmacological agents have been developed for the treatment of stroke either through interrupting the molecular pathways leading to neuronal death or enhancing neuronal survival and regeneration. Except for rtPA, few of these agents have succeeded in clinical trials. Recently, with the understanding of the pathophysiological process of stroke, there is a resurrection of research on developing neuroprotective agents for stroke treatment, and novel molecular targets for neuroprotection and neurorestoration have been discovered to predict or offer clinical benefits. Here we review the latest major progress of pharmacological studies in stroke, especially in ischemic stroke; summarize emerging potential therapeutic mechanisms; and highlight recent clinical trials. The aim of this review is to provide a panorama of pharmacological interventions for stroke and bridge basic and translational research to guide the clinical management of stroke therapy.
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Advantages of magnetoencephalography, neuronavigation and intraoperative MRI in epilepsy surgery re-operations - Shawarba, Julia; Kaspar, Burkhard; Rampp, Stefan; Winter, Fabian; Coras, Roland; Blümcke, Ingmar; Hamer, Hajo; Buchfelder, Michael; Rössler, Karl (Neurological Research, 2021)
Objective: Management of patients after failed epilepsy surgery is still challenging. Advanced diagnostic and intraoperative tools including magneto-encephalography (MEG) as well as neuronavigation and intraoperative magnetic resonance imaging (iopMRI) may contribute to a better postoperative seizure outcome in this patient group. Methods: We retrospectively analyzed consecutive patients after reoperation of failed epilepsy surgery for medically refractory epilepsy at the University of Erlangen between 1988 and 2017. Inclusion criteria for patients were available MEG, neuronavigation and iopMRI data. The Engel scale was used to categorize seizure outcome. Results: We report on 27 consecutive patients (13 female/14 male mean age at first surgery 29.4 years) who had operative revision of the first resection after failed epilepsy surgery. An improved seizure outcome postoperatively was observed in 78% of patients (p < 0.001) with 55% seizure free (Engel I) patients after a mean follow-up time of 4.9 years. In detail, 80% of lesional cases were seizure free compared to 59% of MRI negative patients. Localizing MEG spike activity in the vicinity of the first resection cavity was present in 12 of 27 patients (44%) corresponding to 83% (10/12) of MEG localizing spike patients having advanced seizure outcome after operative revision. Conclusion: Re-operation after failed surgery in refractory epilepsy may lead to a better seizure outcome in the majority of patients. Preoperative MEG may support the decision for surgery and may facilitate targeting epileptogenic tissue for re-resection by employing navigation and iopMR imaging.
CRIS-Team Scopus Importer:2021-01-15
Keywords: Failed epilepsy surgery; intraoperative MR imaging; MEG; neuronavigation; reoperation; seizure outcome

Adverse event grading following CTCAE v3.0 underestimates hypertensive side effects in patients with glioma treated with Bevacizumab - Bumes, Elisabeth; Rzonsa, Sarah; Hutterer, Markus; Proescholdt, Martin; Bogdahn, Ulrich; Riemenschneider, Markus J.; Uhl, Martin; Wendl, Christina; Hau, Peter (Journal of Neuro-Oncology, 2016)
Anti-VEGF therapy with Bevacizumab (BEV) is widely used in cases of relapsed high-grade glioma (HGG). Arterial hypertension is a known side effect of anti-VEGF therapy. 42 Patients with relapsed HGG were treated with BEV 10 mg/kg on days 1 and 15 of 28-day cycles in addition to treatment with 40 mg TMZ daily until disease progression, based on magnetic resonance imaging and/or worsening of clinical status. In a retrospective analysis, hypertensive side effects were evaluated as the primary endpoint, while survival information in addition to toxicity was analyzed as secondary endpoint. Grading which employs the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 detected hypertensive events with a significantly higher sensitivity than CTCAE version 3.0. The rate of severe hypertensive events observed as CTCAE >= °3 were 9.5 % in version 3.0 and 45.2 % in version 4.0. The results presented here indicate that CTCAE version 3.0 may underreport the incidence and grade of BEV-induced hypertension within clinical trials. As hypertension has not only long-term, but also severe short-term side effects, we suggest that arterial hypertension under BEV should be scored according to CTCAE version 4.0 to avoid clinically relevant hypertension-related adverse events in these patients.
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Aetiology, secondary prevention strategies and outcomes of ischaemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation - Polymeris, Alexandros A.; Meinel, Thomas R.; Oehler, Hannah; Hoelscher, Kyra; Zietz, Annaelle; Scheitz, Jan F.; Nolte, Christian H.; Stretz, Christoph; Yaghi, Shadi; Stoll, Svenja; Wang, Ruihao; Haeusler, Karl Georg; et al. (Journal of Neurology Neurosurgery and Psychiatry, 2022)
Objective To investigate the aetiology, subsequent preventive strategies and outcomes of stroke despite anticoagulation in patients with atrial fibrillation (AF).
CRIS-Team WoS Importer:2022-04-22

A Frameless Stereotactic Implantation Technique for Depth Electrodes in Refractory Epilepsy Using Intraoperative Magnetic Resonance Imaging - Roessler, Karl; Sommer, Bjoern; Merkel, Andreas; Rampp, Stefan; Gollwitzer, Stephanie; Hamer, Hajo; Buchfelder, Michael (World Neurosurgery, 2016)
Various complex techniques for depth electrode insertion in refractory epilepsy using preoperative imaging have been investigated. We evaluated a simple, accurate, cost-effective, and timesaving method using intraoperative magnetic resonance imaging (MRI).A neuronavigation-guided insertion tube attached to bone facilitated the placement of stereotactic percutaneous drill holes, bolt implantation, and frameless stereotactic insertion of depth electrodes. Image registration was carried out by head coil fiducials with trajectory planning and intraoperative electrode correction.In 6 patients with refractory epilepsy (3 women and 3 men; mean age, 30.0 years; range, 20-37 years), 58 depth electrodes (9-11 per patient) were placed. The mean length of the inserted electrodes was 37.3 mm ± 8.8 (mean ± SD) (range, 22.1-84.4 mm). The overall target point accuracy was 3.2 mm ± 2.2 (range, 0-8.6 mm), which was significantly different from the overall entry point accuracy of 1.4 mm ± 1.2 (P < 0.0001). All electrodes functioned perfectly, enabling high-quality stereo-electroencephalography recordings over a period of 7.3 days ± 0.5 (range, 7-8 days). The mean implantation time for 9-11 electrodes per patient was 115 minutes ± 36.3 (range, 75-160 minutes; 12 minutes for 1 electrode on average) including the intraoperative MRI (T1 three-dimensional magnetization-prepared rapid acquisition gradient echo, T2, and diffusion tensor imaging). There was no hemorrhage, infection, or neurologic deficit related to the procedure.Our frameless technique of depth electrode insertion using intraoperative MRI guidance is an accurate, reliable, cost-effective, and timesaving method for stereo-electroencephalography.
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Afterdischarges elicited by cortical electric stimulation in humans: When do they occur and what do they mean? - Gollwitzer, Stephanie; Hopfengaertner, Ruediger; Roessler, Karl; Müller, Tamara; Olmes, David Gerhard; Lang, Johannes; Koehn, Julia; Onugoren, Muejgan Dogan; Heyne, Jana; Schwab, Stefan; Hamer, Hajo (Epilepsy and Behavior, 2018)
INTRODUCTION: Afterdischarges (ADs) are a common and unwanted byproduct of direct cortical stimulation during invasive electroencephalography (EEG) recordings. Brief pulse stimulation (BPS) can sometimes terminate ADs. This study investigated AD characteristics and their relevance for emergence of stimulation seizures. In addition, AD response to BPS was analyzed. MATERIAL AND METHODS: Invasive EEG recordings including mapping with direct cortical stimulation in patients with refractory epilepsy at the Erlangen Epilepsy Center were retrospectively reviewed. Afterdischarge defined as stimulation-induced rhythmic epileptiform discharges of more than a two-second duration were analyzed regarding incidence, localization, duration, propagation pattern, morphology, and seizure emergence. In addition, the influence of AD characteristics and stimulation settings on BPS success rate was studied. RESULTS: A number of 4261 stimulation trials in 20 patients were investigated. Afterdischarge occurred in 518 trials (14.2%) and lasted 12.4 s (standard deviation [SD]: 8.6 s) on average. We elicited ADs in the seizure onset zone (SOZ) (n = 64; 19.4%), the irritative zone (n = 105, 20.0%), and outside the irritative area (n = 222, 12.5%). Rhythmic spikes (30.5%) and spike-wave complexes (30.3%) represented predominant morphologies. Afterdischarge morphology in the SOZ and hippocampus differed from other areas with polyspikes and sequential spikes being the most common types there (p = 0.0005; p < 0.0001 respectively). Hippocampal ADs were particularly frequent (n = 50, 38.2%) and long-lasting (mean: 16.6, SD: 8.3 s). Brief pulse stimulation was applied in 18.1% of the AD trials (n = 94) and was successful in 37.4% (n = 40). Success rates were highest when BPS was delivered within 9.5 s (p = 0.0048) and in ADs of spike-wave morphology (p = 0.0004). Fifteen clinical seizures emerged from ADs (3.55%), mostly evolving from sequential spikes. Afterdischarges in patients with stimulation seizures appeared more widespread (p < 0.0001) and lasted longer (mean duration 7.0 s) than in those without (mean duration 21.0 s, p = 0.0054). CONCLUSION: Afterdischarges appear in the epileptogenic and nonepileptogenic cortex. Duration and propagation patterns can help to quantify the risk of stimulation seizures, with sequential spikes being most susceptible to seizure elucidation. The hippocampus is highly sensitive to AD release. Brief pulse stimulation is a safe and efficacious way to terminate ADs, especially when delivered quickly after AD onset.
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Age-dependent clinical outcomes in primary versus oral anticoagulation-related intracerebral hemorrhage - Sprügel, Maximilian; Kuramatsu, Joji; Gerner, Stefan T.; Sembill, Jochen; Madzar, Dominik; Reindl, Caroline; Bobinger, Tobias; Müller, Tamara; Hölter, Philip; Lücking, Hannes; Engelhorn, Tobias; Huttner, Hagen (International Journal of Stroke, 2019)
Aims This study determined the influence of age on bleeding characteristics and clinical outcomes in primary spontaneous (non-OAC), vitamin K antagonist-related (VKA-) and non-vitamin K antagonist oral anticoagulant-related (NOAC-) ICH. Methods Pooled individual patient data of multicenter cohort studies were analyzed by logistic regression modelling and propensity-score-matching (PSM) to explore the influence of advanced age on clinical outcomes among non-OAC-, VKA-, and NOAC-ICH. Primary outcome measure was functional outcome at three months assessed by the modified Rankin Scale, dichotomized into favorable (mRS = 0-3) and unfavorable (mRS = 4-6) functional outcome. Secondary outcome measures included mortality, hematoma characteristics, and frequency of invasive interventions. Results In VKA-ICH 33.5% (670/2001), in NOAC-ICH 44.2% (69/156) and in non-OAC-ICH 25.2% (254/1009) of the patients were >= 80 years. After adjustment for treatment interventions and relevant parameters, elderly ICH patients comprised worse functional outcome at three months (adjusted odds ratio (aOR) in VKA-ICH: 1.49 (1.21-1.84); p < 0.001; NOAC-ICH: 2.01 (0.95-4.26); p = 0.069; non-OAC-ICH: 3.54 (2.50-5.03); p < 0.001). Anticoagulation was significantly associated with worse functional outcome below the age of 70 years, (aOR: 2.38 (1.78-3.16); p < 0.001), but not in patients of >= 70 years (aOR: 1.21 (0.89-1.65); p = 0.217). The differences in initial ICH volume and extent of ICH enlargement between OAC-ICH and non-OAC-ICH gradually decreased with increasing patient age. Conclusions As compared to elderly ICH-patients, in patients <70 years OAC-ICH showed worse clinical outcomes compared to non-OAC-ICH because of larger baseline ICH-volumes and extent of hematoma enlargement. Treatment strategies aiming at neutralizing altered coagulation should be aware of these findings.
CRIS-Team WoS Importer:2020-01-28

Age-dependent increase of perineuronal nets in the human hippocampus and precocious aging in epilepsy - Lehner, Annika; Hoffmann, Lucas; Rampp, Stefan; Coras, Roland; Paulsen, Friedrich; Frischknecht, Renato; Hamer, Hajo; Walther, Katrin; Brandner, Sebastian; Hofer, Wiebke; Pieper, Tom; Reisch, Lea Marie; et al. (Epilepsia Open, 2024)
Objective: Perineuronal nets (PNN) are specialized extracellular matrix (ECM) components of the central nervous system, frequently accumulating at the surface of inhibitory GABAergic interneurons. While an altered distribution of PNN has been observed in neurological disorders including Alzheimer's disease, schizophrenia and epilepsy, their anatomical distribution also changes during physiological brain maturation and aging. Such an age-dependent shift was experimentally associated also with hippocampal engram formation during brain maturation. Our aim was to histopathologically assess PNN in the hippocampus of adult and pediatric patients with temporal lobe epilepsy (TLE) compared to age-matched post-mortem control subjects and to compare PNN-related changes with memory impairment observed in our patient cohort. Methods: Sixty-six formalin-fixed and paraffin-embedded tissue specimens of the human hippocampus were retrieved from the European Epilepsy Brain Bank. Twenty-nine patients had histopathologically confirmed hippocampal sclerosis (HS), and eleven patients suffered from TLE without HS. PNN were immunohistochemically visualized using an antibody directed against aggrecan and manually counted from hippocampus subfields and the subiculum. Results: PNN density increased with age in both human controls and TLE patients. However, their density was significantly higher in all HS patients compared to age-matched controls. Intriguingly, TLE patients presented presurgically with better memory when their hippocampal PNN density was higher (p < 0.05). Significance: Our results were compatible with age-dependent ECM specialization in the human hippocampus and its precocious aging in the epileptic condition. These observations confirm recent experimental animal models and also support the notion that PNN play a role in memory formation in the human brain. Plain Language Summary: “Perineuronal nets” (PNN) are a specialized compartment of the extracellular matrix (ECM), especially surrounding highly active neurons of the mammalian brain. There is evidence that PNN play a role in memory formation, brain maturation, and in some pathologies like Alzheimer's disease, schizophrenia or epilepsy. In this study, we investigated the role of PNN in patients suffering from drug-resistant focal epilepsy compared to controls. We found that with increasing age, more neurons are surrounded by PNN. Similarly, all epilepsy patients but especially patients with better memory performance also had more PNN. This study raises further interest in studying ECM molecules in the human brain under physiological and pathophysiological conditions.
CRIS-Team Scopus Importer:2024-06-21
Keywords: brain; extracellular matrix; hippocampal sclerosis; maturation; neuropathology

Age of epilepsy onset as modulating factor for naming deficit after epilepsy surgery: a voxel-based lesion-symptom mapping study - Reindl, Caroline; Walther, Katrin; Allgäuer, Anna-Lena; Lang, Johannes; Welte, Tamara; Stritzelberger, Jenny; Gollwitzer, Stephanie; Schwarz, Michael; Trollmann, Regina; Madzar, Dominik; Knott, Michael; Dörfler, Arnd; et al. (Scientific Reports, 2023)
Age at onset of epilepsy is an important predictor of deterioration in naming ability following epilepsy surgery. In 141 patients with left hemispheric epilepsy and language dominance who received epilepsy surgery at the Epilepsy Centre Erlangen, naming of objects (Boston naming test, BNT) was assessed preoperatively and 6 months postoperatively. Surgical lesions were plotted on postoperative MRI and normalized for statistical analysis using voxel-based lesion-symptom mapping (VBLSM). The correlation between lesion and presence of postoperative naming deterioration was examined varying the considered age range of epilepsy onsets. The VBLSM analysis showed that volumes of cortex areas in the left temporal lobe, which were associated with postoperative decline of naming, increased with each year of later epilepsy onset. In patients with later onset, an increasing left posterior temporobasal area was significantly associated with a postoperative deficit when included in the resection. For late epilepsy onset, the temporomesial expansion also included the left hippocampus. The results underline that early onset of epilepsy is a good prognostic factor for unchanged postoperative naming ability following epilepsy surgery. For later age of epilepsy onset, the extent of the area at risk of postoperative naming deficit at 6 months after surgery included an increasing left temporobasal area which finally also comprised the hippocampus.
CRIS-Team Scopus Importer:2023-09-08

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies - Hartlage-Rübsamen, Maike; Bluhm, Alexandra; Moceri, Sandra; Machner, Lisa; Köppen, Janett; Schenk, Mathias; Hilbrich, Isabel; Holzer, Max; Weidenfeller, Martin; Richter, Franziska; Coras, Roland; Serrano, Geidy E.; et al. (Acta Neuropathologica, 2021)
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.
CRIS-Team Scopus Importer:2021-08-06
Keywords: Animal models; Dementia with Lewy bodies; Glutaminyl cyclase; Parkinson’s disease; Post-translational modification; Substantia nigra; α-Synuclein

A guideline for head volume conductor modeling in EEG and MEG - Vorwerk, Johannes; Cho, Jae-Hyun; Rampp, Stefan; Hamer, Hajo; Knoesche, Thomas R.; Wolters, Carsten H. (NeuroImage, 2014)
For accurate EEG/MEG source analysis it is necessary to model the head volume conductor as realistic as possible. This includes the distinction of the different conductive compartments in the human head. In this study, we investigated the influence of modeling/not modeling the conductive compartments skull spongiosa, skull compacta, cerebrospinal fluid (CSF), gray matter, and white matter and of the inclusion of white matter anisotropy on the EEG/MEG forward solution. Therefore, we created a highly realistic 6-compartment head model with white matter anisotropy and used a state-of-the-art finite element approach. Starting from a 3-compartment scenario (skin, skull, and brain), we subsequently refined our head model by distinguishing one further of the above-mentioned compartments. For each of the generated five head models, we measured the effect on the signal topography and signal magnitude both in relation to a highly resolved reference model and to the model generated in the previous refinement step. We evaluated the results of these simulations using a variety of visualization methods, allowing us to gain a general overview of effect strength, of the most important source parameters triggering these effects, and of the most affected brain regions. Thereby, starting from the 3-compartment approach, we identified the most important additional refinement steps in head volume conductor modeling. We were able to show that the inclusion of the highly conductive CSF compartment, whose conductivity value is well known, has the strongest influence on both signal topography and magnitude in both modalities. We found the effect of gray/white matter distinction to be nearly as big as that of the CSF inclusion, and for both of these steps we identified a clear pattern in the spatial distribution of effects. In comparison to these two steps, the introduction of white matter anisotropy led to a clearly weaker, but still strong, effect. Finally, the distinction between skull spongiosa and compacta caused the weakest effects in both modalities when using an optimized conductivity value for the homogenized compartment. We conclude that it is highly recommendable to include the CSF and distinguish between gray and white matter in head volume conductor modeling. Especially for the MEG, the modeling of skull spongiosa and compacta might be neglected due to the weak effects; the simplification of not modeling white matter anisotropy is admissible considering the complexity and current limitations of the underlying modeling approach.
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Akute Anpassungen des Gangbildes und Gleichgewichts an ein sensomotorisches Laufbandtraining bei Patienten mit Morbus Parkinson - Klamroth, Sarah; Steib, Simon; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Klucken, Jochen; Pfeifer, Klaus (Moving Minds - Crossing Boundaries in Sport Science, 2015)

Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study - Huhn, Konstantin; Bayas, Antonios; Doerck, Sebastian; Frank, Benedikt; Gerbershagen, Kathrin; Hellwig, Kerstin; Kallmann, Boris; Kleinschnitz, Christoph; Kleiter, Ingo; Lee, De-Hyung; Limmroth, Volker; Maeurer, Mathias; et al. (Journal of Neurology, 2018)
BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach "no evidence of disease activity" status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice. METHODS: Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics. RESULTS: On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia. DISCUSSION: Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.
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ALLERGIC ASTHMA INDUCES THE ACCUMULATION OF SYNOVIAL RESIDENT EOSINOPHILS, TRIGGERING THE RESOLUTION OF INFLAMMATORY ARTHRITIS - Liu, Mao; Andreev, D.; Kachler, K.; Koelle, J.; Rauber, S.; Ramming, Andreas; Finotto, Susetta; Schett, G.; Bozec, A. (ANNALS OF THE RHEUMATIC DISEASES, 2020)
CRIS-Team WoS Importer:2020-08-21

Alpha power decrease in quantitative EEG detects development of cerebral infarction after subarachnoid hemorrhage early - Müller, Tamara; Gollwitzer, Stephanie; Hopfengartner, Ruediger; Rampp, Stefan; Lang, Johannes; Stritzelberger, Jenny; Madzar, Dominik; Reindl, Caroline; Sprügel, Maximilian; Onugoren, Muejgan Dogan; Mühlen, Iris; Kuramatsu, Joji; et al. (Clinical Neurophysiology, 2021)
Objective: In subarachnoid hemorrhage (SAH), transcranial Doppler/color-coded-duplex sonography (TCD/TCCS) is used to detect delayed cerebral ischemia (DCI). In previous studies, quantitative electroencephalography (qEEG) also predicted imminent DCI. This study aimed to compare and analyse the ability of qEEG and TCD/TCCS to early identify patients who will develop later manifest cerebral infarction. Methods: We analysed cohorts of two previous qEEG studies. Continuous six-channel-EEG with artefact rejection and a detrending procedure was applied. Alpha power decline of ≥ 40% for ≥ 5 hours compared to a 6-hour-baseline was defined as significant EEG event. Median reduction and duration of alpha power decrease in each channel was determined. Vasospasm was diagnosed by TCD/TCCS, identifying the maximum frequency and days of vasospasm in each territory. Results: 34 patients were included (17 male, mean age 56 ± 11 years, Hunt and Hess grade: I–V, cerebral infarction: 9). Maximum frequencies in TCD/TCCS and alpha power reduction in qEEG were correlated (r = 0.43; p = 0.015). Patients with and without infarction significantly differed in qEEG parameters (maximum alpha power decrease: 78% vs 64%, p = 0.019; summed hours of alpha power decline: 236 hours vs 39 hours, p = 0.006) but showed no significant differences in TCD/TCCS parameters. Conclusions: There was a moderate correlation of TCD/TCCS frequencies and qEEG alpha power reduction but only qEEG differentiated between patients with and without cerebral infarction. Significance: qEEG represents a non-invasive, continuous tool to identify patients at risk of cerebral infarction.
CRIS-Team Scopus Importer:2021-06-04
Keywords: Delayed cerebral ischemia; Quantitative EEG; Subarachnoid hemorrhage; Vasospasm

Alpha-synuclein activates BV2 microglia dependent on its aggregation state - Hoffmann, Alana; Ettle, Benjamin; Bruno, Ariane; Kulinich, Anna; Hoffmann, Anna-Carin; von Wittgenstein, Julia; Winkler, Jürgen; Xiang, Wei; Schlachetzki, Johannes (Biochemical and Biophysical Research Communications, 2016)
Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are defined by the presence of intracellular alpha-synuclein aggregates in neurons and/or oligodendrocytes. In addition, post mortem tissue analysis revealed profound changes in microglial morphology, indicating microglial activation and neuroinflammation. Thus, alpha-synuclein may directly activate microglia, leading to increased production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-?) and interleukin-1beta (IL-1?), which in turn modulates the disease progression. The distinct alpha-synuclein species, which mediates the activation of microglia, is not well defined. We hypothesized that microglial activation depends on a specific aggregation state of alpha-synuclein. Here, we show that primarily human fibrillar alpha-synuclein increased the production and secretion of pro-inflammatory cytokines by microglial BV2 cells compared to monomeric and oligomeric alpha-synuclein. BV2 cells also preferentially phagocytosed fibrillar alpha-synuclein compared to alpha-synuclein monomers and oligomers. Microglial uptake of alpha-synuclein fibrils and the consequent activation were time- and concentration-dependent. Moreover, the degree of fibrillization determined the efficiency of microglial internalization. Taken together, our study highlights the specific crosstalk of distinct alpha-synuclein species with microglial cells.
EVALuna2:4715

alpha-Synuclein: a Modulator During Inflammatory CNS Demyelination - Kuhbandner, Kristina; Hoffmann, Alana; Alvarado, Maria Nazareth; Seyler, Lisa; Bäuerle, Tobias; Winkler, Jürgen; Linker, Ralf (Journal of Molecular Neuroscience, 2020)
Neuroinflammation and demyelination are hallmarks of several neurological disorders such as multiple sclerosis and multiple system atrophy. To better understand the underlying mechanisms of de- and regeneration in respective diseases, it is critical to identify factors modulating these processes. One candidate factor is alpha-Synuclein (aSyn), which is known to be involved in the pathology of various neurodegenerative diseases. Recently, we have shown that aSyn is involved in the modulation of peripheral immune responses during acute neuroinflammatory processes. In the present study, the effect of aSyn deficiency on de- and regenerative events in the CNS was analyzed by using two different demyelinating animal models: chronic MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) and the cuprizone model. Histopathological analysis of spinal cord cross sections 8 weeks after EAE induction revealed a significant reduction of CNS inflammation accompanied by decreased myelin loss during late-stage inflammatory demyelination in aSyn-deficient mice. In contrast, after cuprizone-induced demyelination or remyelination following withdrawal of cuprizone, myelination and neuroinflammatory patterns were not affected by aSyn deficiency. These data provide further evidence for aSyn as regulator of peripheral immune responses under neuroinflammatory conditions, thereby also modulating degenerative events in late-stage demyelinating disease.
CRIS-Team WoS Importer:2020-04-07

Alpha-Synuclein and Its Role in Melanocytes - Rachinger, Nicole; Mittag, Nora; Böhme-Schäfer, Ines; Xiang, Wei; Kuphal, Silke; Boßerhoff, Anja Katrin (Cells, 2022)
Pigmentation is an important process in skin physiology and skin diseases and presumably also plays a role in Parkinson’s disease (PD). In PD, alpha-Synuclein (aSyn) has been shown to be involved in the pigmentation of neurons. The presynaptic protein is intensively investigated for its pathological role in PD, but its physiological function remains unknown. We hypothesized that aSyn is both involved in melanocytic differentiation and melanosome trafficking processes. We detected a strong expression of aSyn in human epidermal melanocytes (NHEMs) and observed its regulation in melanocytic differentiation via the microphthalmia-associated transcription factor (MITF), a central regulator of differentiation. Moreover, we investigated its role in pigmentation by performing siRNA experiments but found no effect on the total melanin content. We discovered a localization of aSyn to melanosomes, and further analysis of aSyn knockdown revealed an important role in melanocytic morphology and a reduction in melanosome release. Additionally, we found a reduction of transferred melanosomes in co-culture experiments of melanocytes and keratinocytes but no complete inhibition of melanosome transmission. In summary, this study highlights a novel physiological role of aSyn in melanocytic morphology and its so far unknown function in the pigment secretion in melanocytes.
CRIS-Team Scopus Importer:2022-07-15
Keywords: alpha-Synuclein; melanocytes; melanosomes; pigment transport; pigmentation

Alpha-synuclein fine-tunes neuronal response to pro-inflammatory cytokines - Sigutova, Veronika; Xiang, Wei; Regensburger, Martin; Winner, Beate; Prots, Iryna (Brain Behavior and Immunity, 2024)
Pro-inflammatory cytokines are emerging as neuroinflammatory mediators in Parkinson's disease (PD) due to their ability to act through neuronal cytokine receptors. Critical questions persist regarding the role of cytokines in neuronal dysfunction and their contribution to PD pathology. Specifically, the potential synergy of the hallmark PD protein alpha-synuclein (α-syn) with cytokines is of interest. We therefore investigated the direct impact of pro-inflammatory cytokines on neurons and hypothesized that α-syn pathology exacerbates cytokine-induced neuronal deficits in PD. iPSC-derived cortical neurons (CNs) from healthy controls and patients with α-syn gene locus duplication (SNCA dupl) were stimulated with IL-17A, TNF-α, IFN-γ, or a combination thereof. For rescue experiments, CNs were pre-treated with α-syn anti-oligomerisation compound NPT100-18A prior to IL-17A stimulation. Cytokine receptor expression, microtubule cytoskeleton, axonal transport and neuronal activity were assessed. SNCA dupl CNs displayed an increased IL-17A receptor expression and impaired IL-17A-mediated cytokine receptor regulation. Cytokines exacerbated the altered distribution of tubulin post-translational modifications in SNCA dupl neurites, with SNCA dupl-specific IL-17A effects. Tau pathology in SNCA dupl CNs was also aggravated by IL-17A and cytokine mix. Cytokines slowed down mitochondrial axonal transport, with IL-17A-mediated retrograde slowing in SNCA dupl only. The pre-treatment of SNCA dupl CNs with NPT100-18A prevented the IL-17A-induced functional impairments in axonal transport and neural activity. Our work elucidates the detrimental effects of pro-inflammatory cytokines, particularly IL-17A, on human neuronal structure and function in the context of α-syn pathology, suggesting that cytokine-mediated inflammation represents a second hit to neurons in PD which is amenable to disease modifying therapies that are currently in clinical trials.
CRIS-Team Scopus Importer:2024-09-27
Keywords: Alpha-synuclein; Cytokines; Neuroinflammation; Parkinson's disease

alpha-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1 - Winner, Beate; Spencer, Brian; Kosberg, Kori; Roberts, Scott; Patrick, Christina; Winkler, Jürgen; Masliah, Eliezer; et al. (Journal of Biological Chemistry, 2012)
Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of alpha-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that alpha-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that alpha-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for alpha-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.

Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress - Winner, Beate; Menges, Stefanie; Minakaki, Georgia; Schaefer, Patrick; Meixner, Holger; Prots, Iryna; Schlötzer-Schrehardt, Ursula; Friedland, Kristina; Outeiro, Tiago F.; Winklhofer, Konstanze F.; Von Arnim, Christine A. F.; Xiang, Wei; et al. (Scientific Reports, 2017)
Oxidative stress (OS), mitochondrial dysfunction, and dysregulation of alpha-synuclein (aSyn) homeostasis are key pathogenic factors in Parkinson's disease. Nevertheless, the role of aSyn in mitochondrial physiology remains elusive. Thus, we addressed the impact of aSyn specifically on mitochondrial response to OS in neural cells. We characterize a distinct type of mitochondrial fragmentation, following H2O2 or 6-OHDA-induced OS, defined by spherically-shaped and hyperpolarized mitochondria, termed "mitospheres". Mitosphere formation mechanistically depended on the fission factor Drp1, and was paralleled by reduced mitochondrial fusion. Furthermore, mitospheres were linked to a decrease in mitochondrial activity, and preceded Caspase3 activation. Even though fragmentation of dysfunctional mitochondria is considered to be a prerequisite for mitochondrial degradation, mitospheres were not degraded via Parkin-mediated mitophagy. Importantly, we provide compelling evidence that aSyn prevents mitosphere formation and reduces apoptosis under OS. In contrast, aSyn did not protect against Rotenone, which led to a different, previously described donut-shaped mitochondrial morphology. Our findings reveal a dichotomic role of aSyn in mitochondrial biology, which is linked to distinct types of stress-induced mitochondrial fragmentation. Specifically, aSyn may be part of a cellular defense mechanism preserving neural mitochondrial homeostasis in the presence of increased OS levels, while not protecting against stressors directly affecting mitochondrial function.

Alterations of intracerebral connectivity in epilepsy patients with secondary bilateral synchrony - Hammen, T.; Reisert, M.; Juschkat, W.; Egger, K.; Urbach, H.; Zentner, J.; Beck, J.; Hamer, Hajo; Steinhoff, B. J.; Baumgartner, C.; Schulze-Bonhage, A.; Puhahn-Schmeiser, B. (Epilepsy Research, 2020)
Introduction: The aim of our study was to evaluate intracerebral network changes in epilepsy patients demonstrating secondary bilateral synchrony (SBS) in EEG by applying a new Diffusion Tensor Imaging (DTI) method using an energy-based global tracking algorithm. Materials and methods: 10 MRI negative epilepsy patients demonstrating SBS in 10–20 surface EEG were included. EEG findings were analyzed for irritative zones characterized by focal interictal epileptiform discharges (IEDs) triggering SBS. In addition, DTI including an energy-based global tracking algorithm was applied to analyze fiber tract alterations in irritative zones. To measure the deviation of a certain cortical connection in comparison to healthy controls, normalized differences of fiber tract streamline counts (SC) and their p-values were evaluated in comparison to corresponding fibers of the control group. Results: In 6 patients the irritative zone initiating SBS was located in the frontal lobe, in 3 patients in the temporal lobe and in 1 patient in the region surrounding the right central sulcus. All patients demonstrated significantly altered SC in brain lobes where the irritative zone triggering SBS was located (p ≤ 0.05). Seven out of 10 patients demonstrated SC alterations in tracts connecting brain lobes between the ipsilateral and the contralateral hemisphere (p ≤ 0.05). Conclusion: Our data demonstrate that alterations in fiber tracts in irritative zones triggering SBS are not necessarily associated with intracerebral lesions visible in high resolution MRI. Our study gives evidence that diffusion tensor imaging is a promising non-invasive additive tool for intracerebral network analyses even in MRI-negative epilepsy patients.
CRIS-Team Scopus Importer:2020-08-07
Keywords: contralateral propagation; diffusion tensor imaging; epilepsy patients; fiber tracts; intracerebral network changes; irritative zone; MRI negative; secondary bilateral synchrony; streamline counts

Altered autonomic responses to happy and fearful music in patients with a history of mild traumatic brain injury - Hilz, Max-Josef; Wang, Ruihao; Hoesl, K. M.; Muresanu, D. F.; Liu, M. (JOURNAL OF THE NEUROLOGICAL SCIENCES, 2019)
CRIS-Team WoS Importer:2020-03-24

Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury - Ruehl, Lena; Kuramatsu, Joji; Sembill, Jochen; Kallmünzer, Bernd; Madzar, Dominik; Gerner, Stefan; Giede-Jeppe, Antje; Balk, Stefanie; Müller, Tamara; Jäger, Jakob; Schwab, Stefan; Huttner, Hagen; et al. (Journal of Neurology Neurosurgery and Psychiatry, 2022)
Objective This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury. Methods We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated >= 7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days. Results Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079). Conclusions Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.
CRIS-Team WoS Importer:2022-02-11

Ambulatory motor dysfunction in MS assessed by wearable inertial sensor metrics during the timed-up-and-go task (TUG) - Oberndorfer, C.; Barth, J.; Guppy, J. H.; Bush, J.; Needham, R.; Healy, A.; Chockalingam, N.; Herberz, C.; Westling, C. E. I.; Eskofier, B. M.; Roggen, D.; Klucken, Jochen; et al. (2016)
EVALuna2:33513

A Mobile Solution for Rhythmic Auditory Stimulation Gait Training - Aholt, Katharina; Martindale, Christine; Küderle, Arne; Gaßner, Heiko; Gladow, Till; Rojo, Javier; Villanueva-Mascato, Samantha; Klucken, Jochen; Arredondo Waldmeyer, Maria Teresa; Eskofier, Björn (2019 41st Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), 2019)

A monocyte gene expression signature in the early clinical course of Parkinson's disease - Schlachetzki, Johannes; Prots, Iryna; Tao, Jenhan; Chun, Hyun B.; Saijo, Kaoru; Gosselin, David; Winner, Beate; Glass, Christopher K.; Winkler, Jürgen (Scientific Reports, 2018)
Microglia are the main immune cells of the brain and express a large genetic pattern of genes linked to Parkinson's disease risk alleles. Monocytes like microglia are myeloid-lineage cells, raising the questions of the extent to which they share gene expression with microglia and whether they are already altered early in the clinical course of the disease. To decipher a monocytic gene expression signature in Parkinson's disease, we performed RNA-seq and applied the two-sample Kolmogorov-Smirnov test to identify differentially expressed genes between controls and patients with Parkinson's disease and changes in gene expression variability and dysregulation. The gene expression profiles of normal human monocytes and microglia showed a plethora of differentially expressed genes. Additionally, we identified a distinct gene expression pattern of monocytes isolated from Parkinson's disease patients at an early disease stage compared to controls using the Kolmogorov-Smirnov test. Differentially expressed genes included genes involved in immune activation such as HLA-DQB1, MYD88, REL, and TNF-alpha. Our data suggest that future studies of distinct leukocyte subsets are warranted to identify possible surrogate biomarkers and may lead to the identification of novel interventions early in the disease course.
EVALuna2:35780

A monocyte gene expression signature in the early clinical course of Parkinson's disease (vol 8, 10757, 2018) - Winner, Beate; Schlachetzki, Johannes C.M.; Prots, Iryna; Tao, Jenhan; Chun, Hyun B.; Saijo, Kaoru; Gosselin, David; Glass, Christopher K.; Winkler, Jürgen (Scientific Reports, 2020)

A multicenter cohort study on the efficacy, retention, and tolerability of cenobamate in patients with developmental and epileptic encephalopathies - Buhleier, Elisa; Schubert-Bast, Susanne; Knake, Susanne; von Podewils, Felix; Hamer, Hajo; Melzer, Nico; Kurlemann, Gerhard; Klotz, Kerstin Alexandra; Willems, Laurent M.; Rosenow, Felix; Brunklaus, Andreas; Strzelczyk, Adam (Epilepsia, 2025)
Objective: This study was undertaken to evaluate retention and treatment characteristics of cenobamate (CNB) in patients with developmental and epileptic encephalopathies (DEEs) in clinical practice. Methods: This multicenter, retrospective cohort study recruited all patients with DEEs who started CNB treatment between October 2020 and April 2023 at participating epilepsy centers. Results: A total of 41 patients (mean age = 28.3 ± 13.1 years, median = 26 years, range = 4–73 years; 24 male [58.5%]) were treated with CNB. Of these, 33 had Lennox–Gastaut syndrome, seven had tuberous sclerosis complex, and one had Dravet syndrome. The median number of antiseizure medications (ASMs) at enrollment was three, and patients had a median of eight failed ASMs in the past. The retention rate for CNB was 94.9% at 3 months, 82.9% at 6 months, and 72.4% at 12 months of follow-up. Cumulative exposure to CNB was 477 months (39.2 years). Efficacy (50% responder rate) at 3 months was 39% including 7.3% seizure-free patients. Long-term, the 50% responder rate at 12 months was 34.5% (seizure-free [10.3%]). There was no difference in response at 3 months regarding sex, age (adult vs. children), previous and concomitant number of ASMs, or first target dose of CNB. Treatment-emergent adverse events were predominantly sedation and dizziness and were observed in 58.5% of patients. Children and adolescents showed comparable efficacy, retention, and tolerability compared to adults. Significance: The findings from this open-label, retrospective study suggest that CNB may be effective in some patients with DEEs. Its overall use in DEEs seems to be safe and well tolerated. We observed similar response, retention, and adverse event profiles in children and adults.
CRIS-Team Scopus Importer:2025-02-28
Keywords: antiseizure medication; Dravet syndrome; epilepsy; Lennox–Gastaut syndrome; seizure

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany - Strzelczyk, Adam; Schubert-Bast, Susanne; Bast, Thomas; Bettendorf, Ulrich; Fiedler, Barbara; Hamer, Hajo; Herting, Arne; Kalski, Malin; Kay, Lara; Kieslich, Matthias; Klein, Karl Martin; Kluger, Gerhard; et al. (Epilepsia, 2019)
Objective: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. Methods: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). Results: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). Significance: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.
CRIS-Team Scopus Importer:2019-07-09
Keywords: costs; depression; encephalopathy; quality of life; Severe myoclonic epilepsy of infants

A multicenter randomized controlled feasibility trial of a digital self-management intervention for adults with epilepsy - Michaelis, Rosa; Knake, Susanne; Rosenow, Felix; Grönheit, Wenke; Hamer, Hajo; Schmitz, Bettina; Accarie, Alison; Dedeken, Peter; Immisch, Ilka; Habermehl, Lena; Zöllner, Johann Philipp; Mann, Catrin; et al. (Epilepsia Open, 2024)
Objective: Self-management interventions may enhance health-related quality of life (HRQoL) in epilepsy. However, several barriers often impair their implementation in the real world. Digital interventions may help to overcome some of these barriers. Considering this, the Helpilepsy Plus Prototype was developed as a prototype smartphone-delivered self-care treatment program for adults with epilepsy. Methods: The 12-week Helpilepsy Plus Prototype was evaluated through a randomized controlled feasibility trial with a waiting-list control (WLC) group. Outcome measurement at baseline and at 12 weeks assessed adherence to the prototype intervention and changes in epilepsy-related outcomes. The primary endpoint was patient autonomy measured with EASE, and secondary endpoints included HRQoL measured with QOLIE-31, health literacy measured with HLQ, anxiety, and depression symptoms measured with HADS. Semi-structured interviews were conducted with a heterogeneous sample of participants to assess user-friendliness and usefulness. The prototype program was delivered through the Neuroventis Platform (Neuroventis, BV, Overijse, Belgium), a certified medical device (under EU/MDD Class I, and EU/MDR grace period). Results: Ninety-two patients were included (46 in the intervention group, 46 in WLC). Most participants (63%, 58/92 women, median age 30 years) had pharmacoresistant epilepsy (61%, 56/92). Only 22% of participants (10/46) in the intervention group completed at least half of all intervention sessions. No significant differences between the intervention group and WLC were observed. Although there was a larger proportion of patients in the intervention group with meaningful improvements in HRQoL compared to WLC (19/46 versus 11/46), the difference was not significant (p = 0.119). Qualitative feedback showed that participants would appreciate more personalization, such as adaptation of the content to their current epilepsy knowledge level, a more interactive interface, shorter text sections, and interaction through reminders and notifications. Significance: Digital interventions should allow sufficient scope for personalization and interaction to increase patient engagement and enable benefits from self-care apps. Feedback loops allow the participatory development of tailored interventions. Plain Language Summary: In this study, we investigated the effectiveness of an app-based self-help intervention. Study participants were either randomly assigned to a group that had access to the app or a group that received access to the app after the end of the study. Although a larger proportion of participants in the intervention group showed a relevant improvement in quality of life, the difference between the two groups was not statistically significant. Less than one-fifth of participants in the intervention group attended at least half of all intervention sessions; patient feedback showed that patients required more personalization and interactive options.
CRIS-Team Scopus Importer:2024-06-14
Keywords: health literacy; Helpilepsy; mobile health; patient autonomy; quality of life

A multicenter survey of clinical experiences with perampanel in real life in Germany and Austria - Steinhoff, Bernhard J.; Hamer, Hajo; Trinka, Eugen; Schulze-Bonhage, Andreas; Bien, Christian; Mayer, Thomas; Baumgartner, Christoph; Lerche, Holger; Noachtar, Soheyl (Epilepsy Research, 2014)
Perampanel (PER) has been approved by the European Medicines Agency (EMA) for adjunctive treatment of patients with partial-onset seizures from age 12 years on. It has been introduced to the market in Germany and Austria in 2012. This cross-sectional observational study summarizes the clinical experience of nine centers with adjunctive PER. Patients were consecutively followed from the initiation of PER on. Only patients with a minimum observational period of six months (in case of ongoing treatment) were recruited. Efficacy data reflect the preceding three months at last observation, tolerability data were assessed at the last observation carried forward. 281 patients were included. After six months 169 were still on PER so that a retention rate of 60% resulted. 43 patients were seizure-free for the preceding 3 months (15%). Overall incidence of adverse events was 52.0%. The leading adverse events were somnolence (24.6%) and dizziness (19.6%) followed by ataxia (3.9%), aggression (2.8%), nausea (2.5%) and irritability (2.1%). We conclude that adjunctive PER may lead to at least temporary freedom of seizures in some of these highly difficult-to-treat patients. Adverse events are not uncommon.
EVALuna2:22306

A Multisensory Deficit in the Perception of Pleasantness in Parkinson's Disease. - Utz, Kathrin; Martini, Max; Mrochen, Anne; Lambrecht, Vera; Süß, Patrick; Renner, Bertold; Freiherr, Jessica; Schenk, Thomas; Winkler, Jürgen; Marxreiter, Franz (Journal of Parkinson's Disease, 2021)
BACKGROUND: There is growing interest in non-motor symptoms in Parkinson's disease (PD), due to the impact on quality of life. Anhedonia, the inability to experience joy and lust, has a prevalence of up to 46% in PD. The perception of pleasantness of an odor is reduced in anhedonia without PD. We previously showed a reduced hedonic olfactory perception in PD, i.e., patients evaluated odors as less pleasant or unpleasant compared to controls. This deficit correlated with anhedonia. OBJECTIVE: We aimed to confirm these findings. Moreover, we hypothesized that the perception of pleasantness in PD is affected on a multisensory level and correlates with anhedonia. Therefore, we assessed olfactory, visual and acoustic evaluation of pleasantness in PD and healthy individuals. METHODS: Participants had to rate the pleasantness of 22 odors, pictures, and sounds on a nine-point Likert scale. Depression, anhedonia, and apathy were assessed by means of questionnaires. Results of the pleasantness-rating were compared between groups and correlated to scores of the questionnaires. RESULTS: In particular pleasant and unpleasant stimuli across all three modalities are perceived less intense in PD, suggesting that a reduced range of perception of pleasantness is a multisensory phenomenon. However, only a reduction of visual hedonic perception correlated with anhedonia in PD. A correlation of reduced perception of pleasantness with apathy or depression was not present. CONCLUSION: We provide evidence for a multisensory deficit in the perception of pleasantness. Further studies should delineate the underlying neural circuity and the diagnostic value to detect neuropsychiatric symptoms in PD.
EVALuna2:470167

A Multisensory Deficit in the Perception of Pleasantness in Parkinson's Disease - Utz, Kathrin; Martini, Max; Mrochen, Anne; Lambrecht, Vera; Süß, Patrick; Renner, Bertold; Freiherr, Jessica; Schenk, Thomas; Winkler, Jürgen; Marxreiter, Franz (Journal of Parkinson's Disease, 2021)
Background: There is growing interest in non-motor symptoms in Parkinson's disease (PD), due to the impact on quality of life. Anhedonia, the inability to experience joy and lust, has a prevalence of up to 46% in PD. The perception of pleasantness of an odor is reduced in anhedonia without PD. We previously showed a reduced hedonic olfactory perception in PD, i.e., patients evaluated odors as less pleasant or unpleasant compared to controls. This deficit correlated with anhedonia. Objective: We aimed to confirm these findings. Moreover, we hypothesized that the perception of pleasantness in PD is affected on a multisensory level and correlates with anhedonia. Therefore, we assessed olfactory, visual and acoustic evaluation of pleasantness in PD and healthy individuals. Methods: Participants had to rate the pleasantness of 22 odors, pictures, and sounds on a nine-point Likert scale. Depression, anhedonia, and apathy were assessed by means of questionnaires. Results of the pleasantness-rating were compared between groups and correlated to scores of the questionnaires. Results: In particular pleasant and unpleasant stimuli across all three modalities are perceived less intense in PD, suggesting that a reduced range of perception of pleasantness is a multisensory phenomenon. However, only a reduction of visual hedonic perception correlated with anhedonia in PD. A correlation of reduced perception of pleasantness with apathy or depression was not present. Conclusion: We provide evidence for a multisensory deficit in the perception of pleasantness. Further studies should delineate the underlying neural circuity and the diagnostic value to detect neuropsychiatric symptoms in PD.
CRIS-Team Scopus Importer:2021-10-29
Keywords: affective pictures; anhedonia; apathy; depression; hyposmia; non-motor symptoms; Parkinson's disease; Sniffin' Sticks

An Adaptable Inertial Sensor Fusion-Based Approach for Energy Expenditure Estimation. - Schuldhaus, Dominik; Dorn, Sabrina; Leutheuser, Heike; Tallner, Alexander; Klucken, Jochen; Eskofier, Björn (The 15th International Conference on Biomedical Engineering, 2013)

An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington’s disease patient neurons - Krach, Florian; Stemick, Judith; Börstler, Tom; Weiss, Alexander; Lingos, Ioannis; Reischl, Stephanie; Meixner, Holger; Ploetz, Sonja; Farrell, Michaela; Hehr, Ute; Kohl, Zacharias; Winner, Beate; et al. (Nature Communications, 2022)
Huntington’s disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients’ fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD. Branaplam is a splicing modulator currently tested in a phase II study in HD (NCT05111249). The drug lowers total HTT (tHTT) and mHTT levels in fibroblasts, iPSC, cortical progenitors, and neurons in a dose dependent manner at an IC50 consistently below 10 nM without inducing cellular toxicity. Branaplam promotes inclusion of non-annotated novel exons. Among these Branaplam-induced exons, there is a 115 bp frameshift-inducing exon in the HTT transcript. This exon is observed upon Branaplam treatment in Ctrl and HD patients leading to a profound reduction of HTT RNA and protein levels. Importantly, Branaplam ameliorates aberrant alternative splicing in HD patients’ fibroblasts and cortical neurons. These findings highlight the applicability of splicing modulators in the treatment of CAG repeat disorders and decipher their molecular effects associated with the pharmacokinetic and -dynamic properties in patient-derived cellular models.
CRIS-Team Scopus Importer:2022-11-25

Analysing Variables for 90-Day Functional-Outcome Prediction of Endovascular Thrombectomy - Rodriguez Salas, Dalia; Rieß, Christian; Martín Vicario, Celia; Taubmann, Oliver; Ditt, Hendrik; Schwab, Stefan; Dörfler, Arnd (Medical Image Understanding and Analysis. 28th Annual Conference, MIUA 2024, Manchester, UK, July 24–26, 2024, Proceedings, Part II, 2024)
Multiple studies report the impact of variables on predicting long-term functional outcomes following Endovascular Thrombectomy (EVT). Often, the variables are analyzed separately with univariate statistical analysis or combined in a linear regression or logistic regression prediction. Although such linear combinations are easy to interpret, they do not consider nonlinear relationships. Other studies do consider nonlinearities, most notably in deep learning. However, if any, they use separate methods to assess the variable importance, which might not capture their actual contribution to the prediction. In this work, we propose to use an algorithm that combines the predictive power of neural networks and the interpretation of decision trees in a single method. ForestNet is a special artificial neural network that defines its partially connected architecture based on the hierarchical variable importance given by an ensemble of decision trees, providing a means of interpretation in a more generalized fashion. On predicting 90-day favorable functional outcomes, using 10-fold cross-validation, we reach an AUC of 0.82 and 0.86 before and after EVT, respectively. A 90-day Modified Rankin Scale (mRS)<=2 defines a favorable outcome. The analysis of the variable’s contribution shows that the pre-stroke mRS, age, and the National Institutes of Health Stroke Scale (NIHSS) play the most important role in predictions before EVT. After EVT, the infarct volume from the 24h follow-up CT scan, measured directly or in terms of affected brain regions according to the ASPECT score, is the most important variable in providing a more accurate prediction than before EV
Keywords: Stroke outcome prediction; Interpretable machine learning; Thrombectomy 90-day outcome

Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR - Boßelmann, Christian M.; Leu, Costin; Brünger, Tobias; Hoffmann, Lucas; Baldassari, Sara; Chipaux, Mathilde; Coras, Roland; Kobow, Katja; Hamer, Hajo; Delev, Daniel; Rössler, Karl; Bien, Christian G.; et al. (Nature Communications, 2024)
Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations (BRAF, SLC35A2, MTOR, PTPN11), support eight associations without prior statistical support (FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS), and identify novel associations for two genes, DYRK1A and EGFR. Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable target

Analysis of CD4+ CD8+ double-positive T cells in blood, cerebrospinal fluid and multiple sclerosis lesions - Waschbisch, Anne; Sammet, Laura; Schröder, S.; Lee, D. -H.; Barrantes-Freer, A.; Stadelmann, C.; Linker, Ralf (Clinical and Experimental Immunology, 2014)
T cells with a CD4(+) CD8(+) double-positive (DP) phenotype are present in small numbers in the peripheral blood of healthy humans and may have anti-viral capacities. Here we investigate numbers and function of DP T cells in patients with relapsing-remitting multiple sclerosis (MS), either treatment-naive or under therapy with natalizumab. Flow cytometry analysis revealed that frequencies of circulating DP T cells in treatment-naive and natalizumab-treated MS patients are comparable to healthy controls. These cells have a memory phenotype with cytotoxic potential, express high levels of CD49d and are similarly functional in treatment-naive as well as natalizumab-treated MS patients. DP T cells were enriched in the cerebrospinal fluid, but do not invade acutely inflamed MS lesions. In conclusion, DP T cells are functional in MS and may play a role in the immune surveillance of the central nervous system, but do not display functional impairment under natalizumab therapy.
EVALuna2:22346

Analysis of Process Costing for the Use of Navigation Systems in Functional Endoscopic Sinus Surgery - Schwan, Franziska Eva; Traxdorf, Maximilian; Seebauer, Caroline Theresa; Sekita, Alexander; Habekost, Cornelia; Iro, Heinrich; Bohr, Christopher (Applied Sciences, 2021)
Featured Application This paper and its findings are important for any clinic that is thinking about setting up a navigation system for its ENT department, concerning the costs, efficiency in the operating room, and applicability for training purposes. (1) Background: The use of navigation systems is rarely necessary for routine sinus surgery. They may prove to be advantageous for difficult operations, for example, in finding structures that are difficult to reach, in the treatment of cancers, or in revisional surgery. Navigation systems are also said to have positive effects on the self-confidence of surgeons in stressful situations and in the training of doctors. (2) Methods: This retrospective study included patients who underwent surgical treatment for chronic sinusitis from 2012 to 2016 at the ENT clinic of the University Hospital, Erlangen. Two groups were formed; one includes patients without navigated sinus surgery, the other includes those with navigation. The incision-suture times of both groups and cost analysis are compared. An appropriate cost estimate for sinus surgery is determined. (3) Results: From the available results, no economically efficient navigation systems in sinus surgery at the ENT clinic can be shown. The main reason is that lengthening the operating time leads to higher costs. (4) Conclusions: Although the use of a navigation system for endonasal sinus surgery cannot be economically justified, it is an important tool, especially in cases with complex anatomical conditions, and the system is essential for training purposes.
CRIS-Team WoS Importer:2021-10-08

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations - Reinhardt, Annekathrin; Stichel, Damian; Schrimpf, Daniel; Sahm, Felix; Korshunov, Andrey; Reuss, David E.; Koelsche, Christian; Huang, Kristin; Wefers, Annika K.; Hovestadt, Volker; Sill, Martin; Gramatzki, Dorothee; et al. (Acta Neuropathologica, 2018)
Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.
EVALuna2:34582

ANDEXANET ALFA VERSUS USUAL CARE IN PATIENTS WITH DOAC ASSOCIATED INTRACEREBRAL HEMORRHAGE: A PROPENSITY-SCORE BASED HISTORICAL COMPARISON OF PATIENTS FROM ANNEXA4 AND RETRACEII - Huttner, Hagen; Gerner, Stefan; Connolly, S.; Middeldorp, S.; Milling, T.; Beyer-Westendorf, J.; Altevers, J.; Andersohn, F.; Yue, P.; Stross, L.; Schwab, Stefan (INTERNATIONAL JOURNAL OF STROKE, 2020)
CRIS-Team WoS Importer:2021-01-22

Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage - Connolly, Stuart J.; Sharma, Mukul; Cohen, Alexander T.; Demchuk, Andrew M.; Członkowska, Anna; Lindgren, Arne G.; Molina, Carlos A.; Bereczki, Daniel; Toni, Danilo; Seiffge, David J.; Tanne, David; Sandset, Else Charlotte; et al. (New England Journal of Medicine, 2024)
Background Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. Methods We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. Results A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P=0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P=0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. Conclusions Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).
CRIS-Team Scopus Importer:2024-05-31
Keywords: Coagulation; Emergency Medicine; Emergency Medicine General; Hematology/Oncology; Neurology/Neurosurgery; Stroke; Stroke

An Emerging Era in the Management of Parkinson's disease: Wearable Technologies and the Internet of Things - Pasluosta, Cristian Federico; Gaßner, Heiko; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (IEEE Journal of Biomedical and Health Informatics, 2015)

Aneurysmatic subarachnoid haemorrhage - Onur, Oezguer A.; Fink, Gereon R.; Kuramatsu, Joji; Schwab, Stefan (Neurological Research and Practice, 2019)
Introduction: Aneurysmatic Subarachnoid Haemorrhage (aSAH) is typically caused by extravasated blood in the subarachnoid space due to a ruptured aneurysm. aSAH is often life-threatening in the acute stage, but may also cause secondary brain damage due to delayed cerebral ischaemia (DCI) and other complications in the days and weeks after the initial bleeding. Rapid onset of a most severe headache is a typical sign of a non-traumatic aSAH besides a reduced level of consciousness and neurologic deficits. First steps: Immediate diagnostic steps in case of a suspected SAH are cerebral imaging (CCT, MRI) and lumbar puncture. If a SAH is confirmed, a digital subtraction angiography should be performed to detect an aneurysm. If an aneurysm is detected it should be occluded immediately after interdisciplinary consultation with neurosurgeons and neuroradiologists. Comments: If endovascular coiling and surgical clipping are both available and equally suitable, coiling should be preferred due to a better long-time outcome. Often the age of the patient, the location of the aneurysm, and the configuration of the aneurysm result in favouring one or the other technique. Special care aims at avoiding stress, increased intracranial pressure, pain, fever, emesis, and at keeping glucose levels and electrolytes in the normal range. As nimodipine is associated with a better outcome, it should be administered from the beginning. To detect vasospasm, serial transcranial doppler should be performed at least once a day for at least 14 days. If vasospasms are detected, this procedure needs to be continued until flow velocity returns to the normal range. To detect an increased intracranial pressure, external ventricular drainage or intraparenchymal probes are recommended. Regarding haemodynamics, euvolaemia and normotension should be achieved. If vasospasms and/or an increased intracranial pressure occur, mean arterial pressure needs to be adjusted to ensure an adequate cerebral perfusion pressure. Conclusions: If immediate actions are taken to treat the aneurysm and complications in the following weeks are handled with care, a favourable outcome is possible for this otherwise often devastating disease.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Clipping; Coiling; Delayed cerebral ischaemia; Nimodipine; Standard operating procedure; Vasospasm

A New Immortalized Human Lacrimal Gland Cell Line - Gleixner, Sophie; Zahn, Ingrid; Dietrich, Jana; Singh, Swati; Drobny, Alice; Schneider, Yanni; Schwendner, Raphael; Socher, Eileen; Blavet, Nicolas; Bräuer, Lars; Gostian, Antoniu-Oreste; Balk, Matthias; et al. (Cells, 2024)
The lacrimal gland is crucial for maintaining ocular health by producing the aqueous component of the tear film, which hydrates and nourishes the ocular surface. Decreased production of this component results in dry eye disease, a condition affecting over 250 million people worldwide. However, the scarcity of primary human material for studying its underlying mechanisms and the absence of a cell model for human lacrimal gland epithelial cells present significant challenges. Here, we describe the generation of immortalized human lacrimal gland cell lines through the introduction of an SV40 antigen. We successfully isolated and characterized three cell clones from a female lacrimal gland donor, confirming their epithelial identity through genomic and protein analyses, including PCR, RNAseq, immunofluorescence and cultivation in a 3D spheroid model. Our findings represent a significant advancement, providing improved accessibility to investigate the molecular pathogenesis mechanisms of dry eye disease and potential therapeutic interventions. We identified the expression of typical epithelial cell marker genes and demonstrated the cells’ capability to form 2D cell sheets and 3D spheroids. This establishment of immortalized human lacrimal gland cells with epithelial characteristics holds promise for future comprehensive studies, contributing to a deeper understanding of dry eye disease and its cellular mechanisms.<br
Keywords: lacrimal gland; epithelial cells; immortalized; cell line; dry eye; tears; tear secretion

Anforderungen an die Neurorehabilitation nach epilepsiechirurgischen Eingriffen im linken Temporallappen bei Patienten mit neurokognitivem Risikoprofil - Schwarz, Michael; Badstübner, Annabell Sophie; Meyn, Karlotta; Walther, Katrin; Hamer, Hajo (Fortschritte der Neurologie - Psychiatrie, 2023)
Introduction In case of pharmacoresistant focal epilepsy, surgery is often the only way to achieve seizure freedom. These operations may result in cognitive deficits, especially with surgery in the left temporal lobe. The aim of this study was to determine whether patients operated in the left or right tem-poral lobe, respectively, have different cognitive outcomes. Furthermore, it was investigated if there was a positive influence of occupational therapy on neurorehabilitation in epilepsy patients. Methods In all patients cognitive performance was assessed preoperatively and six months postoperatively. Patient groups with surgery in the right and left temporal lobe were compared. Additionally, single cases of patients who had undergone extensive pre- and postoperative occupational therapy were analyzed. Results There was a significantly better cognitive outcome in patients who underwent surgery in their right temporal lobe. Occupational therapy was highly beneficial in patients after left temporal lobe surgery. Conclusion Occupational therapy after left temporal lobe surgery is adapted to find individual solutions for the patient s problems and to implement effective cognitive training strategies.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Epilepsie; Epilepsiechirurgie; Ergotherapie; Neuropsychologie; Temporallappen

Angioedema in Stroke Patients With Thrombolysis - Fröhlich, Katharina; Macha, Kosmas; Gerner, Stefan; Bobinger, Tobias; Schmidt, Manuel; Dörfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Seifert, Frank; Kallmünzer, Bernd; Winder, Klemens (Stroke, 2019)
Background and Purpose- Oral angioedema (OA) is a rare but life-threatening complication in patients with ischemic stroke receiving intravenous thrombolysis with r-tPA (recombinant tissue-type plasminogen activator). This study intended to determine associations between thrombolysis-related OA and ischemic stroke lesion sites using a voxel-wise lesion analysis. Methods- Prospective registry data were used to identify ischemic stroke patients with thrombolysis-related OA between 2002 and 2018. For the study registry, ethics approval was obtained by the Ethics Committee of the Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg (clinical registry registration: 377_17Bc). Ischemic stroke patients with thrombolysis treatment but without OA admitted in the years 2011 and 2012 comprised the control group. Ischemic lesions were manually outlined on magnetic resonance imaging (1.5T or 3T) or computed tomographic scans and transformed into stereotaxic space. We determined the lesion overlap and compared the absence or presence of OA voxel-wise between patients with and without lesions in a given voxel using the Liebermeister test. Stroke severity was rated using the National Institutes of Health Stroke Scale score, and blood pressure, heart rate, blood glucose levels, and body temperature were determined on admission. Results- Fifteen ischemic stroke patients with thrombolysis-related OA were identified. The voxel-wise analysis yielded associations between OA and ischemic lesions in the insulo-opercular region with a right hemispheric dominance. Mean blood pressure was significantly lower in patients with OA than in controls. Age, National Institutes of Health Stroke Scale scores, infarct volumes, heart rate, and blood glucose levels did not differ between patients with and without OA. Conclusions- The voxel-wise analysis linked thrombolysis-related OA to right insulo-opercular lesions. The lower blood pressure in patients with thrombolysis-related OA may reflect bradykinin effects causing vasodilatation and increasing vascular permeability.
CRIS-Team Scopus Importer:2019-07-19
Keywords: angioedema; autonomic nervous system; brain ischemia; neuroimaging; stroke; tissue-type plasminogen activator

Angiographic CT with intravenous contrast agent application for monitoring of intracranial flow diverting stents - Saake, Marc; Struffert, Tobias; Gölitz, Philipp; Ott, Sabine; Seifert, Frank; Ganslandt, Oliver; Dörfler, Arnd (Neuroradiology, 2012)
Introduction: Intracranial flow diverting devices are increasingly used to treat cerebral aneurysms. A reliable, noninvasive follow-up modality would be desirable. Our aim was to compare intra-arterial digital subtraction angiography (ia DSA) to angiographic computed tomography with intravenous contrast agent application (iv ACT) in the visualisation of flow diverting devices and aneurysm lumina. Methods: Follow-up monitoring by iv ACT (n=36) and ia DSA (n=25) in 14 patients treated with flow diverting devices for intracranial aneurysms was evaluated retrospectively. Images were evaluated by two neuroradiologists in anonymous consensus reading regarding the device deployment, wall apposition, neck coverage of the aneurysm, opacification of the vessel and device lumen, as well as the degree of aneurysm occlusion. Results: Corresponding ia DSA and iv ACT images were scored identically in all patients regarding the stent deployment, wall apposition and neck coverage, as well as the degree of aneurysm occlusion and patency status of the device and parent artery. Opacification of the parent vessel lumen and perfused parts of the aneurysm was considered slightly inferior for iv ACT in comparison with ia DSA (seven of 36 cases), without impact on diagnosis. Conclusions: We demonstrated the feasibility and diagnostic value of iv ACT in follow-up imaging of intracranial flow diverting devices. Due to its high spatial resolution and non-invasive character, this novel technique might become a valuable imaging modality in these patients. © Springer-Verlag 2011.
CRIS-Team Scopus Importer:2022-08-05
Keywords: Angiography; Computed tomography; Flat detector; Flow diverting stent; Follow-up; Intravenous

Angiographic CT with intravenous contrast injection compared with conventional rotational angiography in the diagnostic work-up of cerebral aneurysms - Gölitz, Philipp; Struffert, Tobias; Knossalla, F.; Saake, Marc; Ott, Sabine; Ganslandt, Oliver; Dörfler, Arnd (American Journal of Neuroradiology, 2012)
BACKGROUND AND PURPOSE: Noninvasive imaging of cerebral aneurysms is still considered inferior to conventional angiography. The purpose of this study was to evaluate the diagnostic accuracy of ivACT in the assessment of intracranial aneurysms compared with 3D-DSA. MATERIALS AND METHODS: We included 13 patients with 15 incidental unruptured saccular aneurysms scheduled for diagnostic angiographic work-up in our study. In each patient, we performed an ivACT and a conventional angiography including a 3D rotational run. During postprocessing, MPR images were generated for each technique. Maximal aneurysm diameter, neck diameter, aneurysm height, maximum width, bulge height, parent artery diameter, and angle between the parent artery and aneurysm apex were measured for each aneurysm. RESULTS: 3D-DSA and ivACT both provided images of high quality without artificial disturbances (ie, motion artifacts). Measurements of all parameters resulted in comparable values for both modalities with a strong correlation (P ≤ .001). CONCLUSIONS: ivACT is feasible for the noninvasive visualization of saccular cerebral aneurysms and may provide reliable diagnostic information for the assessment of aneurysm size and geometry comparable with conventional intra-arterial 3D rotational angiography. These preliminary results might be a first promising step to replacing conventional angiography in preinterventional aneurysm imaging.
CRIS-Team Scopus Importer:2022-08-05

Angiotensin IV is induced in experimental autoimmune encephalomyelitis but fails to influence the disease - Manzel, Arndt; Domenig, Oliver; Ambrosius, Bjoern; Kovacs, Agnes; Stegbauer, Johannes; Poglitsch, Marko; Mueller, Dominik N.; Gold, Ralf; Linker, Ralf (Journal of Neuroimmune Pharmacology, 2014)
In multiple sclerosis (MS) and its corresponding animal models, over-activity of the renin-angiotensin system (RAS) has been reported and pharmacological RAS blockade exerts beneficial effects. The RAS generates a number of bioactive angiotensins, thereby primarily regulating the body's sodium homeostasis and blood pressure. In this regard, angiotensin IV (AngIV), a metabolite of the RAS has been shown to modulate inflammatory responses. Here we studied potential implications of AngIV signalling in myelin oligodendrocyte glycoprotein (MOG) peptide induced murine experimental autoimmune encephalomyelitis (EAE), a close-to-MS animal model. Mass spectrometry revealed elevated plasma levels of AngIV in EAE. Expression of cognate AT4 receptors was detected in macrophages and T cells as major drivers of pathology in EAE. Yet, AngIV did not modulate macrophage or T cell functions in vitro or displayed detectable effects on neuroantigen specific immune responses in vivo. The data argue against a major contribution of AngIV signalling in the immunopathogenesis of MOG-EAE.
EVALuna2:22281

An inertial sensor-based gait analysis pipeline for the assessment of real-world stair ambulation parameters - Roth, Nils; Küderle, Arne; Prossel, Dominik; Gaßner, Heiko; Eskofier, Björn; Kluge, Felix (Sensors, 2021)
Climbing stairs is a fundamental part of daily life, adding additional demands on the postural control system compared to level walking. Although real-world gait analysis studies likely contain stair ambulation sequences, algorithms dedicated to the analysis of such activities are still missing. Therefore, we propose a new gait analysis pipeline for foot-worn inertial sensors, which can segment, parametrize, and classify strides from continuous gait sequences that include level walking, stair ascending, and stair descending. For segmentation, an existing approach based on the hidden Markov model and a feature-based gait event detection were extended, reaching an average segmentation F1 score of 98.5 % and gait event timing errors below ±10 ms for all conditions. Stride types were classified with an accuracy of 98.2 % using spatial features derived from a Kalman filter-based trajectory reconstruction. The evaluation was performed on a dataset of 20 healthy participants walking on three different staircases at different speeds. The entire pipeline was additionally validated end-to-end on an independent dataset of 13 Parkinson’s disease patients. The presented work aims to extend real-world gait analysis by including stair ambulation parameters in order to gain new insights into mobility impairments that can be linked to clinically relevant conditions such as a patient’s fall risk and disease state or progression.
CRIS-Team Scopus Importer:2021-10-15
Keywords: Ascending; Classification; Descending; ETKF; Free-living; HMM; IMU; Segmentation; Trajectory; ZUPT

Anisocoria After Direct Light Stimulus is Associated with Poor Outcomes Following Acute Brain Injury - Doyle, Brittany R.; Aiyagari, Venkatesh; Yokobori, Shoji; Kuramatsu, Joji; Barnes, Arianna; Puccio, Ava; Nairon, Emerson B.; Marshall, Jade L.; Olson, Dai Wai M. (Neurocritical Care, 2024)
Background: Assessing pupil size and reactivity is the standard of care in neurocritically ill patients. Anisocoria observed in critically ill patients often prompts further investigation and treatment. This study explores anisocoria at rest and after light stimulus determined using quantitative pupillometry as a predictor of discharge modified Rankin Scale (mRS) scores. Methods: This analysis includes data from an international registry and includes patients with paired (left and right eye) quantitative pupillometry readings linked to discharge mRS scores. Anisocoria was defined as the absolute difference in pupil size using three common cut points (> 0.5 mm, > 1 mm, and > 2 mm). Nonparametric models were constructed to explore patient outcome using three predictors: the presence of anisocoria at rest (in ambient light); the presence of anisocoria after light stimulus; and persistent anisocoria (present both at rest and after light). The primary outcome was discharge mRS score associated with the presence of anisocoria at rest versus after light stimulus using the three commonly defined cut points. Results: This analysis included 152,905 paired observations from 6,654 patients with a mean age of 57.0 (standard deviation 17.9) years, and a median hospital stay of 5 (interquartile range 3–12) days. The mean admission Glasgow Coma Scale score was 12.7 (standard deviation 3.5), and the median discharge mRS score was 2 (interquartile range 0–4). The ranges for absolute differences in pupil diameters were 0–5.76 mm at rest and 0–6.84 mm after light. Using an anisocoria cut point of > 0.5 mm, patients with anisocoria after light had worse median mRS scores (2 [interquartile range 0–4]) than patients with anisocoria at rest (1 [interquartile range 0–3]; P <.0001). Patients with persistent anisocoria had worse median mRS scores (3 [interquartile range 1–4]) than those without persistent anisocoria (1 [interquartile range 0–3]; P <.0001). Similar findings were observed using a cut point for anisocoria of > 1 mm and > 2 mm. Conclusions: Anisocoria after light is a new biomarker that portends worse outcome than anisocoria at rest. After further validation, anisocoria after light should be considered for inclusion as a reported and trended assessment value.
CRIS-Team Scopus Importer:2024-07-05
Keywords: Anisocoria; Cranial nerves; Pupillary light reflex; Pupils

A novel splice variant expands the LAMC3-associated cortical phenotype to frontal only polymicrogyria and adult-onset epilepsy - Kasper, Burkhard; Kraus, Cornelia; Schwarz, Michael; Rösch, Julie; Thiel, Christian; Reis, André; Zweier, Christiane (American Journal of Medical Genetics Part A, 2020)
Bi-allelic loss-of-function variants in LAMC3, encoding extracellular matrix protein laminin gamma 3, represent a rare cause of occipital polymicrogyria with epilepsy, developmental delay and cognitive impairment. So far, only five families have been reported. We now identified a novel, homozygous splice variant in LAMC3 in an individual with an unusual manifestation of cortical malformation. She presented with polymicrogyria in the frontal but not the occipital lobes, with adult-onset seizures and normal psychomotor development and cognition. Additionally, ictal asystole, requiring implantation of a pacemaker, and nonepileptic seizures occurred. This case expands the spectrum of LAMC3-associated cortical malformation phenotypes to frontal only polymicrogyria and adult-onset of epilepsy.
CRIS-Team Scopus Importer:2020-09-18
Keywords: cortical malformation; epilepsy; LAMC3; polymicrogyria; seizures

An Overview of Smart Shoes in the Internet of Health Things: Gait and Mobility Assessment in Health Promotion and Disease Monitoring - Eskofier, Björn; Lee, Sunghoon I.; Manuela, Baron; Simon, Andre; Martindale, Christine; Gaßner, Heiko; Klucken, Jochen (Applied Sciences, 2017)
New smart technologies and the internet of things increasingly play a key role in healthcare and wellness, contributing to the development of novel healthcare concepts. These technologies enable a comprehensive view of an individual’s movement and mobility, potentially supporting healthy living as well as complementing medical diagnostics and the monitoring of therapeutic outcomes. This overview article specifically addresses smart shoes, which are becoming one such smart technology within the future internet of health things, since the ability to walk defines large aspects of quality of life in a wide range of health and disease conditions. Smart shoes offer the possibility to support prevention, diagnostic work-up, therapeutic decisions, and individual disease monitoring with a continuous assessment of gait and mobility. This overview article provides the technological as well as medical aspects of smart shoes within this rising area of digital health applications, and is designed especially for the novel reader in this specific field. It also stresses the need for closer interdisciplinary interactions between technological and medical experts to bridge the gap between research and practice. Smart shoes can be envisioned to serve as pervasive wearable computing systems that enable innovative solutions and services for the promotion of healthy living and the transformation of health care
Keywords: smart shoes; digital health; eHealth; mHealth; machine learning; Parkinson’s disease; sensor-based gait analysis; telehealth

Antagonizing dabigatran by idarucizumab in cases of ischemic stroke or intracranial hemorrhage in Germany—Updated series of 120 cases - Kermer, Pawel; Eschenfelder, Christoph C.; Diener, Hans Christoph; Grond, Martin; Abdalla, Yasser; Abraham, Alexej; Althaus, Katharina; Becks, Gebhard; Berrouschot, Jörg; Berthel, Jörg; Bode, Felix J.; Burghaus, Lothar; et al. (International Journal of Stroke, 2020)
Background: Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims: To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods: Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results: One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion: Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.
CRIS-Team Scopus Importer:2020-02-04
Keywords: dabigatran; Idarucizumab; intracranial hemorrhage; ischemic stroke; outcome; thrombolysis

Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage - Kuramatsu, Joji; Gerner, Stefan; Schellinger, Peter D.; Glahn, Joerg; Endres, Matthias; Sobesky, Jan; Flechsenhar, Julia; Neugebauer, Hermann; Juettler, Eric; Grau, Armin; Palm, Frederick; Roether, Joachim; et al. (Journal of the American Medical Association, 2015)
Although use of oral anticoagulants (OACs) is increasing, there is a substantial lack of data on how to treat OAC-associated intracerebral hemorrhage (ICH).To assess the association of anticoagulation reversal and blood pressure (BP) with hematoma enlargement and the effects of OAC resumption.Retrospective cohort study at 19 German tertiary care centers (2006-2012) including 1176 individuals for analysis of long-term functional outcome, 853 for analysis of hematoma enlargement, and 719 for analysis of OAC resumption.Reversal of anticoagulation during acute phase, systolic BP at 4 hours, and reinitiation of OAC for long-term treatment.Frequency of hematoma enlargement in relation to international normalized ratio (INR) and BP. Incidence analysis of ischemic and hemorrhagic events with or without OAC resumption. Factors associated with favorable (modified Rankin Scale score, 0-3) vs unfavorable functional outcome.Hemorrhage enlargement occurred in 307 of 853 patients (36.0%). Reduced rates of hematoma enlargement were associated with reversal of INR levels <1.3 within 4 hours after admission (43/217 [19.8%]) vs INR of >=1.3 (264/636 [41.5%]; P < .001) and systolic BP <160 mm Hg at 4 hours (167/504 [33.1%]) vs >=160 mm Hg (98/187 [52.4%]; P < .001). The combination of INR reversal <1.3 within 4 hours and systolic BP of <160 mm Hg at 4 hours was associated with lower rates of hematoma enlargement (35/193 [18.1%] vs 220/498 [44.2%] not achieving these values; OR, 0.28; 95% CI, 0.19-0.42; P < .001) and lower rates of in-hospital mortality (26/193 [13.5%] vs 103/498 [20.7%]; OR, 0.60; 95% CI, 0.37-0.95; P = .03). OAC was resumed in 172 of 719 survivors (23.9%). OAC resumption showed fewer ischemic complications (OAC: 9/172 [5.2%] vs no OAC: 82/547 [15.0%]; P < .001) and not significantly different hemorrhagic complications (OAC: 14/172 [8.1%] vs no OAC: 36/547 [6.6%]; P = .48). Propensity-matched survival analysis in patients with atrial fibrillation who restarted OAC showed a decreased HR of 0.258 (95% CI, 0.125-0.534; P < .001) for long-term mortality. Functional long-term outcome was unfavorable in 786 of 1083 patients (72.6%).Among patients with OAC-associated ICH, reversal of INR <1.3 within 4 hours and systolic BP <160 mm Hg at 4 hours were associated with lower rates of hematoma enlargement, and resumption of OAC therapy was associated with lower risk of ischemic events. These findings require replication and assessment in prospective studies.clinicaltrials.gov Identifier: NCT01829581.
EVALuna2:22354

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subset - Lehmann, C. H. K.; Baranska, A.; Heidkamp, G. F.; Heger, L.; Neubert, K.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Brückner, Christin; Beck, S.; Seeling, M.; Kießling, Melissa; et al. (2017)
EVALuna2:33396

Antigen targeting of Fc-receptors induces strong T cell responses in vivo independent of ITAM signaling but dependent on dendritic cell subsets - Lehmann, Christian; Baranska, A.; Heidkamp, Gordon Frederik; Heger, Lukas; Neubert, K.; Lühr, Jennifer; Hoffmann, Alana; Reimer, Katharina; Brückner, Christin; Beck, S.; Seeling, Michaela; Kießling, Melissa; et al. (2017)
EVALuna2:33397

Antiplatelet Therapy in Intracerebral Hemorrhage - Sprügel, Maximilian; Kuramatsu, Joji; Gerner, Stefan; Sembill, Jochen; Beuscher, Vanessa D.; Hagen, Manuel; Röder, Sebastian; Lücking, Hannes; Struffert, Tobias; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen (STROKE, 2019)
CRIS-Team WoS Importer:2019-08-23

Antiplatelet Therapy in Primary Spontaneous and Oral Anticoagulation-Associated Intracerebral Hemorrhage - Sprügel, Maximilian; Kuramatsu, Joji; Gerner, Stefan; Sembill, Jochen; Beuscher, Vanessa D.; Hagen, Manuel; Röder, Sebastian; Lücking, Hannes; Struffert, Tobias; Dörfler, Arnd; Schwab, Stefan; Huttner, Hagen (Stroke, 2018)
Background and Purpose- This study determined the influence of concomitant antiplatelet therapy (APT) on hematoma characteristics and outcome in primary spontaneous intracerebral hemorrhage (ICH), vitamin K antagonist (VKA)- and non-VKA oral anticoagulant-associated ICH. Methods- Data of retrospective cohort studies and a prospective single-center study were pooled. Functional outcome, mortality, and radiological characteristics were defined as primary and secondary outcomes. Propensity score matching and logistic regression analyses were performed to determine the association between single or dual APT and hematoma volume. Results- A total of 3580 patients with ICH were screened, of whom 3545 with information on APT were analyzed. Three hundred forty-six (32.4%) patients in primary spontaneous ICH, 260 (11.4%) in VKA-ICH, and 30 (16.0%) in non-VKA oral anticoagulant-associated ICH were on APT, and these patients had more severe comorbidities. After propensity score matching VKA-ICH patients on APT presented with less favorable functional outcome (modified Rankin Scale score, 0-3; APT, 48/202 [23.8%] versus no APT, 187/587 [31.9%]; P=0.030) and higher mortality (APT, 103/202 [51.0%] versus no APT, 237/587 [40.4%]; P=0.009), whereas no significant differences were present in primary spontaneous ICH and non-VKA oral anticoagulant-associated ICH. In VKA-ICH, hematoma volume was significantly larger in patients with APT (21.9 [7.4-61.4] versus 15.7 [5.7-44.5] mL; P=0.005). Multivariable regression analysis revealed an association of APT and larger ICH volumes (odds ratio, 1.80 [1.20-2.70]; P=0.005), which was more pronounced in dual APT and supratherapeutically anticoagulated patients. Conclusions- APT does not affect ICH characteristics and outcome in primary spontaneous ICH patients; however, it is associated with larger ICH volume and worse functional outcome in VKA-ICH, presumably by additive antihemostatic effects. Combination of anticoagulation and APT should, therefore, be diligently evaluated and restricted to the shortest possible time frame.
EVALuna2:34909

Anti-SARS-CoV-2 vaccination immune response in MS patients: interim results of a multicentre, prospective cohort study - Berthele, A.; Goedel, C.; Kallmann, B.; Kowarik, M.; Lehmann-Horn, K.; Marziniak, M.; Meyer, C.; Rauer, S.; Rothhammer, Veit; Sprenger, T.; Wildemann, B. C.; Schirduan, K. (MULTIPLE SCLEROSIS JOURNAL, 2022)
CRIS-Team WoS Importer:2022-12-09

Antiseizure medication and perceived “fair” cost allocation: A factorial survey among neurologists, persons with epilepsy, their relatives, and a control group - Stritzelberger, Jenny; Walther, Katrin; Olmes, David; Gollwitzer, Stefanie; Graf, Wolfgang; Welte, Tamara; Lang, Johannes; Reindl, Caroline; Schwab, Stefan; Kriwy, Peter; Hamer, Hajo (Epilepsia, 2022)
Objective: Because resources are limited in modern health care systems, the decision on the allocation of expensive drugs can be supported by a public consent. This study examines how various factors influence subjectively perceived “fair” pricing of antiseizure medication (ASM) among four groups including physicians, persons with epilepsy (PWEs), their relatives, and a control group. Methods: We conducted a factorial survey. Vignettes featured a fictional PWE receiving a fictional ASM. The characteristics of the fictional PWE, ASM, and epilepsy varied. Participants were asked to assess the subjectively appropriate annual cost of ASM treatment per year for each scenario. Results: Fifty-seven PWEs (mean age (SD) 37.7 ± 12.3, 45.6% female), 44 relatives (age 48.4 ± 15.7, 51.1% female), 46 neurologists (age 37.1 ± 9.6, 65.2% female), and 47 persons in the control group (age 31.2 ± 11.2, 68.1% female) completed the questionnaire. The amount of money that respondents were willing to spend for ASM treatment was higher than currently needed in Germany and increased with disease severity among all groups. All groups except for PWEs accepted higher costs of a drug with better seizure control. Physicians and the control group, but not PWEs and their relatives, tended to do so also for minor or no side effects. Physicians reduced the costs for unemployed patients and the control group spent less money for older patients. Significance: ASM effectiveness appears to justify higher costs. However, the control group attributed less money to older PWEs and physicians allocated fewer drug costs to unemployed PWEs.
CRIS-Team Scopus Importer:2022-08-19

Anti-seizure medication is not associated with an increased risk to develop cancer in epilepsy patients - Stritzelberger, Jenny; Lang, Johannes; Mueller, Tamara M.; Reindl, Caroline; Westermayer, Vivien; Kostev, Karel; Hamer, Hajo (Journal of Neurology, 2021)
Objective: Whether anti-seizure medication (ASM) increases the risk for cancer has been debated for decades. While for some ASM, a carcinoma-promoting effect has been suspected, carcinoma-protective effects have been shown for other ASM. However, the issue remains unresolved as data from preclinical and clinical studies have been inconsistent and contradictory. Methods: We collected anonymous patient data from practice neurologists throughout Germany between 2009 and 2018 using the IMS Disease Analyzer database (QuintilesIMS, Frankfurt, Germany). People with epilepsy (PWE) with an initial cancer diagnosis and antiepileptic therapy prior to the index date were 1:1 matched with a control group of PWE without cancer according to age, gender, index year, Charlson Comorbidity Index, and treating physician. For both groups, the risk to develop cancer under treatment with different ASMs was analyzed using three different models (ever use vs. never use (I), effect per one (II) and per five therapy years (III). Results: A total of 3152 PWE were included (each group, n = 1,576; age = 67.3 ± 14.0 years). The risk to develop cancer was not significantly elevated for any ASM. Carbamazepine was associated with a decreased cancer risk (OR Model I: 0.699, p <.0001, OR Model II: 0.952, p =.4878, OR Model III: 0.758, p <.0004). Significance: Our findings suggest that ASM use does not increase the risk of cancer in epilepsy patients.
CRIS-Team Scopus Importer:2021-02-05
Keywords: Antiseizure medication; Carbamazepine; Carcinogenicity; Epilepsy

Apheresis therapies for NMOSD attacks: A retrospective study of 207 therapeutic interventions - Kleiter, Ingo; Gahlen, Anna; Borisow, Nadja; Fischer, Katrin; Wernecke, Klaus-Dieter; Hellwig, Kerstin; Pache, Florence; Ruprecht, Klemens; Havla, Joachim; Kumpfel, Tania; Aktas, Orhan; Hartung, Hans-Peter; et al. (Neurology, Neuroimmunology and Neuroinflammation, 2018)
To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody-seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04-144.91, = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89-0.99, = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76-631.17, = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03-21.62, = 0.046).Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
EVALuna2:51614

Apraxia and the representation of knowledge: where is the boundary between the cognitive and the motor domain? - Schenk, Thomas (Cortex, 2014)
EVALuna2:22284

A prospective community-based study of stroke in Germany - The Erlangen Stroke Project (ESPro): Incidence and case fatality at 1, 3, and 12 months - Kolominsky-Rabas, Peter; Sarti, Cinzia; Heuschmann, Peter U.; Graf, Christian; Siemonsen, Sven; Neundörfer, Bernhard; Katalinic, Alexandar; Lang, Erich; Gaßmann, Karl-Günter; Von Stockert, Theodor Ritter (Stroke, 1998)
Background and Purpose - In Germany, basic data on stroke morbidity are lacking. If a population-based register in former East Germany is excluded, only routine mortality statistics have thus far provided information on epidemiology of stroke. Therefore, a population-based register of stroke was set up in Southern Germany to determine incidence and case fatality in a defined German population. Methods - The Erlangen Stroke Project (ESPro) is a prospective community-based study among the 101 450 residents of the city of Erlangen, Bavaria, Germany. Standard definitions and overlapping case- finding methods were used to identify all cases of first-ever stroke in all age-groups, occurring in the 2 years of registration (April 1, 1994, to March 31, 1996). All identified cases of first-ever strokes were followed up at 3 and 12 months from onset. Results - During 2 years of registration, 354 first-ever-in-a-lifetime strokes (FELS) were registered. The diagnosis and stroke type were confirmed by CT scan in 95% of cases. Fifty-one percent of all FELS occurred in the age group ≥75 years of age. The crude annual incidence rate was 1.74 per 1000 (1.47 for men and 2.01 for women). After age-adjustment to the European population, the incidence rate was 1.34 per 1000 (1.48 for men and 1.25 for women). The annual crude incidence rate of cerebral infarction was 1.37/1000, intracerebral hemorrhage 0.24/1000, subarachnoid hemorrhage 0.06/1000, and unspecified stroke 0.08/1000. Overall case fatality at 28 days was 19.4%, at 3 months it was 28.5%, and at 1 year 37.3%. Conclusions - The first prospective community-based stroke register including all age groups in Germany revealed incidence rates of stroke similar to those reported from other population-based studies in western industrialized countries, but lower than that observed in former East Germany.
Created from Fastlane, Scopus look-up
Keywords: Epidemiology; Germany; Incidence; Mortality; Prognosis

A prospective, multicenter study of cardiac-based seizure detection to activate vagus nerve stimulation - Boon, Paul; Vonck, Kristl; Van Rijckevorsel, Kenou; El Tahry, Riem; Elger, Christian E.; Mullatti, Nandini; Schulze-Bonhage, Andreas; Wagner, Louis; Diehl, Beate; Hamer, Hajo; Reuber, Markus; Kostov, Hrisimir; et al. (Seizure-European Journal of Epilepsy, 2015)
This study investigates the performance of a cardiac-based seizure detection algorithm (CBSDA) that automatically triggers VNS (NCT01325623).Thirty-one patients with drug resistant epilepsy were evaluated in an epilepsy monitoring unit (EMU) to assess algorithm performance and near-term clinical benefit. Long-term efficacy and safety were evaluated with combined open and closed-loop VNS.Sixty-six seizures (n=16 patients) were available from the EMU for analysis. In 37 seizures (n=14 patients) a >=20% heart rate increase was found and 11 (n=5 patients) were associated with ictal tachycardia (iTC, 55% or 35bpm heart rate increase, minimum of 100bpm). Multiple CBSDA settings achieved a sensitivity of >=80%. False positives ranged from 0.5 to 7.2/h. 27/66 seizures were stimulated within ±2min of seizure onset. In 10/17 of these seizures, where triggered VNS overlapped with ongoing seizure activity, seizure activity stopped during stimulation. Physician-scored seizure severity (NHS3-scale) showed significant improvement for complex partial seizures (CPS) at EMU discharge and through 12 months (p<0.05). Patient-scored seizure severity (total SSQ score) showed significant improvement at 3 and 6 months. Quality of life (total QOLIE-31-P score) showed significant improvement at 12 months. The responder rate (>=50% reduction in seizure frequency) at 12 months was 29.6% (n=8/27). Safety profiles were comparable to prior VNS trials.The investigated CBSDA has a high sensitivity and an acceptable specificity for triggering VNS. Despite the moderate effects on seizure frequency, combined open- and closed-loop VNS may provide valuable improvements in seizure severity and QOL in refractory epilepsy patients.
EVALuna2:22375

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson’s disease - Schmidt, Sebastian; Stautner, Constantin; Vu, Duc Tung; Heinz, Alexander; Regensburger, Martin; Karayel, Ozge; Trümbach, Dietrich; Artati, Anna; Kaltenhäuser, Sabine; Nassef, Mohamed Zakaria; Hembach, Sina; Steinert, Letyfee; et al. (Nature Communications, 2023)
Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the α-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD.
CRIS-Team Scopus Importer:2023-12-08

A roadmap for implementation of patient-centered digital outcome measures in Parkinson's disease obtained using mobile health technologies - Espay, Alberto J.; Hausdorff, Jeffrey M.; Sánchez-Ferro, Álvaro; Klucken, Jochen; Merola, Aristide; Bonato, Paolo; Paul, Serene S.; Horak, Fay B.; Vizcarra, Joaquin A.; Mestre, Tiago A.; Reilmann, Ralf; Nieuwboer, Alice; et al. (Movement Disorders, 2019)
Obtaining reliable longitudinal information about everyday functioning from individuals with Parkinson's disease (PD) in natural environments is critical for clinical care and research. Despite advances in mobile health technologies, the implementation of digital outcome measures is hindered by a lack of consensus on the type and scope of measures, the most appropriate approach for data capture (eg, in clinic or at home), and the extraction of timely information that meets the needs of patients, clinicians, caregivers, and health care regulators. The Movement Disorder Society Task Force on Technology proposes the following objectives to facilitate the adoption of mobile health technologies: (1) identification of patient-centered and clinically relevant digital outcomes; (2) selection criteria for device combinations that offer an acceptable benefit-to-burden ratio to patients and that deliver reliable, clinically relevant insights; (3) development of an accessible, scalable, and secure platform for data integration and data analytics; and (4) agreement on a pathway for approval by regulators, adoption into e-health systems and implementation by health care organizations. We have developed a tentative roadmap that addresses these needs by providing the following deliverables: (1) results and interpretation of an online survey to define patient-relevant endpoints, (2) agreement on the selection criteria for use of device combinations, (3) an example of an open-source platform for integrating mobile health technology output, and (4) recommendations for assessing readiness for deployment of promising devices and algorithms suitable for regulatory approval. This concrete implementation guidance, harmonizing the collaborative endeavor among stakeholders, can improve assessments of individuals with PD, tailor symptomatic therapy, and enhance health care outcomes. © 2019 International Parkinson and Movement Disorder Society.
CRIS-Team Scopus Importer:2019-05-21
Keywords: mobile health technologies; Parkinson's disease; remote monitoring; wearable technology

Artistic presentation of seizure semiology—A remarkable painting Künstlerische Darstellung von Anfallssemiologie – ein besonderes Gemälde - Schiele, Martina; Kasper, Burkhard S. (Clinical Epileptology, 2025)
A painting is shown that depicts the seizure semiology of a patient, i.e., Martina Schiele the painter and co-author of this article. It is illustrated that the artistic act helped to express and better understand her symptoms, which were hardly describable in words. A contextualisation and perspective on epilepsy and art is given.
CRIS-Team Scopus Importer:2025-05-23
Keywords: Art; Aura; Epilepsy; Neurology; Neuroscience

Aryl Hydrocarbon Receptor Activation in Astrocytes by Laquinimod Ameliorates Autoimmune Inflammation in the CNS - Rothhammer, Veit; Kenison, Jessica E.; Li, Zahorong; Tjon, Emily; Takenaka, Maisa C.; Chao, Chun Cheih; Alves de Lima, Kalil; Borucki, Davis M.; Kaye, Joel; Quintana, Francisco J. (Neurology, Neuroimmunology and Neuroinflammation, 2021)
OBJECTIVE: MS is an autoimmune demyelinating disease of the CNS, which causes neurologic deficits in young adults and leads to progressive disability. The aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, can drive anti-inflammatory functions in peripheral immune cells and also in CNS-resident cells. Laquinimod is a drug developed for the treatment of MS known to activate AHR, but the cellular targets of laquinimod are still not completely known. In this work, we analyzed the contribution of AHR activation in astrocytes to its beneficial effects in the experimental autoimmune encephalomyelitis (EAE) preclinical model of MS. METHODS: We used conditional knockout mice, in combination with genome-wide analysis of gene expression by RNA-seq and in vitro culture systems to investigate the effects of laquinimod on astrocytes. RESULTS: We found that AHR activation in astrocytes by laquinimod ameliorates EAE, a preclinical model of MS. Genome-wide RNA-seq transcriptional analyses detected anti-inflammatory effects of laquinimod in glial cells during EAE. Moreover, we established that the Delaq metabolite of laquinimod dampens proinflammatory mediator production while activating tissue-protective mechanisms in glia. CONCLUSIONS: Taken together, these findings suggest that AHR activation by clinically relevant AHR agonists may represent a novel therapeutic approach for the treatment of MS.
CRIS-Team Scopus Importer:2021-04-09

Aryl Hydrocarbon Receptor Plasma Agonist Activity Correlates With Disease Activity in Progressive MS - Tsaktanis, Thanos; Beyer, Tobias; Nirschl, Lucy; Linnerbauer, Mathias; Grummel, Verena; Bussas, Mathias; Tjon, Emily; Mühlau, Mark; Korn, Thomas; Hemmer, Bernhard; Quintana, Francisco J.; Rothhammer, Veit (Neurology, Neuroimmunology and Neuroinflammation, 2021)
OBJECTIVE: The relationship between serum aryl hydrocarbon receptor (AHR) agonistic activity levels with disease severity, its modulation over the course of relapsing-remitting MS (RRMS), and its regulation in progressive MS (PMS) are unknown. Here, we report the analysis of AHR agonistic activity levels in cross-sectional and longitudinal serum samples of patients with RRMS and PMS. METHODS: In a cross-sectional investigation, a total of 36 control patients diagnosed with noninflammatory diseases, 84 patients with RRMS, 35 patients with secondary progressive MS (SPMS), and 41 patients with primary progressive MS (PPMS) were included in this study. AHR activity was measured in a cell-based luciferase assay and correlated with age, sex, the presence of disease-modifying therapies, Expanded Disability Status Scale scores, and disease duration. In a second longitudinal investigation, we analyzed AHR activity in 13 patients diagnosed with RRMS over a period from 4 to 10 years and correlated AHR agonistic activity with white matter atrophy and lesion load volume changes. RESULTS: In RRMS, AHR ligand levels were globally decreased and associated with disease duration and neurologic disability. In SPMS and PPMS, serum AHR agonistic activity was decreased and correlated with disease severity. Finally, in longitudinal serum samples of patients with RRMS, decreased AHR agonistic activity was linked to progressive CNS atrophy and increased lesion load. CONCLUSIONS: These findings suggest that serum AHR agonist levels negatively correlate with disability in RRMS and PMS and decrease longitudinally in correlation with MRI markers of disease progression. Thus, serum AHR agonistic activity may serve as novel biomarker for disability progression in MS.
CRIS-Team Scopus Importer:2021-01-15

Ascending axonal degeneration of the corticospinal tract in pure hereditary spastic paraplegia: A cross-sectional DTI study - List, Julia; Kohl, Zacharias; Winkler, Jürgen; Marxreiter, Franz; Dörfler, Arnd; Schmidt, Manuel (Brain Sciences, 2019)
Objective: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). Methods: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. Results: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. Conclusion: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.
CRIS-Team Scopus Importer:2019-10-25
Keywords: Corticospinal tract; Diffusion tensor imaging; Fractional anisotropy; Hereditary spastic paraplegia; Tract-based spatial statistics (TBSS)

A sensorimotor enhanced neuromusculoskeletal model for simulating postural control of upright standing - Shanbhag, Julian; Fleischmann, Sophie; Wechsler, Iris; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Koelewijn, Anne; Wartzack, Sandro; Miehling, Jörg (Frontiers in Neuroscience, 2024)
The human's upright standing is a complex control process that is not yet fully understood. Postural control models can provide insights into the body's internal control processes of balance behavior. Using physiologically plausible models can also help explaining pathophysiological motion behavior. In this paper, we introduce a neuromusculoskeletal postural control model using sensor feedback consisting of somatosensory, vestibular and visual information. The sagittal plane model was restricted to effectively six degrees of freedom and consisted of nine muscles per leg. Physiologically plausible neural delays were considered for balance control. We applied forward dynamic simulations and a single shooting approach to generate healthy reactive balance behavior during quiet and perturbed upright standing. Control parameters were optimized to minimize muscle effort. We showed that our model is capable of fulfilling the applied tasks successfully. We observed joint angles and ranges of motion in physiologically plausible ranges and comparable to experimental data. This model represents the starting point for subsequent simulations of pathophysiological postural control behavior.<br
Keywords: postural control; standing; simulation; forward dynamics; neuromusculoskeletal modeling; neural control; motor control; biomechanics

A Short Progressive Supranuclear Palsy Quality of Life Scale - Jensen, Ida; Stiel, Stephanie; Bebermeier, Sarah; Schrag, Anette; Greten, Stephan; Doll-Lee, Johanna; Wegner, Florian; Ye, Lan; Heine, Johanne; Krey, Lea; Höllerhage, Matthias; Süß, Patrick; et al. (Movement Disorders, 2024)
Objective: The Progressive Supranuclear Palsy quality of life scale (PSP-QoL) has been shown to be a useful tool for capturing health-related quality of life of patients in “everyday life” and in progressive supranuclear palsy (PSP) research. However, at 45 items in length, the questionnaire can take a long time, exhausting PSP patients, in particular if cognitive impaired, which can have a negative impact on the assessment. The aim of this study was to establish a condensed version of the PSP-QoL for research and routine clinical care. Methods: In this retrospective study, data originating from a German cohort of PSP patients was analyzed. Data from 245 PSP patients were included in this study. The short PSP-QoL questionnaire was created using a two-factor solution and item-total and inter-item correlations for mental and physical aspects of daily living of the PSP-QoL followed by confirmatory factor analysis. Results: The final scale included 12 items representing mental (five items) and physical symptoms (seven items). The specified two-factor model displayed an excellent fit in the confirmatory factor analysis. The short Progressive Supranuclear Palsy Quality of Life scale (PSP-ShoQoL) correlated moderately with the PSP Rating Scale (r [243] = 0.514, P < 0.001) and Geriatric depression scale (r [231] = 0.548, P < 0.001). Sensitivity to change confirmed a significant decrease in QoL after 12 months. Discussion: In this study, we created a 12-item PSP-ShoQoL designed to “facilitate” daily clinical work that correlated strongly with the PSP-QoL and was sensitive to change. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
CRIS-Team Scopus Importer:2024-08-09
Keywords: health-related quality of life; progressive supranuclear palsy; PSP Quality of Life scale; rating scale

A Single Bout of Aerobic Exercise Improves Motor Skill Consolidation in Parkinson’s Disease - Steib, Simon; Wanner, Philipp; Adler, Werner; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Frontiers in Aging Neuroscience, 2018)
Background: Motor learning is impaired in Parkinson’s disease (PD), with patients demonstrating deficits in skill acquisition (online learning) and consolidation (offline learning) compared to healthy adults of similar age. Recent studies in young adults suggest that single bouts of aerobic exercise (AEX), performed in close temporal proximity to practicing a new motor task, may facilitate motor skill learning. Thus, we aimed at investigating the effects of a single bout of aerobic cycling on online and offline learning in PD patients. Methods: 17 PD patients (Hoehn and Yahr 1 – 2.5, age: 64.4 - 6.2) participated in this crossover study. Immediately prior to practicing a novel balance task, patients either performed 30 min of (i) moderate intensity (60–70% VO2max) aerobic cycling, or (ii) seated rest (order counterbalanced). The task required patients to stabilize a balance platform (stabilometer) in a horizontal position for 30 s. For each experimental condition, patients performed 15 acquisition trials, followed by a retention test 24 h later. We calculated time in balance (platform within ±5° from horizontal) for each trial, and analyzed within- and between-subjects differences in skill acquisition (online learning) and skill retention (offline learning) using mixed repeated-measures ANOVA. Results: We found that the exercise bout had no effect on performance level or online gains during acquisition, despite affecting the time course of skill improvements (larger initial and reduced late skill gains). Aerobic cycling significantly improved offline learning, as reflected by larger 24-h skill retention compared to the rest condition. Conclusion: Our results suggest that a single bout of moderate-intensity AEX is effective in improving motor skill consolidation in PD patients. Thus, acute exercise may represent an effective strategy to enhance motor memory formation in this population. More work is necessary to understand the underlying mechanisms, the optimal scheduling of exercise, and the applicability to other motor tasks. Further, the potential for patients in later disease stages need to be investigated. The study was a priori registered at ClinicalTrials.gov (NCT03245216).
Keywords: cardiovascular exercise; motor learning; online learning; offline learning; memory; neuroplasticity; neurorehabilitation; Parkinsonism

A Single Bout of Cardiovascular Exercise Improves Motor Memory Consolidation in Parkinson’s Disease - Steib, Simon; Wanner, Philipp; Adler, Werner; Winkler, Jürgen; Klucken, Jochen; Pfeifer, Klaus (Abstractband zur 16. Jahrestagung der dvs-Sektion Sportmotorik vom 16.-18. Januar 2019 in Bern, 2019)

A single-center observational study on long-term neurodevelopmental outcomes in children with tuberous sclerosis complex - Mammadova, Dilbar; Vecko, Julia; Hofmann, Marlene; Schüssler, Stephanie; Deiters, Ludger; Canda, A.; Wieland, Anna; Gollwitzer, Stephanie; Hamer, Hajo; Trollmann, Regina (Orphanet Journal of Rare Diseases, 2023)
Background: Tuberous sclerosis complex (TSC) is a rare multisystem disorder caused by mutations in the TSC1 or TSC2 gene. More than 90% of patients with TSC develop neurological and/or neuropsychiatric manifestations. The aim of the present study was to determine the developmental and cognitive long-term outcomes of pediatric TSC patients. Methods: This cross-sectional, monocenter study included pediatric TSC patients who received multidisciplinary long-term care with a last visit between 2005 and 2019. Neurological manifestations and cognitive development (BSID, K-ABC) were analyzed in relation to age and type of mutation. Results: Thirty-five patients aged 13.5 ± 7.8 years were included in the study. Diagnosis was confirmed genetically in 65.7% of patients (TSC1, 26.1%; TSC2, 65.2%; NMI, 8.7%). Mean age at diagnosis was 1.3 ± 3.5 years; 74.3% of the patients had been diagnosed within the first year of life due to seizures (62.9%) or/and cardiac rhabdomyomas (28.6%). The most common TSC manifestations included structural brain lesions (cortical tubers, 91.4%; subependymal nodules, 82.9%), epilepsy (85.7%), and cardiac rhabdomyomas (62.9%). Mean age at seizure onset was 1.5 ± 2.3 years, with onset in 80.0% of patients within the first two years of life. Infantile spasms, which were the first seizure type in 23.3% of the patients, developed earlier (0.6 ± 0.4 years) than focal seizures (1.8 ± 2.5 years). Refractory epilepsy was present in 21 (70.0%) patients, mild or severe intellectual impairment in 66.6%, and autism spectrum disorders in 11.4%. Severe cognitive impairment (33.3%) was significantly associated with epilepsy type and age at seizure onset (p < 0.05). Conclusions: The results emphasized the phenotypic variability of pediatric-onset TSC and the high rate of neurological and neuropsychiatric morbidity. Early-onset refractory epilepsy was associated with impaired cognitive development. Children of all ages with TSC require multidisciplinary long-term care and individual early-intervention programs.
CRIS-Team Scopus Importer:2023-11-17
Keywords: Antiseizure medication; Autism; Cognition; Rare disease; Refractory epilepsy; Tuberous sclerosis complex

A Single Injection of N-Oleoyldopamine, an Endogenous Agonist for Transient Receptor Potential Vanilloid-1, Induced Brain Hypothermia, but No Neuroprotective Effects in Experimentally Induced Cerebral Ischemia in Rats - De Rink, Maria Mercedes Tejada; Naumann, Ulrike; Kollmar, Rainer; Schwab, Stefan; Dietel, Barbara; Harada, Hideki; Tauchi, Miyuki (Therapeutic Hypothermia and Temperature Management, 2019)
Targeted temperature management, or therapeutic hypothermia, is a potent neuroprotective approach after ischemic brain injury. Hypothermia should be induced as soon as possible after the onset of acute stroke to assure better outcomes. Accordingly, drugs with a fast-acting hypothermic effect sustainable through the period of emergency transportation to hospital would have clinical advantages. Activation of the transient receptor potential vanilloid-1 (TRPV1) can induce hypothermia. Our immunohistochemical investigations confirmed that TRPV1 was distributed to perivascular and periventricular regions of the rat brain, where TRPV1 can be easily detected by TRPV1 agonists. An endogenous TRPV1 selective agonist, N-oleoyldopamine (OLDA), and a synthetic antagonist, AMG 9810, were injected intraperitoneally into healthy adult male Wister rats, and brain and core temperatures and gross motor activities were monitored. Comparison with baseline temperatures showed that TRPV1 injection immediately induced mild hypothermia (p < 0.05 in brain and p < 0.01 in body), and AMG 9810 induced immediate mild hyperthermia (not significant). However, the OLDA-induced hypothermia did not decrease lesion volume after middle carotid artery occlusion in rats. Relative to vehicle, OLDA yielded poorer outcomes and AMG 9810 yielded better outcomes in neurological scores and lesion size. Our study showed that, as an agonist of TRPV1, OLDA has suitable hypothermia-inducing properties, but did not decrease lesion volume. Therefore, the search for novel TRPV1 agonists and/or antagonists providing hypothermia and neuroprotection should continue. Further investigations should also target OLDA-induced transient hypothermia combined with long-term hypothermia maintenance with surface cooling, which mimics the anticipated clinical use of this class of drug.
CRIS-Team WoS Importer:2019-06-18

A Sphingosine-1-Phosphate Receptor Modulator Attenuated Secondary Brain Injury and Improved Neurological Functions of Mice after ICH - Bobinger, Tobias; Bäuerle, Tobias; Seyler, L.; von Hörsten, Stephan; Schwab, Stefan; Huttner, Hagen; Manaenko, A. (Oxidative Medicine and Cellular Longevity, 2020)
Background. Stroke activates the immune system and induces brain infiltration by immune cells, aggravating brain injury. Poststroke immunomodulation via (S1P-)receptor modulation is beneficial; however, the S1P-modulator in clinical use (FTY-720) is unspecific, and undesirable side effects have been reported. Previously, we tested effects of a novel selective S1P-receptor modulator, Siponimod, on ICH-induced brain injury in acute stage of the disease. In the current study, we investigated whether protective effects of Siponimod, evaluated in a short-term study, will protect the brain of ICH animals at long term as well. Methods. 134 C57BL/6N mice were divided into sham and ICH-operated groups. Collagenase model of ICH was employed. ICH animals were divided into Siponimod treated and nontreated. Dose- and time-dependent effects of Siponimod were investigated. Contraplay between development of brain injury and the number of lymphocytes infiltrating the brain was investigated by forelimb placing, T-Maze test, brain water content calculation, MRI scanning, and immunostaining. Results. Depending on the therapeutic strategy, Siponimod attenuated the development of brain edema, decreased ICH-induced ventriculomegaly and improved neurological functions of animals after ICH. It was associated with less lymphocytes in the brain of ICH animals. Conclusion. Siponimod is able to decrease the brain injury and improves neurological functions of animals after ICH.
CRIS-Team Scopus Importer:2020-10-09

Assessing comfort in the epilepsy monitoring unit: Psychometric testing of an instrument - Egger-Rainer, Andrea; Trinka, Eugen; Zimmermann, Georg; Arnold, Stephan; Boßelmann, Christian; Hamer, Hajo; Hengsberger, Anna; Lang, Johannes; Lerche, Holger; Noachtar, Soheyl; Pataraia, Ekaterina; Schulze-Bonhage, Andreas; et al. (Epilepsy & Behavior, 2020)
Purpose: The purpose of the study was to evaluate the psychometric properties of the newly developed Epilepsy Monitoring Unit Comfort Questionnaire (EMUCQ) according to the consensus-based standards for the selection of health measurements instruments (COSMIN). Moreover, we aimed to assess changes in comfort-levels. Methods: From October 2018 to November 2019, a total of 267 patients participated in a quantitative study in ten epilepsy centers in Austria and southern Germany. For basic item analysis, descriptive analysis and correlational analysis were computed. An exploratory factor analysis (EFA) was undertaken to detect the factor structure. Reliability was checked through internal consistency (Cronbach's alpha) and the measurement error. In the validity domain, convergent validity and structural validity were estimated. t-Tests were used to detect changes in comfort-levels. Results: Due to unfavorable statistical properties, two items were removed. Exploratory factor analysis showed a three-factorial solution. The EMUCQ was found to be a reliable instrument (Cronbach's alpha 0.77–0.81 for the subscales, 0.88 for the scale total comfort); convergent validity could be supported, too. Confirmatory factor analysis (CFA) supported the hypothesis that structural validity for the three subscales holds. The patients' comfort levels were lower at the end of the stay than at the beginning and lower in nonseizure-free patients compared with seizure-free patients. Conclusion: Validity and reliability are supported for the 42-item EMUCQ in the three-factorial solution. Owing to the item reduction and modifications made in the CFA, a new test should be carried out on a different sample.
CRIS-Team Scopus Importer:2020-10-02
Keywords: Comfort; Epilepsy monitoring unit; Questionnaire; Validation study

Assessing the value of topiramate in refractory status epilepticus - Madzar, Dominik; Kuramatsu, Joji; Gerner, Stefan; Huttner, Hagen (Seizure-European Journal of Epilepsy, 2016)
The aim of this study was to assess factors associated with the use of topiramate (TPM) in refractory status epilepticus (RSE).We retrospectively reviewed RSE episodes over a 12-year period. Episodes treated with and without TPM were compared in terms of demographics, RSE characteristics, clinical course, and outcome in univariate and multivariate analyses. Subgroups defined by type of RSE were studied separately. Functional outcome was assessed with the modified Rankin Scale.Among 71 episodes, 17 (23.9%) were treated with TPM and seizure control was achieved in all of these. The results of unadjusted comparisons suggested a use of TPM in younger and healthier patients who received more perseverant treatment indicated by a higher number of antiepileptic drugs applied. In multivariate analysis adjusting for RSE duration, however, these associations lost significance. Furthermore, TPM was not a predictor of successful RSE termination in neither the overall cohort, nor in the subgroup of complex-partial RSE.After multivariate adjustment, no significant differences were observed between episodes treated with and without TPM in baseline characteristics, treatment, and outcome. Regarding the latter, this study does therefore not yield evidence for a particular efficacy of TPM in RSE.
EVALuna2:22475

Assessing viability of extracorporeal preserved muscle transplants using external field stimulation: a novel tool to improve methods prolonging bridge-to-transplantation time. - Taeger, Christian; Friedrich, Oliver; Dragu, Adrian; Weigand, Annika; Hobe, Frieder; Drechsler, Caroline; Geppert, Carol-Immanuel; Arkudas, Andreas; Münch, Frank; Buchholz, Rainer; Pollmann, Charlotte; Schramm, Axel; et al. (Scientific Reports, 2015)
Preventing ischemia-related cell damage is a priority when preserving tissue for transplantation. Perfusion protocols have been established for a variety of applications and proven to be superior to procedures used in clinical routine. Extracorporeal perfusion of muscle tissue though cumbersome is highly desirable since it is highly susceptible to ischemia-related damage. To show the efficacy of different perfusion protocols external field stimulation can be used to immediately visualize improvement or deterioration of the tissue during active and running perfusion protocols. This method has been used to show the superiority of extracorporeal perfusion using porcine rectus abdominis muscles perfused with heparinized saline solution. Perfused muscles showed statistically significant higher ability to exert force compared to nonperfused ones. These findings can be confirmed using Annexin V as marker for cell damage, perfusion of muscle tissue limits damage significantly compared to nonperfused tissue. The combination of extracorporeal perfusion and external field stimulation may improve organ conservation research.

Assessment of gait parameters and physical function in patients with advanced cancer participating in a 12-week exercise and nutrition programme: A controlled clinical trial - Schink, Kristin; Gaßner, Heiko; Reljic, Dejan; Herrmann, Hans J.; Kemmler, Wolfgang; Schwappacher, Raphaela; Meyer, Julia; Eskofier, Björn; Winkler, Jürgen; Neurath, Markus; Klucken, Jochen; Zopf, Yurdagül (European Journal of Cancer Care, 2019)
Objective: Gait is a sensitive marker for functional declines commonly seen in patients treated for advanced cancer. We tested the effect of a combined exercise and nutrition programme on gait parameters of advanced-stage cancer patients using a novel wearable gait analysis system. Methods: Eighty patients were allocated to a control group with nutritional support or to an intervention group additionally receiving whole-body electromyostimulation (WB-EMS) training (2×/week). At baseline and after 12 weeks, physical function was assessed by a biosensor-based gait analysis during a six-minute walk test, a 30-s sit-to-stand test, a hand grip strength test, the Karnofsky Index and EORTC QLQ–C30 questionnaire. Body composition was measured by bioelectrical impedance analysis and inflammation by blood analysis. Results: Final analysis included 41 patients (56.1% male; 60.0 ± 13.0 years). After 12 weeks, the WB-EMS group showed higher stride length, gait velocity (p <.05), six-minute walking distance (p <.01), bodyweight and skeletal muscle mass, and emotional functioning (p <.05) compared with controls. Correlations between changes in gait and in body composition, physical function and inflammation were detected. Conclusion: Whole-body electromyostimulation combined with nutrition may help to improve gait and functional status of cancer patients. Sensor-based mobile gait analysis objectively reflects patients’ physical status and could support treatment decisions.
CRIS-Team Scopus Importer:2019-12-24
Keywords: cancer; exercise; gait; nutrition; physical function; whole-body electromyostimulation

Association between cognition and gait in multiple sclerosis: A smartphone-based longitudinal analysis - Ibrahim, Alzhraa; Adler, Werner; Gaßner, Heiko; Rothhammer, Veit; Kluge, Felix; Eskofier, Björn (International Journal of Medical Informatics, 2023)
Background: Gait and cognition impairments are common problems among People with Multiple Sclerosis (PwMS). Previous studies have investigated cross-sectional associations between gait and cognition. However, there is a lack of evidence regarding the longitudinal association between these factors in PwMS. Therefore, the objective of this study was to explore this longitudinal relationship using smartphone-based data from the Floodlight study. Methods: Using the publicly available Floodlight dataset, which contains smartphone-based longitudinal data, we used a linear mixed model to investigate the longitudinal relationship between cognition, measured by the Symbol Digit Modalities Test (SDMT), and gait, measured by the 2 Minute Walking test (2 MW) step count and Five-U-Turn Test (FUTT) turning speed. Four mixed models were fitted to explore the association between: 1) SDMT and mean step count; 2) SDMT and variability of step count; 3) SDMT and mean FUTT turning speed; and 4) SDMT and variability of FUTT turningt speed. Results: After controlling for age, sex, weight, and height, there were significant correlations between SDMT and the variability of 2 MW step count, the mean of FUTT turning speed. No significant correlation was observed between SDMT and the 2 MW mean step count. Significance: Our findings support the evidence that gait and cognition are associated in PwMS. This may support clinicians to adjust treatment and intervention programs that address both gait and cognitive impairments.
CRIS-Team Scopus Importer:2023-07-28
Keywords: Cognition; Gait; MS; Smartphone sensor

Association between infection with Helicobacter pylori and Chlamydia pneumoniae and risk of ischemic stroke subtypes: Results from a population-based case-control study - Maass, Matthias; Faller, Gerhard; Gesslein, Markus; Neureiter, Daniel; Neundörfer, Bernhard; Craiovan, Benjamin; Beck, Georg; Kolominsky-Rabas, Peter; Heuschmann, Peter U. (2001)
Background and Purpose - Helicobacter pylori and Chlamydia pneumoniae have been associated epidemiologically and pathogenetically with coronary atherosclerosis. However, population-based data on chronic infection and stroke are lacking. Therefore, we investigated the association of both bacterial pathogens and ischemic stroke subtypes in a population-based case-control study. Methods - Patients with first ischemic stroke in the population-based Erlangen Stroke Project were collected as cases. Neighborhood controls were drawn from the study population, matched for age, sex, and place of residence. IgG antibodies to H pylori were measured by enzyme immunoassay, and IgG antibodies to C pneumoniae were measured by microimmunofluorescence technique. Conditional logistic regression was used. Analyses were stratified for etiologic stroke subtypes according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results - A total of 145 case and 260 control subjects were included. Chronic H pylori infection was associated with a higher risk of stroke caused by small-artery occlusion (adjusted odds ratio, 3.31; 95% CI, 1.15 to 9.56) and a lower risk of cardioembolic stroke (adjusted odds ratio, 0.21; 95% CI, 0.06 to 0.71). Overall, elevated H pylori as well as elevated C pneumoniae antibodies were not associated with ischemic stroke. Conclusions - Our population-based study does not provide evidence of any strong association between the immune response to C pneumoniae as a marker of prior infection and ischemic stroke. Further studies are required to reveal the role of chronic H pylori infection as an independent risk factor for the subgroup small-artery occlusion.
Created from Fastlane, Scopus look-up
Keywords: Chlamydia pneumoniae; Helicobacter pylori; Seroepidemiologic studies; Stroke

Association of early phenotypic behavioral alterations in human alpha-synuclein overexpressing transgenic rats with alpha-synuclein/huntingtin/amyloid-beta protein cross-seeding - Moceri, Sandra; Canneva, Fabio; Habermeyer, Johanna; Dobner, Julia; Schulze-Krebs, Anja; Puchades, Maja; Bjaalie, Jan G.; Kohl, Zacharias; Winkler, Jürgen; Timotius, Ivanna; Eskofier, Björn; Schilling, Stephan; et al. (Advances in Alzheimer's and Parkinson's Therapies an AAT-AD/PD Focus Meeting, 2018)

Association of interictal epileptiform discharges and serum concentration of levetiracetam and lamotrigine - Lang, Johannes; Willno, Alexander; Reindl, Caroline; Welte, Tamara; Stritzelberger, Jenny; Gollwitzer, Stephanie; Walther, Katrin; Hamer, Hajo (Frontiers in Neurology, 2024)
Background: Interictal epileptiform discharges (IEDs) are an electrographic biomarker of epilepsy. Despite their crucial role in diagnosing epilepsy, heterogeneous findings exist on the mechanisms underlying their occurrence and the effects of anti-seizure medications (ASMs) on IEDs. Methods: We conducted a study to investigate the association between IED frequency and the serum concentration of two commonly used ASMs, levetiracetam (LEV) and lamotrigine (LTG). We included 56 patients undergoing a continuous video EEG monitoring in our center with tapering of ASM. IED frequency was analyzed using automated and semiautomated methods and serum samples were collected sequentially throughout the stay. Results: The cohort consisted of 41 patients (23 female, 18 male), between 19 and 64 years (mean 37.42 years), most of which were diagnosed with focal epilepsy (93%). IED frequency increased after ASM reduction revealing a negative correlation similarly with LEV and LTG serum concentrations (p = 0.0057 and p = 0.0426, respectively). Discussion: Notably, we observed a significant increase in IED frequency following dose reduction or discontinuation of both medications. This effect was reversed after ASM were re-dosed. This may indicate the suppressive properties of LEV and LTG against epileptic seizures. Furthermore, our study highlights the importance of ASM discontinuation, which may be required for capturing IEDs during diagnostic continuous EEG monitoring, and not be fully explained by circadian or ultradian rhythms alone. Conclusion: Our findings contribute to the understanding of ASM effects on IED frequency dynamics and suggest seizure suppressive properties of LEV and LTG.
CRIS-Team Scopus Importer:2025-04-01
Keywords: anti-seizure medication; anticonvulsants; antiepileptic drugs; interictal epileptiform discharges; spikes

Association of Intrathecal Immunoglobulin G Synthesis with Disability Worsening in Multiple Sclerosis - Gasperi, Christiane; Salmen, Anke; Antony, Gisela; Bayas, Antonios; Heesen, Christoph; Kümpfel, Tania; Linker, Ralf; Paul, Friedemann; Stangel, Martin; Tackenberg, Björn; Bergh, Florian Then; Warnke, Clemens; et al. (JAMA Neurology, 2019)
Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. Design, Setting, and Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. Exposure: Patients were offered standard immunotherapies per national treatment guidelines. Main Outcomes and Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P =.01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. Conclusions and Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
CRIS-Team Scopus Importer:2019-05-17

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis. - Kuramatsu, Joji; Gerner, Stefan; Ziai, Wendy; Bardutzky, Juergen; Sembill, Jochen; Sprügel, Maximilian; Mrochen, Anne; Kölbl, Kathrin; Ram, Malathi; Avadhani, Radhika; Falcone, Guido J.; Selim, Magdy H.; et al. (Stroke, 2022)
BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.
EVALuna2:505459

Association of non-contrast CT markers with long-term functional outcome in deep intracerebral hemorrhage. - Kölbl, Kathrin; Hock, Stefan; Xu, Mingming; Sembill, Jochen; Mrochen, Anne; Balk, Stefanie; Lang, Stefan; Volbers, Bastian; Engelhorn, Tobias Martin; Kallmünzer, Bernd; Kuramatsu, Joji (Frontiers in Neurology, 2024)
OBJECTIVE: Hematoma expansion (HE) is the most important therapeutic target during acute care of patients with intracerebral hemorrhage (ICH). Imaging biomarkers such as non-contrast CT (NCCT) markers have been associated with increasing risk for HE. The aim of the present study was to evaluate the influence of NCCT markers with functional long-term outcome and with HE in patients with deep (basal ganglia and thalamus) ICH who represent an important subgroup of patients at the highest risk for functional deterioration with HE due to the eloquence of the affected brain region. METHODS: From our prospective institutional database, all patients maximally treated with deep ICH were included and retrospectively analyzed. NCCT markers were recorded at diagnostic imaging, ICH volume characteristics were volumetrically evaluated, and all patients received follow-up imaging within 0-48 h. We explored associations of NCCT makers with unfavorable functional outcome, defined as modified Rankin scale 4-6, after 12 months and with HE. Bias and confounding were addressed by multivariable regression modeling. RESULTS: In 322 patients with deep ICH, NCCT markers were distributed as follows: irregular shape: 69.6%, heterogenous density: 55.9%, hypodensities: 52.5%, island sign: 19.3%, black hole sign: 11.5%, and blend sign: 4.7%. Upon multivariable regression analyses, independent associations were documented with the functional outcome for irregular shape (aOR: 2.73, 95%CI: 1.42-5.22, p = 0.002), heterogenous density (aOR: 2.62, 95%CI: 1.40-4.90, p = 0.003) and island sign (aOR: 2.54, 95%CI: 1.05-6.14, p = 0.038), and with HE for heterogenous density (aOR: 5.01, 95%CI: 1.93-13.05, p = 0.001) and hypodensities (aOR: 3.75, 95%CI: 1.63-8.62, p = 0.002). CONCLUSION: NCCT markers are frequent in deep ICH patients and provide important clinical implications. Specifically, markers defined by diverging intra-hematomal densities provided associations with a 5-times higher risk for HE and a 2.5-times higher likelihood for unfavorable functional long-term outcome. Hence, these markers allow the identification of patients with deep ICH at high risk for clinical deterioration due to HE.
EVALuna2:552372

Association of prothrombin complex concentrate administration and hematoma enlargement in non-vitamin K antagonist oral anticoagulant-related intracerebral hemorrhage - Gerner, Stefan; Kuramatsu, Joji; Sembill, Jochen; Sprügel, Maximilian; Endres, Matthias; Haeusler, Karl Georg; Vajkoczy, Peter; Ringleb, Peter A.; Purrucker, Jan; Rizos, Timolaos; Erbguth, Frank; Schellinger, Peter D.; et al. (Annals of Neurology, 2018)
To investigate parameters associated with hematoma enlargement in non-vitamin K antagonist oral anticoagulant (NOAC)-related intracerebral hemorrhage (ICH).This retrospective cohort study includes individual patient data for 190 patients with NOAC-associated ICH over a 5-year period (2011-2015) at 19 departments of neurology across Germany. Primary outcome was the association of prothrombin complex concentrate (PCC) administration with hematoma enlargement. Subanalyses were calculated for blood pressure management and its association with the primary outcome. Secondary outcomes include associations with in-hospital mortality and functional outcome at 3 months assessed using the modified Rankin Scale.The study population for analysis of primary and secondary outcomes consisted of 146 NOAC-ICH patients with available follow-up imaging. Hematoma enlargement occurred in 49/146 (33.6%) patients with NOAC-related ICH. Parameters associated with hematoma enlargement were blood pressure >= 160mmHg within 4 hours and-in the case of factor Xa inhibitor ICH-anti-Xa levels on admission. PCC administration prior to follow-up imaging was not significantly associated with a reduced rate of hematoma enlargement either in overall NOAC-related ICH or in patients with factor Xa inhibitor intake (NOAC: risk ratio [RR] = 1.150, 95% confidence interval [CI] = 0.632-2.090; factor Xa inhibitor: RR = 1.057, 95% CI = 0.565-1.977), regardless of PCC dosage given or time interval until imaging or treatment. Systolic blood pressure levels < 160mmHg within 4 hours after admission were significantly associated with a reduction in the proportion of patients with hematoma enlargement (RR = 0.598, 95% CI = 0.365-0.978). PCC administration had no effect on mortality and functional outcome either at discharge or at 3 months.In contrast to blood pressure control, PCC administration was not associated with a reduced rate of hematoma enlargement in NOAC-related ICH. Our findings support the need of further investigations exploring new hemostatic reversal strategies for patients with factor Xa inhibitor-related ICH. Ann Neurol 2018;83:186-196.
EVALuna2:22552

Association of seizure duration and outcome in refractory status epilepticus - Madzar, Dominik; Geyer, Anna; Knappe, Ruben U.; Gollwitzer, Stephanie; Kuramatsu, Joji; Gerner, Stefan; Hamer, Hajo; Huttner, Hagen (Journal of Neurology, 2016)
The aim of the study was to identify factors influencing long-term outcome and to evaluate the prognostic power of the Status Epilepticus Severity Score (STESS) in refractory status epilepticus (RSE). We retrospectively extracted data on baseline characteristics, RSE details, and hospital course including complications from all patients treated for RSE in our institution between January 2001 and January 2013. Functional outcome was assessed using the modified Rankin Scale (mRS) and was defined as good when either RSE did not lead to functional decline or when the resulting mRS score was 2 or below. Seventy-one episodes in 65 patients were analyzed. The median follow-up time was 12 weeks (IQR 6-35), two patients were lost to follow-up. Poor functional long-term outcome was observed in 42/69 (60.9%) episodes. In-hospital mortality occurred in 13/71 (18.3%) episodes. Multivariable analysis revealed that STESS >= 3, longer RSE duration, and sepsis were independently related to poor functional long-term outcome. Receiver operating characteristics (ROC) curve analyses confirmed the cut-off dichotomization into STESS >= 3 and STESS < 3 for optimal discrimination between good and poor outcome (AUC = 0.671, p = 0.002, YI = 0.368, NPV = 0.607, PPV = 0.756) and revealed an RSE duration of 10 days as a significant cut-off point associated with outcome (AUC = 0.712, p = 0.012, YI = 0.310; NPV = 0.545, PPV = 0.750). In conclusion, STESS and RSE duration represent relevant scores and parameters impacting long-term outcome after RSE. A shorter RSE duration is associated with better outcome and, therefore, rapid and adequate treatment for seizure termination should be enforced.
EVALuna2:22460

Association of smoking but not HLA-DRB1*15:01, APOE or body mass index with brain atrophy in early multiple sclerosis - Graetz, Christiane; Groeger, Adriane; Luessi, Felix; Salmen, Anke; Zoeller, Daniela; Schultz, Janine; Siller, Nelly; Fleischer, Vinzenz; Bellenberg, Barbara; Berthele, Achim; Biberacher, Viola; Havla, Joachim; et al. (Multiple sclerosis journal, 2019)
Background: The course of multiple sclerosis (MS) shows substantial inter-individual variability. The underlying determinants of disease severity likely involve genetic and environmental factors. Objective: The aim of this study was to assess the impact of APOE and HLA polymorphisms as well as smoking and body mass index (BMI) in the very early MS course. Methods: Untreated patients (n = 263) with a recent diagnosis of relapsing-remitting (RR) MS or clinically isolated syndrome underwent standardized magnetic resonance imaging (MRI). Genotyping was performed for single-nucleotide polymorphisms (SNPs) rs3135388 tagging the HLA-DRB1*15:01 haplotype and rs7412 (190;2) and rs429358 (190;4) in APOE. Linear regression analyses were applied based on the three SNPs, smoking and BMI as exposures and MRI surrogate markers for disease severity as outcomes. Results: Current smoking was associated with reduced gray matter fraction, lower brain parenchymal fraction and increased cerebrospinal fluid fraction in comparison to non-smoking, whereas no effect was observed on white matter fraction. BMI and the SNPs in HLA and APOE were not associated with structural MRI parameters. Conclusions: Smoking may have an unfavorable effect on the gray matter fraction as a potential measure of MS severity already in early MS. These findings may impact patients' counseling upon initial diagnosis of MS.
CRIS-Team WoS Importer:2019-04-12

Association of Surgical Hematoma Evacuation vs Conservative Treatment With Functional Outcome in Patients With Cerebellar Intracerebral Hemorrhage - Kuramatsu, Joji; Biffi, Alessandro; Gerner, Stefan; Sembill, Jochen; Sprügel, Maximilian; Leasure, Audrey; Sansing, Lauren; Matouk, Charles; Falcone, Guido J.; Endres, Matthias; Haeusler, Karl Georg; Sobesky, Jan; et al. (Journal of the American Medical Association, 2019)
Importance: The association of surgical hematoma evacuation with clinical outcomes in patients with cerebellar intracerebral hemorrhage (ICH) has not been established. Objective: To determine the association of surgical hematoma evacuation with clinical outcomes in cerebellar ICH. Design, Setting, and Participants: Individual participant data (IPD) meta-analysis of 4 observational ICH studies incorporating 6580 patients treated at 64 hospitals across the United States and Germany (2006-2015). Exposure: Surgical hematoma evacuation vs conservative treatment. Main Outcomes and Measures: The primary outcome was functional disability evaluated by the modified Rankin Scale ([mRS] score range: 0, no functional deficit to 6, death) at 3 months; favorable (mRS, 0-3) vs unfavorable (mRS, 4-6). Secondary outcomes included survival at 3 months and at 12 months. Analyses included propensity score matching and covariate adjustment, and predicted probabilities were used to identify treatment-related cutoff values for cerebellar ICH. Results: Among 578 patients with cerebellar ICH, propensity score-matched groups included 152 patients with surgical hematoma evacuation vs 152 patients with conservative treatment (age, 68.9 vs 69.2 years; men, 55.9% vs 51.3%; prior anticoagulation, 60.5% vs 63.8%; and median ICH volume, 20.5 cm3 vs 18.8 cm3). After adjustment, surgical hematoma evacuation vs conservative treatment was not significantly associated with likelihood of better functional disability at 3 months (30.9% vs 35.5%; adjusted odds ratio [AOR], 0.94 [95% CI, 0.81 to 1.09], P = .43; adjusted risk difference [ARD], -3.7% [95% CI, -8.7% to 1.2%]) but was significantly associated with greater probability of survival at 3 months (78.3% vs 61.2%; AOR, 1.25 [95% CI, 1.07 to 1.45], P = .005; ARD, 18.5% [95% CI, 13.8% to 23.2%]) and at 12 months (71.7% vs 57.2%; AOR, 1.21 [95% CI, 1.03 to 1.42], P = .02; ARD, 17.0% [95% CI, 11.5% to 22.6%]). A volume range of 12 to 15 cm3 was identified; below this level, surgical hematoma evacuation was associated with lower likelihood of favorable functional outcome (volume ≤12 cm3, 30.6% vs 62.3% [P = .003]; ARD, -34.7% [-38.8% to -30.6%]; P value for interaction, .01), and above, it was associated with greater likelihood of survival (volume ≥15 cm3, 74.5% vs 45.1% [P < .001]; ARD, 28.2% [95% CI, 24.6% to 31.8%]; P value for interaction, .02). Conclusions and Relevance: Among patients with cerebellar ICH, surgical hematoma evacuation, compared with conservative treatment, was not associated with improved functional outcome. Given the null primary outcome, investigation is necessary to establish whether there are differing associations based on hematoma volume.
CRIS-Team Scopus Importer:2019-10-15

ASSOCIATION OF SYSTEMIC INFLAMMATION WITH PERIHEMORRHAGIC EDEMA IN INTRACEREBRAL HEMORRHAGE - Volbers, Bastian; Jesse, C.; Seiffge, D.; Lepine, A.; Signer, B.; El-Koussy, M.; Dobrocky, T.; Fung, C.; Bervini, D.; Graggen, W. Z.; Fischer, U. (INTERNATIONAL JOURNAL OF STROKE, 2020)
CRIS-Team WoS Importer:2021-01-22

Associations of neutrophil-to-lymphocyte ratio with mortality in spontaneous intracerebral hemorrhage - Giede-Jeppe, A.; Bobinger, Tobias; Gerner, Stefan; Sembill, Jochen; Lücking, Hannes; Kuramatsu, J. B.; Huttner, Hagen; Hölter, Philip (2017)
EVALuna2:22568

A Stearoyl–Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in α-Synuclein Mice - Nuber, Silke; Nam, Alice Y.; Rajsombath, Molly M.; Cirka, Haley; Hronowski, Xiaoping; Wang, Junmin; Hodgetts, Kevin; Kalinichenko, Liubov; Müller, Christian P.; Lambrecht, Vera; Winkler, Jürgen; Weihofen, Andreas; et al. (Annals of neurology, 2020)
Objective: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD. Based on previous lipidomic analyses, we conducted a mouse trial of a stearoyl–coenzyme A desaturase (SCD) inhibitor (“5b”) that prevented αS-positive vesicular inclusions and cytotoxicity in cultured human neurons. Methods: Oral dosing and brain activity of 5b were established in nontransgenic mice. 5b in drinking water was given to mice expressing wild-type human αS (WT) or an amplified familial PD αS mutation (E35K + E46K + E61K ["3K"]) beginning near the onset of nigral and cortical neurodegeneration and the robust PD-like motor syndrome in 3K. Motor phenotypes, brain cytopathology, and SCD-related lipid changes were quantified in 5b- versus placebo-treated mice. Outcomes were compared to effects of crossing 3K to SCD1−/− mice. Results: 5b treatment reduced αS hyperphosphorylation in E46K-expressing human neurons, in 3K neural cultures, and in both WT and 3K αS mice. 5b prevented subtle gait deficits in WT αS mice and the PD-like resting tremor and progressive motor decline of 3K αS mice. 5b also increased αS tetramers and reduced proteinase K-resistant lipid-rich aggregates. Similar benefits accrued from genetically deleting 1 SCD allele, providing target validation. Interpretation: Prolonged reduction of brain SCD activity prevented PD-like neuropathology in multiple PD models. Thus, an orally available SCD inhibitor potently ameliorates PD phenotypes, positioning this approach to treat human α-synucleinopathies. ANN NEUROL 2020.
CRIS-Team Scopus Importer:2020-10-30

Asthma and allergic diseases: Cross talk of immune system and environmental factors - Beerweiler, Claudia C.; Masanetz, Rebecca Katharina; Schaub, Bianca (European Journal of Immunology, 2023)
Air pollution and immune-related diseases including allergy and asthma are constantly on the rise worldwide. Thus, a comprehensive investigation of environmentally induced immune regulation is required for a deeper understanding of disease pathogenesis, progression as well as prevention. Here, we summarize the current knowledge on environmental factors such as microbiome or geographical locations with harmful or protective effects for human health and their different routes of exposure. This review comprises a brief outline regarding the latest findings on the interaction of environmental factors with innate and adaptive regulation of the immune system, exemplarily for one protective and one harmful environmental factor, respectively.
CRIS-Team WoS Importer:2023-03-03

Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation - Linnerbauer, Mathias; Lößlein, Lena; Farrenkopf, Daniel; Vandrey, Oliver; Tsaktanis, Thanos; Naumann, Ulrike; Rothhammer, Veit (Frontiers in Immunology, 2022)
Astrocytes are the most abundant glial cells in the central nervous system (CNS) with the capacity to sense and react to injury and inflammatory events. While it has been widely documented that astrocytes can exert tissue-degenerative functions, less is known about their protective and disease-limiting roles. Here, we report the upregulation of pleiotrophin (PTN) by mouse and human astrocytes in multiple sclerosis (MS) and its preclinical model experimental autoimmune encephalomyelitis (EAE). Using CRISPR-Cas9-based genetic perturbation systems, we demonstrate in vivo that astrocyte-derived PTN is critical for the recovery phase of EAE and limits chronic CNS inflammation. PTN reduces pro-inflammatory signaling in astrocytes and microglia and promotes neuronal survival following inflammatory challenge. Finally, we show that intranasal administration of PTN during the late phase of EAE successfully reduces disease severity, making it a potential therapeutic candidate for the treatment of progressive MS, for which existing therapies are limited.
CRIS-Team Scopus Importer:2022-01-28
Keywords: astrocytes; autoimmunity; CNS inflammation; multiple sclerosis; protective

Astrocyte phenotypes in acute multiple sclerosis lesions - Lößlein, Lena; Cirac, A.; Tsaktanis, Thanos; Linnerbauer, Mathias; Schuetz, O.; Beyer, T.; Quintana, F. J.; Rothhammer, Veit (MULTIPLE SCLEROSIS JOURNAL, 2021)
CRIS-Team WoS Importer:2021-12-03

Atrial Fibrillation Detected before or after Stroke: Role of Anticoagulation - Lyrer, Flurina; Zietz, Annaelle; Seiffge, David J.; Koga, Masatoshi; Volbers, Bastian; Wilson, Duncan; Bonetti, Bruno; Schaedelin, Sabine; Gensicke, Henrik; Yoshimura, Sohei; Macha, Kosmas; Ambler, Gareth; et al. (Annals of Neurology, 2023)
Background: Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk. Methods: Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation. Results: Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death. Conclusion: Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023.
CRIS-Team Scopus Importer:2023-04-28

Attitudes of medical staff potentially participating in the organ donation process towards organ donation and transplantation in Bavaria - Grammenos, D.; Bein, T.; Briegel, J.; Eckardt, Kai-Uwe; Gerresheim, G.; Lang, C.; Niess, C.; Zeman, F.; Breidenbach, T. (Deutsche Medizinische Wochenschrift, 2014)
Background: Organ donation rates in Germany are lower than in other countries and have declined further after manipulations of the waiting lists in some German transplant centers became public. Attitudes and commitment of medical personnel are crucial for successful organ donation. Therefore, we studied the attitudes of hospital staff towards organ donation and transplantation. Method: In 50 Bavarian hospitals, medical professionals working in units relevant to organ donation were asked to respond to an anonymous questionnaire. Results: 2983 questionnaires could be evaluated. The majority of all respondents had a positive attitude towards organ donation; 71 % were willing to donate their organs after brain death and 57 % were willing to accept a transplant in case of organ failure. Rates of positive attitude were lower among nurses than among physicians. 28 % indicated that recent developments had a negative impact on their attitude and of those approximately half evaluated the work of transplant centers negatively. Overall only 23 % considered organ allocation as fair. The majority of nurses and a large proportion of physicians considered themselves as not well informed. Conclusion: The current loss of confidence into organ donation and transplantation also affects the attitude of medical personnel. Intensified measures of information and full transparency of all procedures are urgently needed.
EVALuna2:3694

Attitudes toward epilepsy assessed by the SAPE questionnaire in Germany - Comparison of its psychometric properties and results in a web-based vs. face-to-face survey - May, Theodor W.; Pfaefflin, Margarete; Bien, Christian G.; Hamer, Hajo; Holtkamp, Martin; Rating, Dietz; Schulze-Bonhage, Andreas; Straub, Hans-Beatus; Strzelczyk, Adam; Thorbecke, Rupprecht (Epilepsy and Behavior, 2022)
Objective: The aims of this study were (1) to investigate psychometric properties of a new questionnaire (SAPE, Scales of the Attitudes toward People with Epilepsy) that assesses attitudes toward people with epilepsy (PWE) (2) to compare the effects of mode of survey administration (web-based vs. face-toface) on attitudes, and (3) to identify predictors of attitudes.Methods: A face-to-face and a web-based survey were performed in Germany. Weighting factors were used to achieve representative samples of the German population. Reliability and validity of the 6 scales of the SAPE (social distance, stereotypes, personal concerns, and emotional reactions differentiated by fear, anger, and pity) were evaluated and compared for both surveys. Epilepsy knowledge was also assessed. General linear models were performed to investigate predictors of attitudes toward PWE including the type of survey. Results: In total, 1001 participants of the web-based survey and 1026 participants of face-to-face survey were included. Psychometric analyses indicated satisfactory reliability and validity of the scales and differed only slightly between modes of survey. In both surveys, fears and concerns were more pronounced than stereotypes and social distance. However, mean values of two scales were slightly or moderately higher in the face-to-face survey indicating more negative attitudes toward PWE (p < 0.001). Fewer participants of the face-to-face survey reported personal experience with PWE, claiming to know what to do in case of a seizure and claiming to know that seizures can be treated successfully (p < 0.001). These variables proved to be important predictors of positive attitudes toward PWE, besides demographic factors (e.g. age < 65, female gender). When controlling for them, the differences remained significant only for the scales Social Distance (moderately) and Fear (slightly).Significance: In total, psychometric analyses show that web-based surveys using the SAPE may be an alternative to face-to-face surveys to assess attitudes toward PWE. This applies also to the scales Social Distance and Emotional Reactions that allow comparisons with other diseases, e.g. psychiatric disorders. Most scales differ only slightly between survey modes, except social distance. This indicates that single components of attitudes toward PWE may be dependent on the mode of survey or different characteristics of respondents.(c) 2022 Elsevier Inc. All rights reserved.
CRIS-Team WoS Importer:2022-05-20

Attitudes toward persons with epilepsy as friends: Results of a factorial survey - Walther, Katrin; Kriwy, Peter; Stritzelberger, Jenny; Graf, Wolfgang; Gollwitzer, Stefanie; Lang, Johannes; Reindl, Caroline; Schwab, Stefan; Welte, Tamara; Hamer, Hajo (Epilepsia, 2023)
Objective: Discrimination against persons with epilepsy (PWEs) may persist. The aim of this study was to examine whether epilepsy is an obstacle to desired friendship.Methods: A factorial survey (vignettes), which is less biased by social desirability, was applied to PWEs, their relatives, and lay persons. The vignettes described a person who was varied by the dimensions of age (younger, same age, older), gender (male, female), disease (healthy, mild epilepsy, severe epilepsy [generalized toni-clonic seizures], diabetes), origin (German, non-German), contact (phone/internet, activities at home, activities outside), frequency of contacts (weekly, monthly), and distance (around the corner, 10 km away). Respondents rated their willingness to befriend the person on a 10-point Likert scale. Multivariate regression determined the contribution of each dimension on the judgment.Results: Participants were 64 PWEs (age = 37.1 +/- 14.0 years), 64 relatives of PWEs (age = 45.1 +/- 13.6 years), and 98 controls without contact with PWEs (age = 24.4 +/- 10.1 years). Controls were less interested in a friendship with a PWE with mild epilepsy (-3.4%) and even more avoided PWEs with severe epilepsy (-11.7%), whereas in PWEs with toni-clonic seizures, a mild form of epilepsy was actually conducive to friendship (+7.0%). Controls preferred females (+5.0%) and disliked younger people (-12.3%) and contacts via the internet or telephone (-7.3%). PWEs were also less interested in younger people (-5.8%), and relatives of PWEs had a lower preference for friendships with longer distance (-2.3%).Significance: PWEs still suffer from a risk of social avoidance, and this becomes more evident with generalized motor seizures.
CRIS-Team WoS Importer:2023-02-03

Author Correction: A monocyte gene expression signature in the early clinical course of Parkinson’s disease (Scientific Reports, (2018), 8, 1, (10757), 10.1038/s41598-018-28986-7) - Schlachetzki, Johannes; Prots, Iryna; Tao, Jenhan; Chun, Hyun B.; Saijo, Kaoru; Gosselin, David; Winner, Beate; Glass, Christopher K.; Winkler, Jürgen (Scientific Reports, 2020)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2020-04-17

Author Correction: Non-professional phagocytosis: a general feature of normal tissue cells (Scientific Reports, (2019), 9, 1, (11875), 10.1038/s41598-019-48370-3) - Seeberg, Jacob; Loibl, Monika; Moser, Fabian; Schwegler, Manuela; Büttner-Herold, Maike; Daniel, Christoph; Engel, Felix; Hartmann, Arndt; Schlötzer-Schrehardt, Ursula; Goppelt-Strübe, Margarete; Schellerer, Vera; Naschberger, Elisabeth; et al. (Scientific Reports, 2020)
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
CRIS-Team Scopus Importer:2020-06-16

Author Response: Multimodal CT or MRI for IV Thrombolysis in Ischemic Stroke With Unknown Time of Onset. - Macha, Kosmas; Hölter, Philip; Kallmünzer, Bernd (Neurology, 2021)
EVALuna2:470177

Author response: Peak perihemorrhagic edema correlates with functional outcome in intracerebral hemorrhage - Volbers, Bastian; Huttner, Hagen (Neurology, 2018)
EVALuna2:201935

Automated ASPECT scoring in acute ischemic stroke: comparison of three software tools - Hölter, Philip; Mühlen, Iris; Gölitz, Philipp; Beuscher, Vanessa; Schwab, Stefan; Dörfler, Arnd (Neuroradiology, 2020)
Purpose: Various software applications offer support in the diagnosis of acute ischemic stroke (AIS), yet it remains unclear whether the performance of these tools is comparable to each other. Our study aimed to evaluate three fully automated software applications for Alberta Stroke Program Early CT (ASPECT) scoring (Syngo.via Frontier ASPECT Score Prototype V2, Brainomix e-ASPECTS® and RAPID ASPECTS) in AIS patients. Methods: Retrospectively, 131 patients with large vessel occlusion (LVO) of the middle cerebral artery or the internal carotid artery, who underwent endovascular therapy (EVT), were included. Pre-interventional non-enhanced CT (NECT) datasets were assessed in random order using the automated ASPECT software and by three experienced neuroradiologists in consensus. Interclass correlation coefficient (ICC), Bland-Altman, and receiver operating characteristics (ROC) were applied for statistical analysis. Results: Median ASPECTS of the expert consensus reading was 8 (7–10). Highest correlation was between the expert read and Brainomix (r = 0.871 (0.818, 0.909), p < 0.001). Correlation between expert read and Frontier V2 (r = 0.801 (0.719, 0.859), p < 0.001) and between expert read and RAPID (r = 0.777 (0.568, 0.871), p < 0.001) was high, respectively. There was a high correlation among the software tools (Frontier V2 and Brainomix: r = 0.830 (0.760, 0.880), p < 0.001; Frontier V2 and RAPID: r = 0.847 (0.693, 0.913), p < 0.001; Brainomix and RAPID: r = 0.835 (0.512, 0.923), p < 0.001). An ROC curve analysis revealed comparable accuracy between the applications and expert consensus reading (Brainomix: AUC = 0.759 (0.670–0.848), p < 0.001; Frontier V2: AUC = 0.752 (0.660–0.843), p < 0.001; RAPID: AUC = 0.734 (0.634–0.831), p < 0.001). Conclusion: Overall, there is a convincing yet developable grade of agreement between current ASPECT software evaluation tools and expert evaluation with regard to ASPECT assessment in AIS.
CRIS-Team Scopus Importer:2020-05-15
Keywords: Acute ischemic stroke; Aspects; Diagnostics; Software anylsis

Automated assessment of foot elevation in adults with hereditary spastic paraplegia using inertial measurements and machine learning - Ollenschläger, Malte; Höfner, Patrick; Ullrich, Martin; Kluge, Felix; Greinwalder, Teresa; Loris, Evelyn; Regensburger, Martin; Eskofier, Björn; Winkler, Jürgen; Gaßner, Heiko (Orphanet Journal of Rare Diseases, 2023)
Background: Hereditary spastic paraplegias (HSPs) cause characteristic gait impairment leading to an increased risk of stumbling or even falling. Biomechanically, gait deficits are characterized by reduced ranges of motion in lower body joints, limiting foot clearance and ankle range of motion. To date, there is no standardized approach to continuously and objectively track the degree of dysfunction in foot elevation since established clinical rating scales require an experienced investigator and are considered to be rather subjective. Therefore, digital disease-specific biomarkers for foot elevation are needed. Methods: This study investigated the performance of machine learning classifiers for the automated detection and classification of reduced foot dorsiflexion and clearance using wearable sensors. Wearable inertial sensors were used to record gait patterns of 50 patients during standardized 4 × 10 m walking tests at the hospital. Three movement disorder specialists independently annotated symptom severity. The majority vote of these annotations and the wearable sensor data were used to train and evaluate machine learning classifiers in a nested cross-validation scheme. Results: The results showed that automated detection of reduced range of motion and foot clearance was possible with an accuracy of 87%. This accuracy is in the range of individual annotators, reaching an average accuracy of 88% compared to the ground truth majority vote. For classifying symptom severity, the algorithm reached an accuracy of 74%. Conclusion: Here, we show that the present wearable gait analysis system is able to objectively assess foot elevation patterns in HSP. Future studies will aim to improve the granularity for continuous tracking of disease severity and monitoring therapy response of HSP patients in a real-world environment.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Classification; Gait analysis; Motion capture; Muscle spasticity; Range of motion; Wearable sensors

AUTOMATED PUPILLOMETRY FOR PREDICTION OF SPACE-OCCUPYING HEMISPHERIC INFARCTION AFTER ENDOVASCULAR TREATMENT - Köhn, Julia; Kobus, Franca; Kossel, Clara-Sophie; Borutta, Matthias; Kuramatsu, Joji; Schwab, Stefan (JOURNAL OF NEUROTRAUMA, 2022)
CRIS-Team WoS Importer:2022-09-02

Automated Pupillometry Identifies Absence of Intracranial Pressure Elevation in Intracerebral Hemorrhage Patients - Giede-Jeppe, Antje; Sprügel, Maximilian; Huttner, Hagen; Borutta, Matthias; Kuramatsu, Joji; Hölter, Philip; Engelhorn, Tobias; Schwab, Stefan; Koehn, Julia (Neurocritical Care, 2020)
Introduction Although automated pupillometry is increasingly used in critical care settings, predictive value of automatically assessed pupillary parameters during different intracranial pressure (ICP) levels and possible clinical implications are unestablished. Methods This retrospective cohort study at the neurocritical care unit of the University of Erlangen-Nuremberg (2016-2018) included 23 nontraumatic supratentorial (intracerebral hemorrhage) ICH patients without signs of abnormal pupillary function by manual assessment, i.e., absent light reflex. We assessed ICP levels by an external ventricular drain simultaneously with parameters of pupillary reactivity [i.e., maximum and minimum apertures, light reflex latency (Lat), constriction and redilation velocities (CV, DV), and percentage change of apertures (per-change)] using a portable pupillometer (NeurOptics (R)). Computed tomography (CT) scans were analyzed to determine lesion location, size, intraventricular hemorrhage, hydrocephalus, midline shift, and compression or absence of the basal cisterns. We performed receiver operating characteristics analysis to investigate associations of ICP levels with pupillary parameters and to determine best cutoff values for prediction of ICP elevation. After dichotomization of assessments according to ICP values (normal: < 20 mmHg, elevated: >= 20 mmHg), prognostic performance of the determined cutoff parameters of pupillary function versus of CT-imaging findings was analyzed by calculating sensitivity, specificity, positive and negative predictive values (logistic regression, corresponding ORs with 95% CIs). Results In 23 patients (11 women, median age 59.0 (51.0-69.0) years), 1,934 assessments were available for analysis. A total of 74 ICP elevations >= 20 mmHg occurred in seven patients. Best discriminative thresholds for ICP elevation were: CV < 0.8 mm/s (AUC 0.740), per-change < 10% (AUC 0.743), DV < 0.2 mm/s (AUC 0.703), and Lat > 0.3 s (AUC 0.616). Positive predictive value of all four parameters to indicate ICP elevation ranged between 7.2 and 8.3% only and was similarly low for CT abnormalities (9.1%). We found high negative predictive values of pupillary parameters [CV: 99.2% (95% CI 98.3-99.6), per-change: 98.7% (95% CI 97.8-99.2), DV: 98.0% (95% CI 97.0-98.7), Lat: 97.0% (95% CI 96.0-97.7)], and CT abnormalities [99.7% (95% CI 99.2-99.9)], providing evidence that both techniques adequately identified ICH patients without ICP elevation. Conclusions Our data suggest an association between noninvasively detected changes in pupillary reactivity and ICP levels in sedated ICH patients. Although automated pupillometry and neuroimaging seem not sufficient to noninvasively indicate ICP elevation, both techniques, however, adequately identified ICH patients without ICP elevation. This finding may facilitate routine management by saving invasive ICP monitoring or repeated CT controls in patients with specific automated pupillometry readings.
CRIS-Team WoS Importer:2021-01-08

Automatic clinical gait test detection from inertial sensor data - Fischer, Stefan; Ullrich, Martin; Küderle, Arne; Gaßner, Heiko; Klucken, Jochen; Eskofier, Björn; Kluge, Felix (2020 42nd Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC), 2020)
The analysis of gait data is one approach to support clinicians with the diagnosis and therapy of diseases, for example Parkinson’s disease (PD). Traditionally, gait data of standardized tests in the clinic is analyzed, ensuring a predefined setting. In recent years, long-term home-based gait analysis has been used to acquire a more representative picture of the patient’s disease status. Data is recorded in a less artifical setting and therefore allows a more realistic perception of the disease progression. However, fully unsupervised gait data without additional context information impedes interpretation. As an intermediate solution, performance of gait tests at home was introduced. Integration of instrumented gait test requires annotations of those tests for their identification and further processing. To overcome these limitations, we developed an algorithm for automatic detection of standardized gait tests from continuous sensor data with the goal of making manual annotations obsolete. The method is based on dynamic time warping, which compares an input signal with a predefined template and quantifies similarity between both. Different templates were compared and an optimized template was created. The classification scored a F1-measure of 86.7% for evaluation on a data set acquired in a clinical setting. We believe that this approach can be transferred to home-monitoring systems and will facilitate a more efficient and automated gait analysi
Keywords: Turning; Diseases; Instruments; Legged locomotion; Gyroscopes; Hospitals; Reliability

Automatic dementia screening and scoring by applying deep learning on clock-drawing tests - Chen, Shuqing; Stromer, Daniel; Alnasser Alabdalrahim, Harb; Schwab, Stefan; Weih, Markus; Maier, Andreas (Scientific Reports, 2020)
Dementia is one of the most common neurological syndromes in the world. Usually, diagnoses are made based on paper-and-pencil tests and scored depending on personal judgments of experts. This technique can introduce errors and has high inter-rater variability. To overcome these issues, we present an automatic assessment of the widely used paper-based clock-drawing test by means of deep neural networks. Our study includes a comparison of three modern architectures: VGG16, ResNet-152, and DenseNet-121. The dataset consisted of 1315 individuals. To deal with the limited amount of data, which also included several dementia types, we used optimization strategies for training the neural network. The outcome of our work is a standardized and digital estimation of the dementia screening result and severity level for an individual. We achieved accuracies of 96.65% for screening and up to 98.54% for scoring, overcoming the reported state-of-the-art as well as human accuracies. Due to the digital format, the paper-based test can be simply scanned by using a mobile device and then be evaluated also in areas where there is a staff shortage or where no clinical experts are available.<br

Automatic multimodal detection for long-term seizure documentation in epilepsy - Fuerbass, F.; Kampusch, S.; Kaniusas, E.; Koren, J.; Pirker, S.; Hopfengaertner, R.; Stefan, Hermann; Kluge, T.; Baumgartner, C. (Clinical Neurophysiology, 2017)
This study investigated sensitivity and false detection rate of a multimodal automatic seizure detection algorithm and the applicability to reduced electrode montages for long-term seizure documentation in epilepsy patients.An automatic seizure detection algorithm based on EEG, EMG, and ECG signals was developed. EEG/ECG recordings of 92 patients from two epilepsy monitoring units including 494 seizures were used to assess detection performance. EMG data were extracted by bandpass filtering of EEG signals. Sensitivity and false detection rate were evaluated for each signal modality and for reduced electrode montages.All focal seizures evolving to bilateral tonic-clonic (BTCS, n=50) and 89% of focal seizures (FS, n=139) were detected. Average sensitivity in temporal lobe epilepsy (TLE) patients was 94% and 74% in extratemporal lobe epilepsy (XTLE) patients. Overall detection sensitivity was 86%. Average false detection rate was 12.8 false detections in 24h (FD/24h) for TLE and 22 FD/24h in XTLE patients. Utilization of 8 frontal and temporal electrodes reduced average sensitivity from 86% to 81%.Our automatic multimodal seizure detection algorithm shows high sensitivity with full and reduced electrode montages.Evaluation of different signal modalities and electrode montages paces the way for semi-automatic seizure documentation systems.
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Automatic Recognition of Parkinsons Disease Using Surface Electromyography During Standardized Gait Tests - Kugler, Patrick; Jaremenko, Christian; Schlachetzki, Johannes; Winkler, Jürgen; Klucken, Jochen; Eskofier, Björn (Engineering in Medicine and Biology Society (EMBC), 2013 35th Annual International Conference of the IEEE, 2013)
Diagnosis and severity staging of Parkinsons disease (PD) relies mainly on subjective clinical examination. To better monitor disease progression and therapy success in PD patients, new objective and rater independent parameters are required. Surface electromyography (EMG) during dynamic movements is one possible modality. However, EMG signals are often difficult to understand and interpret clinically. In this study pattern recognition was applied to find suitable parameters to differentiate PD patients from healthy controls. EMG signals were recorded from 5 patients with PD and 5 younger healthy controls, while performing a series of standardized gait tests. Wireless surface electrodes were placed bilaterally on tibialis anterior and gastrocnemius medialis and lateralis. Accelerometers were positioned on both heels and used for step segmentation. Statistical and frequency features were extracted and used to train a Support Vector Machine classifier. Sensitivity and specificity were high at 0.90 using leave-one-subject-out cross-validation. Feature selection revealed kurtosis and mean frequency as best features, with a significant difference in kurtosis (p=0.013). Evaluated on a bigger population, this could lead to objective diagnostic and staging tools for P

Automatic seizure detection in long-term scalp EEG using an adaptive thresholding technique: a validation study for clinical routine - Hopfengärtner, Rüdiger; Kasper, Burkhard; Graf, Wolfgang; Gollwitzer, Stephanie; Kreiselmeyer, Gernot; Stefan, Hermann; Hamer, Hajo (Clinical Neurophysiology, 2014)
In a previous study we proposed a robust method for automatic seizure detection in scalp EEG recordings. The goal of the current study was to validate an improved algorithm in a much larger group of patients in order to show its general applicability in clinical routine.For the detection of seizures we developed an algorithm based on Short Time Fourier Transform, calculating the integrated power in the frequency band 2.5-12 Hz for a multi-channel seizure detection montage referenced against the average of Fz-Cz-Pz. For identification of seizures an adaptive thresholding technique was applied. Complete data sets of each patient were used for analyses for a fixed set of parameters.159 patients (117 temporal-lobe epilepsies (TLE), 35 extra-temporal lobe epilepsies (ETLE), 7 other) were included with a total of 25,278 h of EEG data, 794 seizures were analyzed. The sensitivity was 87.3% and number of false detections per hour (FpH) was 0.22/h. The sensitivity for TLE patients was 89.9% and FpH=0.19/h; for ETLE patients sensitivity was 77.4% and FpH=0.25/h.The seizure detection algorithm provided high values for sensitivity and selectivity for unselected large EEG data sets without a priori assumptions of seizure patterns.The algorithm is a valuable tool for fast and effective screening of long-term scalp EEG recordings.
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Autonomic challenges suggest that Fingolimod induced cardiac autonomic changes might be reversible - Wang, Ruihao; Roy, Sankanika; de Rojas Leal, Carmen; Liu, Mao; Hoesl, K.; Lee, De-Hyung; Linker, Ralf; Hilz, M. J. (2017)
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Autonomic disorders in clinical practice - Micieli, Giuseppe; Hilz, Max-Josef; Cortelli, Pietro (Springer International Publishing, 2023)
The autonomic nervous system (ANS) is a subcomponent of the peripheral nervous system (PNS) and dysfunction of one or more subdivisions of the ANS, when accompanying other diseases, is linked to a worse prognosis of the latter. In some circumstances or when severe, dysfunction of ANS itself results in symptoms and disability. A myriad of factors can cause autonomic dysfunction and more than one can concur even in the same patient; due to the expansive nature of the ANS, patients can be affected by a wide range of conditions. Each chapter is characterized by a similar structure and is devoted to a different dysfunction. For each pathology, the book offers the essential information on mechanisms of action, treatments and outcomes. Written by experts in the research of these disorders, the volume addresses primarily Neurologists, but will be a useful tool also for Gastroenterologists, Ophthalmologists, Urologists, Cardiologists and Internal medicine specialists.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Autonomic Nervous System (ANS); Diagnostic approach to autonomic dysfunctions; Pathologies related to autonomic dysfunctions; Possible therapies; Symptoms

Autonomic dysfunction in the neurological intensive care unit - Hilz, Max-Josef; Liu, Mao; Roy, Sankanika; Wang, Ruihao (Clinical Autonomic Research, 2019)
Autonomic dysfunction is common in neuro-critical care patients and may compromise the function of various organs. Among the many diseases causing or being associated with autonomic dysfunction are traumatic brain injury, cerebrovascular diseases, epilepsy, Guillain–Barré syndrome (GBS), alcohol withdrawal syndrome, botulism and tetanus, among many others. Autonomic dysfunction may afflict various organs and may involve hyper- or hypo-activity of the sympathetic or parasympathetic system. In this short overview, we address only a small number of neuro-intensive care diseases with autonomic dysfunction. In GBS, autonomic dysfunction is frequent and may account for increased mortality rates; rapid changes between sympathetic and parasympathetic hypo- or hyper-activity may cause life-threatening cardiovascular complications. Paroxysmal sympathetic hyperactivity occurs after brain injury, hypoxia and cerebrovascular and other events, causes paroxysmal tachycardia, hypertension, tachypnoea and hyperthermia and is associated with a poorer prognosis and prolonged intensive care treatment. Other, at times life-threatening autonomic complications with exaggerated sympathetic activity and compromised baroreflex sensitivity arise during the alcohol withdrawal syndrome triggered by abrupt cessation of alcohol consumption. Botulism and tetanus are examples of life-threatening autonomic dysfunction caused by bacterial neurotoxins. Common neurological diseases, such as epilepsy, stroke or subarachnoid haemorrhage, are also associated with autonomic dysfunction that can on occasion cause critical deterioration of disease severity and prognosis.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Alcohol withdrawal syndrome; Autonomic dysfunction; Botulism; Guillain–Barré-syndrome; Neurological intensive care medicine; Paroxysmal sympathetic hyperactivity; Tetanus

Autonomic nervous system education in Europe: EAN/EFAS/INUS survey on curricula and skills in autonomic medicine of European neurology residents and consultants - Reis-Carneiro, Diogo; Skoric, Magdalena Krbot; Habek, Mario; Adamec, Ivan; Calandra-Buonaura, Giovanna; Cortelli, Pietro; van Dijk, J. Gert; Falup-Pecurariu, Cristian; Guaraldi, Pietro; Hilz, Max-Josef; Iodice, Valeria; Jordan, Jens; et al. (European Journal of Neurology, 2024)
Background and purpose: Centers for training in autonomic nervous system (ANS) disorders are not widely available and the recent coronavirus 2019 pandemic temporarily reduced training opportunities in autonomic medicine across European countries. Here we evaluated the current state of education, clinical skills and postgraduate educational preferences on ANS disorders of European neurology residents and consultants. Methods: A 23-item questionnaire was developed and distributed online amongst European neurology residents and consultants via mailing lists of the European Academy of Neurology. The questions assessed demographics, current training opportunities and learning preferences in ANS disorders. Six multiple-choice questions were used to self-evaluate knowledge of ANS disorders. Results: In all, 285 individuals answered the survey (60% female, mostly 25–34 years of age). All respondents considered clinical autonomic skills necessary for good clinical neurological practice, and 92% would like to increase their ANS knowledge. Female respondents and those who trained in Southern/Eastern/Greater Europe more frequently judged ANS skills important for clinical practice than male respondents (p = 0.012) and respondents from Northern/Western Europe (p = 0.011). Female and younger respondents felt less confident in managing ANS disorders (p = 0.001 and p < 0.001, respectively). Respondents below 45 years of age (p < 0.001) and those with lower confidence in managing ANS disorders (p = 0.004) were more likely to recommend that ANS education is embedded in the residency curriculum. Conclusions: Most European neurology residents and consultants reported a need for more autonomic education, with additional gender, age and regional differences. These findings underscore the importance of increasing the educational content on autonomic medicine in European medical and postgraduate curricula.
CRIS-Team Scopus Importer:2024-10-18
Keywords: autonomic nervous system disorders; clinical neurology; medical education; residency program

Autophagy inhibition promotes SNCA/alpha-synuclein release and transfer via extracellular vesicles with a hybrid autophagosome-exosome-like phenotype - Minakaki, Georgia; Menges, Stefanie; Kittel, Agnes; Emmanouilidou, Evangelia; Schäffner, Iris; Barkovits, Katalin; Bergmann, Anna; Rockenstein, Edward; Adame, Anthony; Marxreiter, Franz; Mollenhauer, Brit; Galasko, Douglas; et al. (Autophagy, 2017)
The autophagy-lysosome pathway (ALP) regulates intracellular homeostasis of the cytosolic protein SNCA/alpha-synuclein and is impaired in synucleinopathies, including Parkinson disease and dementia with Lewy bodies (DLB). Emerging evidence suggests that ALP influences SNCA release, but the underlying cellular mechanisms are not well understood. Several studies identified SNCA in exosome/extracellular vesicle (EV) fractions. EVs are generated in the multivesicular body compartment and either released upon its fusion with the plasma membrane, or cleared via the ALP. We therefore hypothesized that inhibiting ALP clearance 1) enhances SNCA release via EVs by increasing extracellular shuttling of multivesicular body contents, 2) alters EV biochemical profile, and 3) promotes SNCA cell-to-cell transfer. Indeed, ALP inhibition increased the ratio of extra- to intracellular SNCA and upregulated SNCA association with EVs in neuronal cells. Ultrastructural analysis revealed a widespread, fused multivesicular body-autophagosome compartment. Biochemical characterization revealed the presence of autophagosome-related proteins, such as LC3-II and SQSTM1. This distinct "autophagosome-exosome-like" profile was also identified in human cerebrospinal fluid (CSF) EVs. After a single intracortical injection of SNCA-containing EVs derived from CSF into mice, human SNCA colocalized with endosome and neuronal markers. Prominent SNCA immunoreactivity and a higher number of neuronal SNCA inclusions were observed after DLB patient CSF EV injections. In summary, this study provides compelling evidence that a) ALP inhibition increases SNCA in neuronal EVs, b) distinct ALP components are present in EVs, and c) CSF EVs transfer SNCA from cell to cell in vivo. Thus, macroautophagy/autophagy may regulate EV protein composition and consequently progression in synucleinopathies.
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Autophagy modulates SNCA/?-synuclein release, thereby generating a hostile microenvironment - Pöhler, Anne-Maria; Xiang, Wei; Spitzer, Philipp; May, Verena Elisabeth Luise; Meixner, Holger; Rockenstein, Edward; Chutna, Oldriska; Outeiro, Tiago Fleming; Winkler, Jürgen; Masliah, Eliezer; Klucken, Jochen; Klucken, Jochen (Autophagy, 2014)
SNCA/?-synuclein aggregation plays a crucial role in synucleinopathies such as Parkinson disease and dementia with Lewy bodies. Aggregating and nonaggregating SNCA species are degraded by the autophagy-lysosomal pathway (ALP). Previously, we have shown that the ALP is not only responsible for SNCA degradation but is also involved in the intracellular aggregation process of SNCA. An additional role of extracellular SNCA in the pathology of synucleinopathies substantiating a prion-like propagation hypothesis has been suggested since released SNCA species and spreading of SNCA pathology throughout neural cells have been observed. However, the molecular interplay between intracellular pathways, SNCA aggregation, release, and response of the local microenvironment remains unknown. Here, we attributed SNCA-induced toxicity mainly to secreted species in a cell culture model of SNCA aggregation and in SNCA transgenic mice: We showed that ALP inhibition by bafilomycinA1 reduced intracellular SNCA aggregation but increased secretion of smaller oligomers that exacerbated microenvironmental response including uptake, inflammation, and cellular damage. Low-aggregated SNCA was predominantly released by exosomes and RAB11A-associated pathways whereas high-aggregated SNCA was secreted by membrane shedding. In summary, our study revealed a novel role of the ALP by linking protein degradation to nonclassical secretion for toxic SNCA species. Thus, impaired ALP in the diseased brain not only limits intracellular degradation of misfolded proteins, but also leads to a detrimental microenvironmental response due to enhanced SNCA secretion. These findings suggest that the major toxic role of SNCA is related to its extracellular species and further supports a protective role of intracellular SNCA aggregation.
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A Wireless Joint Communication and Localization EMG-Sensing Concept for Movement Disorder Assessment - Brückner, Stefan; Weber, Jasmin; Michler, Fabian; Shanin, Nikita; Schober, Robert; Hagelauer, Amelie; Weigel, Robert; Gaßner, Heiko; Winkler, Jürgen; Eskofier, Björn; Vossiek, Martin (IEEE Journal of Electromagnetics, RF and Microwaves in Medicine and Biology, 2023)
Real-time sensory recording of the musculoskeletal system function is an important tool for the diagnosis, treatment planning, and optimal treatment execution of diseases, such as Parkinson's disease and osteoarthritis. This article presents a new wireless joint communication and localization electromyography (EMG)-sensing concept. An on-body sensor beacon measures EMG signals and wirelessly transmits them. At the same time, the spatial position and movement of the beacon is determined with high precision in real time using these transmitted radio signals. The seamless integration of multiple sensors avoids the need to synchronize and individually set up multiple independently operating sensors. An outstanding feature of the radio localization approach is that it does not require proprietary ultra-wideband signals or complicated time synchronization protocols, allowing for small and energy-efficient implementation. To demonstrate this novel concept, a wireless 3D-localizable EMG sensor was developed and experimentally evaluated. This new type of sensing concept allows, for the first time, the time-synchronous measurement of muscle activity and the underlying movement of the associated body part. URL: https://ieeexplore.ieee.org/stamp/stamp.jsp?tp=&arnumber=10286030&isnumber=8000303<br
Keywords: Array signal processing; EMG; localization; radar tracking; radio communication

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons - Güner, Fabian; Pozner, Tatyana; Krach, Florian; Prots, Iryna; Loskarn, Sandra; Schlötzer-Schrehardt, Ursula; Winkler, Jürgen; Winner, Beate; Regensburger, Martin (Frontiers in Neuroscience, 2021)
Pathogenic variants in SPG11 are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs. To investigate whether mitochondrial pathology is present in SPG11, we differentiated MNs from induced pluripotent stem cells derived from SPG11 patients and controls. MN derived from human embryonic stem cells and an isogenic SPG11 knockout line were also included in the study. Morphological analysis of mitochondria in the MN soma versus neurites revealed specific alterations of mitochondrial morphology within SPG11 neurites, but not within the soma. In addition, impaired mitochondrial membrane potential was indicative of mitochondrial dysfunction. Moreover, we reveal neuritic aggregates further supporting neurite pathology in SPG11. Correspondingly, using a microfluidic-based MN culture system, we demonstrate that axonal mitochondrial transport was significantly impaired in SPG11. Overall, our data demonstrate that alterations in morphology, function, and transport of mitochondria are an important feature of axonal dysfunction in SPG11 MNs.
CRIS-Team Scopus Importer:2021-08-06
Keywords: SPG11; alpha motor neuron; axonal transport; hereditary spastic paraplegia; induced pluripotent stem cells; mitochondria

Balance and mobility in geriatric patients - Jahn, Klaus; Freiberger, Ellen; Eskofier, Björn; Bollheimer, Cornelius; Klucken, Jochen (Zeitschrift für Gerontologie und Geriatrie, 2019)
Background: Personal autonomy in advanced age critically depends on mobility in the environment. Geriatric patients are often not able to walk safely with sufficient velocity. In many cases, multiple factors contribute to the deficit. Diagnostic identification of single components enables a specific treatment. Objective: This article describes the most common neurological causes of imbalance and impaired gait that are relevant for a pragmatic approach for the assessment of deficits in clinical and natural environments taking into account the physiology of balance and gait control, typical morbidities in older people and the potential of innovative assessment technologies. Material and methods: Expert opinion based on a narrative review of the literature and with reference to selected research topics. Results and discussion: Common neurological causes of impaired balance and mobility are sensory deficits (reduced vision, peripheral neuropathy, vestibulopathy), neurodegeneration in disorders with an impact on movement control and motoric functions (Parkinsonian syndromes, cerebellar ataxia, vascular encephalopathy) and functional (psychogenic) disorders, particularly a fear of falling. Clinical tests and scores in laboratory environments are complemented by the assessment in the natural environment. Wearable sensors, mobile smartphone-based assessment of symptoms and functions and adopted strategies for analysis are currently emerging. Use of these data enables a personalized treatment. Furthermore, sensor-based assessment ensures that effects are measured objectively.
CRIS-Team Scopus Importer:2019-06-21
Keywords: Dizziness; Falls; Gait disorder; Postural control; Vertigo

Barcoded viral tracing of single-cell interactions in central nervous system inflammation - Clark, Iain C.; Gutiérrez-Vázquez, Cristina; Wheeler, Michael A.; Li, Zhaorong; Rothhammer, Veit; Linnerbauer, Mathias; Sanmarco, Liliana M.; Guo, Lydia; Blain, Manon; Zandee, Stephanie E.J.; Chao, Chun Cheih; Batterman, Katelyn V.; et al. (Science, 2021)
Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.
CRIS-Team Scopus Importer:2021-05-14

Baroreflex dysfunction is more severe in patients with a history of moderate or severe TBI than in patients after mild TBI - Hilz, Max-Josef; Roy, Sankanika; Wang, R.; Ammon, Fabian; Hoesl, K.; Markus, Jörg; Muresanu, D. (EUROPEAN JOURNAL OF NEUROLOGY, 2019)
CRIS-Team WoS Importer:2019-07-30

Baseline magnetic resonance imaging of the optic nerve provides limited predictive information on short-term recovery after acute optic neuritis - Berg, Sebastian; Kaschka, Iris; Utz, Kathrin S.; Huhn, Konstantin; Laemmer, Alexandra; Lämmer, Robert; Waschbisch, Anne; Kloska, Stephan; Lee, De-Hyung; Dörfler, Arnd; Linker, Ralf (PLoS ONE, 2015)
In acute optic neuritis, magnetic resonance imaging (MRI) may help to confirm the diagnosis as well as to exclude alternative diagnoses. Yet, little is known on the value of optic nerve imaging for predicting clinical symptoms or therapeutic outcome.To evaluate the benefit of optic nerve MRI for predicting response to appropriate therapy and recovery of visual acuity.Clinical data as well as visual evoked potentials (VEP) and MRI results of 104 patients, who were treated at the Department of Neurology with clinically definite optic neuritis between December 2010 and September 2012 were retrospectively reviewed including a follow up within 14 days.Both length of the Gd enhancing lesion (r = -0.38; p = 0.001) and the T2 lesion (r = -0.25; p = 0.03) of the optic nerve in acute optic neuritis showed a medium correlation with visual acuity after treatment. Although visual acuity pre-treatment was little but nonsignificantly lower if Gd enhancement of the optic nerve was detected via orbital MRI, improvement of visual acuity after adequate therapy was significantly better (0.40 vs. 0.24; p = 0.04). Intraorbitally located Gd enhancing lesions were associated with worse visual improvement compared to canalicular, intracranial and chiasmal lesions (0.35 vs. 0.54; p = 0.02).Orbital MRI is a broadly available, valuable tool for predicting the improvement of visual function. While the accurate individual prediction of long-term outcomes after appropriate therapy still remains difficult, lesion length of Gd enhancement and T2 lesion contribute to its prediction and a better short-term visual outcome may be associated with detection and localization of Gd enhancement along the optic nerve.
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BASH: Biomechanical Animated Skinned Human for Visualization of Kinematics and Muscle Activity - Schleicher, Robert; Nitschke, Marlies; Martschinke, Jana; Stamminger, Marc; Eskofier, Björn; Klucken, Jochen; Koelewijn, Anne (Proceedings of the 16th International Joint Conference on Computer Vision, Imaging and Computer Graphics Theory and Applications - Volume 1: GRAPP, 2021)
Biomechanical analysis of human motion is applied in medicine, sports and product design. However, visualizations of biomechanical variables are still highly abstract and technical since the body is visualized with a skeleton and muscles are represented as lines. We propose a more intuitive and realistic visualization of kinematics and muscle activity to increase accessibility for non-experts like patients, athletes, or designers. To this end, the Biomechanical Animated Skinned Human (BASH) model is created and scaled to match the anthropometry defined by a musculoskeletal model in OpenSim file format. Motion is visualized with an accurate pose transformation of the BASH model using kinematic data as input. A statistical model contributes to a natural human appearance and realistic soft tissue deformations during the animation. Finally, muscle activity is highlighted on the model surface. The visualization pipeline is easily applicable since it requires only the musculoskeletal model, kinematics and muscle activation patterns as input. We demonstrate the capabilities for straight and curved running simulated with a full-body musculoskeletal model. We conclude that our visualization could be perceived as intuitive and better accessible for non-experts than conventional skeleton and line representations. However, this has to be confirmed in future usability and perception studies.<br
Keywords: Biomechanics; Surface Visualization; Animation; Statistical Human Model; Kinematics; Muscle Activity

Bedeutung der Muskelsonographie in der Detektion von Faszikulationen bei der ALS - German, Alexander; Türk, Matthias; Schramm, Axel; Regensburger, Martin (Klinische Neurophysiologie, 2023)
In amyotrophic lateral sclerosis, fasciculations are frequently present at early stages in multiple body regions which is why they were included in guidelines and diagnostic criteria. While invasive EMG recording remains indispensable for detecting acute and chronic neurogenic changes in motor unit action potentials and firing patterns as well as to confirm the presence of fasciculation potentials, muscle ultrasonography provides a highly sensitive method to rapidly and non-invasively detect fasciculations in the different body regions. In this review, we summarize current data on the use of muscle ultrasonography for the detection of fasciculations, and we describe how muscle ultrasonography allows targeted EMG diagnosis in clinical practice. Current research studies aim to analyze fasciculations more precisely regarding their quantity and morphology, as well as their potential as a progression parameter.
CRIS-Team Scopus Importer:2023-03-31
Keywords: amyotrophic lateral sclerosis; fasciculations; muscle ultrasonography

Bedside Catheter Hematoma Evacuation in Vitamin K Antagonist-Related Intracerebral Hemorrhage: A Safe and Feasible Approach - Volbers, Bastian; Niesen, Wolf Dirk; Amiri-Soltani, Samuel; Staykov, Dimitre; Shah, Mukesch Johannes; Lang, Stefan; Lücking, Hannes; Kuramatsu, Joji; Huttner, Hagen; Schwab, Stefan; Bardutzky, Jürgen (Frontiers in Neurology, 2020)
Background and Purpose: Although outcome in intracerebral hemorrhage (ICH) patients is generally not improved by surgical intervention, the use of minimally invasive surgery (MIS) has shown promising results. However, vitamin K antagonist (VKA)-related ICH patients are underrepresented in surgical treatment trials. We therefore assessed the safety and efficacy of a bedside MIS approach including local application of urokinase in VKA-related ICH. Methods: Patients with a VKA-related ICH > 20 ml who received bedside hematoma evacuation treatment (n = 21) at the University Medical Center Freiburg were retrospectively included for analysis and compared to a historical control group (n = 35) selected from an institutional database (University Medical Center Erlangen) according to identical inclusion criteria. Propensity score matching was performed to obtain comparable cohorts. The evolution of hematoma and peri-hemorrhagic edema (PHE) volumes, midline shift, and the occurrence of adverse events were analyzed. Furthermore, we assessed the modified Rankin Scale and NIHSS scores recorded at discharge. Results: Propensity score matching resulted in 16 patients per group with well-balanced characteristics. Median ICH volume at admission was 45.7 (IQR: 24.2–56.7) ml in the control group and 48.4 (IQR: 28.7–59.6) ml in the treatment group (p = 0.327). ICH volume at day 7 was less pronounced in the treatment group [MIS: 23.2 ml (IQR: 15.8–32.3) vs. control: 43.2 ml (IQR: 27.5–52.4); p = 0.013], as was the increase in midline shift up to day 7 [MIS: −3.75 mM (IQR: −4.25 to −2) vs. control: 1 mM (IQR: 0–2); p < 0.001]. No group differences were observed in PHE volume on day 7 [MIS: 42.4 ml (IQR: 25.0–72.3) vs. control: 31.0 ml (IQR: 18.8–53.8); p = 0.274] or mRS at discharge [MIS: 5 (IQR: 4–5) and 5 (IQR: 4–5); p = 0.949]. No hematoma expansion was observed. The catheter had to be replaced in 1 patient (6%). Conclusions: Bedside catheter-based hematoma evacuation followed by local thrombolysis with urokinase appears to be feasible and safe in cases of large VKA-related ICH. Further studies that assess the functional outcome associated with this technique are warranted. Clinical Trial Registration: DRKS00007908 (German Clinical Trial Register; www.drks.de).
CRIS-Team Scopus Importer:2020-09-11
Keywords: intracerebral hemorrhage; midline shift; minimally invasive surgery; peri-hemorrhagic edema; vitamin K antagonist

Bedside Ultrasound After Decompressive Craniectomy: A New Standard? - Bobinger, Tobias; Huttner, Hagen; Schwab, Stefan (Neurocritical Care, 2017)
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Behandlung nach dem ersten Anfall? Pro - Hamer, Hajo (Der Nervenarzt, 2014)
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Behavioural changes in patients with intellectual disability treated with brivaracetam - Andres, Elisa; Kerling, Frank; Hamer, Hajo; Winterholler, Martin (Acta Neurologica Scandinavica, 2018)
OBJECTIVE: The purpose of this study was to evaluate the tolerability and efficacy of brivaracetam (BRV) in residential patients at our epilepsy centre. PATIENTS AND METHODS: We assessed retrospectively 33 patients (14 females; mean age 38.2 years, with range 17-63 years) with intellectual disability (ID) and drug-resistant epilepsy using an industry-independent, non-interventional study design based on standardized daily seizure records. Mean seizure frequency was compared between the 3-month baseline period and subsequent 3-month treatment period. Evaluation, including calculation of retention rate, was carried out for the intervals 3-6 and 9-12 months after brivaracetam initiation. Responders were defined as having a 50% reduction in seizure frequency. The Clinical Global Impression scale (CGI) was applied to allow assessment of qualitative changes in seizure severity, and the Aggressive Behaviour Scale (ABS) gave further insights into challenging behaviour. RESULTS: The responder rate was 19%, and one non-responder attained an improvement in CGI score. The retention rate after 12 months was 37%. Brivaracetam treatment was stopped because of adverse events (n = 3), lack of efficacy (n = 8) or both (n = 6). Thirteen patients experienced behavioural changes, with aggressive behaviour being the commonest effect. We also observed ataxia (n = 2), gastrointestinal disorder (n = 3) and sedation (n = 2). The ABS showed deterioration, or new occurrence, of aggressive behaviour in 13 patients. CONCLUSIONS: Brivaracetam seems to be effective in a small number of patients suffering from difficult-to-treat epilepsy and intellectual disability. Challenging behaviour was documented in a relevant number of patients, with psychiatric illness being a risk factor for this.
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Behavioural changes in patients with intellectual disability treated with perampanel - Andres, E.; Kerling, Frank; Hamer, Hajo; Kasper, Burkhard; Winterholler, Martin (Acta Neurologica Scandinavica, 2017)
The aim of this cross-sectional retrospective study was to assess the tolerability and efficacy of perampanel in patients with drug-resistant epilepsy who also suffered from intellectual disability (ID).We used an industry-independent, non-interventional retrospective evaluation based on standardized, daily seizure records. Twenty-seven patients with ID and drug-resistant epilepsy were started on perampanel between September 2012 and November 2015 after a 3-month observation period without perampanel treatment. Perampanel was given at a maximum dosage of 4-12 mg daily. Evaluation was carried out after 6, 12 and 24 months, including calculation of the retention rate. Mean seizure frequency was compared between the 3-month baseline period and subsequent 3-month treatment periods. The Clinical Global Impression scale was applied to assess qualitative changes in seizure severity, and the Aggressive Behaviour Scale (ABS) gave further insights into challenging behaviour.Perampanel was efficacious and well tolerated in five of 25 patients. In 18 patients, perampanel treatment was stopped, mainly because of adverse events (n=6), lack of efficacy (n=3) or both (n=9). Behavioural changes were documented in 15 of 27 patients, with aggressive behaviour being the commonest effect; we observed ataxia (n=6) and sedation (n=8) in further patients. The ABS showed worsening of aggressive behaviour in six patients.Perampanel was well tolerated and efficacious in one-fifth of our patients. We observed challenging behaviour, ataxia and sedation in a relevant number of patients with ID under perampanel treatment. Further studies are warranted to explore the tolerability of perampanel in patients with ID.
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Benchmarking Foot Trajectory Estimation Methods for Mobile Gait Analysis. - Hannink, Julius; Ollenschläger, Malte; Kluge, Felix; Roth, Nils; Klucken, Jochen; Eskofier, Björn (Sensors, 2017)
Mobile gait analysis systems based on inertial sensing on the shoe are applied in a wide range of applications. Especially for medical applications, they can give new insights into motor impairment in, e.g., neurodegenerative disease and help objectify patient assessment. One key component in these systems is the reconstruction of the foot trajectories from inertial data. In literature, various methods for this task have been proposed. However, performance is evaluated on a variety of datasets due to the lack of large, generally accepted benchmark datasets. This hinders a fair comparison of methods. In this work, we implement three orientation estimation and three double integration schemes for use in a foot trajectory estimation pipeline. All methods are drawn from literature and evaluated against a marker-based motion capture reference. We provide a fair comparison on the same dataset consisting of 735 strides from 16 healthy subjects. As a result, the implemented methods are ranked and we identify the most suitable processing pipeline for foot trajectory estimation in the context of mobile gait analysi

Berthold Kihn und das Kihnsche Pulver: Über ein vergessenes Therapeutikum in seinem problematischen historischen Kontext - Kasper, Burkhard; Graf, Wolfgang; Lang, Johannes; Krämer, Günter (Zeitschrift für Epileptologie, 2021)
Berthold Kihn (1895–1964) was a German psychiatrist. This article describes his life and works with respect to his contributions to the treatment of epilepsy, for which he invented and broadly used his own pharmaceutical treatment, Kihn’s powder. Particular attention is paid to an overt discrepancy in Kihnʼs actions when comparing his later and earlier career years, when he was a National Socialism ideologist and not only an advocate of sterilization and so-called euthanasia but also an active protagonist during the Nazi regime.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Aktion T4; Epilepsy; Erlangen; Euthanasia; Kihn

Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage - Custal, Christina; Koehn, Julia; Borutta, Matthias; Mrochen, Anne; Brandner, Sebastian; Eyupoglu, Ilker Y.; Lücking, Hannes; Hölter, Philip; Kuramatsu, Joji; Kornhuber, Johannes; Schwab, Stefan; Huttner, Hagen; et al. (Cerebrovascular Diseases, 2021)
Background: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far. Objective: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors. Methods: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses - including utility-weighted mRS - were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months. Results: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval CI]: 0.872 [0.817-0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760-0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013-1.198]) to be independently associated with self-reported subjective health. Conclusion: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.
CRIS-Team WoS Importer:2021-08-06

Biceps electromyography in dialeptic and automotor seizures with and without secondary generalization - Hagge, Mareike; Nunnemann, Sebastian; Bauer, Sebastian; Gollwitzer, Stephanie; Oertel, Wolfgang H.; Knake, Susanne; Rosenow, Felix; Hamer, Hajo (Clinical Neurophysiology, 2016)
Localization of seizure onset during presurgical video-EEG monitoring is indispensable for successful epilepsy surgery. Sometimes analysis of ictal EEG and video fails to identify this zone. Therefore, this study explored the hypothesis that ictal EMG recordings contribute to the lateralization or localization of focal epilepsy.All patients with automotor or dialeptic seizures with or without secondary generalization were prospectively included during presurgical video-EEG monitoring over a 5years study period. We analyzed characteristics of ictal biceps EMG and compared the results to EEG and video findings.79 patients with 185 seizures were included (51.9% male; 73.5% automotor and 26.5% dialeptic seizures; 24.3% seizures secondarily generalized). Even in dialeptic seizures, muscle tone increased bilaterally within seconds after EEG seizure onset (66.7%) without clinical movements. Bilateral "spindle-shaped" EMG activity during the automotor phase predicted secondary generalization in 88.7%. Increase of muscle activity in the contralateral side of the body in the beginning of the secondarily generalized tonic-clonic phase was detected in 78.1% after automotor seizures whereas this phenomenon was less pronounced after dialeptic seizures (69.2%). 38.5% of dialeptic seizures evolved into generalized tonic-unilateral clonic seizures.Ictal EMG recordings provide lateralizing signs especially in secondarily generalized automotor seizures. In addition, the study suggested that secondary generalization in automotor seizures is determined early already during the automotor phase. Dialeptic seizures can evolve only unilaterally into a tonic-clonic seizure while the other side of the body remains tonic.Ictal biceps EMG can provide further information regarding lateralization of epileptic seizures.
EVALuna2:22271

Binding of α-synuclein oligomers to Cx32 facilitates protein uptake and transfer in neurons and oligodendrocytes - Reyes, Juan F.; Sackmann, Christopher; Hoffmann, Alana; Svenningsson, Per; Winkler, Jürgen; Ingelsson, Martin; Hallbeck, Martin (Acta Neuropathologica, 2019)
The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson’s disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes. In vitro, we demonstrate a clear correlation between Cx32 expression and oα-syn uptake. Pharmacological and genetic strategies targeting Cx32 successfully blocked oα-syn uptake. In cellular and transgenic mice modeling PD and MSA, we observed significant upregulation of Cx32 which correlates with α-syn accumulation. Notably, we could also demonstrate a direct interaction between α-syn and Cx32 in two out of four human PD cases that was absent in all four age-matched controls. These data are suggestive of a link between Cx32 and PD pathophysiology. Collectively, our results provide compelling evidence for Cx32 as a novel target for therapeutic intervention in PD and related α-synucleinopathies.
CRIS-Team Scopus Importer:2019-06-25
Keywords: alpha-Synuclein (α-syn); Alzheimer’s disease (AD); Cell-to-cell transfer; Cx32; Gap junction proteins; GJB1; Multiple system atrophy (MSA); Parkinson’s disease (PD); Prion-like transfer

Biochemical markers of neurodegeneration in hereditary diffuse leucoencephalopathy with spheroids - Spitzer, Philipp; Kohl, Zacharias; Gölitz, Philipp; Coras, Roland; Blümcke, Ingmar; Brueck, Wolfgang; Dörfler, Arnd; Maihöfner, Christian (BMJ Case Reports, 2014)
Hereditary diffuse leucoencephalopathy with spheroids (HDLS) is a rare autosomal dominantly inherited disease with unknown pathophysiology. Diagnosis of neurodegenerative diseases is increasingly based on biomarkers. Although lumbar puncture is routinely performed during the diagnostic workup of HDLS, reports on alterations of neurodegeneration-specific biochemical markers have not been documented so far. We report a 35-year-old woman with clinical, radiological and neuropathological signs of HDLS. She suffered from a rapidly progressive frontal lobe syndrome. Brain MRI revealed diffuse leucoencephalopathy with predominant involvement of the periventricular white matter and corpus callosum. Although she was severely impaired and leucoencephalopathy was prominent, only cerebrospinal fluid total-? was moderately elevated. Other markers of neuronal (NSE) and astrocytic (S100B) damage were within normal range. Therefore, biochemical markers of central nervous system damage are not helpful in the diagnosis of HDL
EVALuna2:7264

Biomechanical factors may explain why grasping violates Weber's law - Utz, Kathrin S.; Hesse, Constanze; Aschenneller, Nina; Schenk, Thomas (Vision research, 2015)
For grasping, Ganel, Chajut, and Algom (2008) demonstrated that the variability of the maximum grip aperture (MGA) does not increase with the size of the target object. This seems to violate Weber's law, a fundamental law of psychophysics. They concluded that the visual representations guiding grasping are distinct from representations used for perceptual judgments. Weber's law is however only relevant for one component of the measurable variability of MGA, namely the variability in the sensory system. We argue that when looking at the relationship between object size and grasping, the gain (often called slope) governing the relationship between target size and MGA can be used as an approximation to estimate the contribution of sensory noise to MGA variability. To test the idea that differences in gain modulate the relationship between target size and MGA variability, we examined grasping under a variety of conditions. We found that gain varied quite significantly across different tasks, but irrespective of gain Weber's law could not be found in any of the grasping tasks. Instead we repeatedly found an inverse relationship between variability and object size, i.e. variability decreased for bigger objects. This trend may reflect the reduced biomechanical freedom found for movements at the end an effector's effective range of motion. MGA variability may thus be dominated by non-sensory factors and therefore may constitute a poor choice to estimate the variability of the visual signals used by the brain to guide our grasping actions.
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Biometric and Mobile Gait Analysis for Early Detection and Therapy Monitoring in Parkinson's Disease - Barth, Jens; Klucken, Jochen; Kugler, Patrick; Kammerer, Thomas; Steidl, Ralph; Winkler, Jürgen; Hornegger, Joachim; Eskofier, Björn (Engineering in Medicine and Biology Society,EMBC, 2011 Annual International Conference of the IEEE, 2011)
Parkinson's disease (PD) is the most frequent neurodegenerative movement disorder. Early diagnosis and effective therapy monitoring is an important prerequisite to treat patients and reduce health care costs. Objective and non-invasive assessment strategies are an urgent need in order to achieve this goal. In this study we apply a mobile, lightweight and easy applicable sensor based gait analysis system to measure gait patterns in PD and to distinguish mild and severe impairment of gait. Examinations of 16 healthy controls, 14 PD patients in an early stage, and 13 PD patients in an intermediate stage were included. Subjects performed standardized gait tests while wearing sport shoes equipped with inertial sensors (gyroscopes and accelerometers). Signals were recorded wirelessly, features were extracted, and distinct subpopulations classified using different classification algorithms. The presented system is able to classify patients and controls (for early diagnosis) with a sensitivity of 88% and a specificity of 86%. In addition it is possible to distinguish mild from severe gait impairment (for therapy monitoring) with 100% sensitivity and 100% specificity. This system may be able to objectively classify PD gait patterns providing important and complementary information for patients, caregivers and therapists. © 2011 IEEE.

Biosensorische Bewegungserfassung beim Parkinson-Syndrom - Klucken, Jochen; Barth, J.; Eskofier, Björn; Winkler, Jürgen (Neurologie und Rehabilitation, 2013)
Movement disorders can occur at every age. They restrict the affected persons' mobility and limit his or her quality of life. The most common neurodegenerative movement disorder in the elderly is Parkinson's disease. During disease progression movement impairments increase and become the main therapeutic target for patients and physicians. So far, the extent of motor impairments is based on the individual case history, which is influenced by the patients' emotions and cognitive abilities. An additional physical examination further helps the physician to estimate the degree of disability. However, the course of movement disorders throughout the day as well as over a period of several days or weeks is the main therapeutic criteria, which cannot be determined in single-phase surveys. This survey intends to present a variety of inpatient and mobile systems for sensorbased and automatic movement monitoring, which allow objective and quantitatively comparable evidence about motor impairments. We will focus on a study, which investigated a mobile gait analysis system allowing the monitoring of Parkinson-associated movement disorders via movement sensors attached to the patients' shoes. Via this system information about the extent of motor disorders and the diseases' stage can be collected independently and help the therapist with his or her assessment. In the future, these invisible sensor systems embedded in the patients' clothing may support diagnosis and therapy of other motor disorders as well and may be applied in prevention and therapy. © Hippocampus Verlag 2013.
CRIS-Team Scopus Importer:2023-03-07
Keywords: Biosensors; Gait analysis; Movement disorders; Parkinson's disease

Blood biomarker changes following therapeutic hypothermia in ischemic stroke - Palà, Elena; Penalba, Anna; Bustamante, Alejandro; García-Berrocoso, Teresa; Lamana-Vallverdú, Marcel; Meisel, Christian; Meisel, Andreas; van der Worp, H. Bart; R Macleod, Malcolm; Kallmünzer, Bernd; Schwab, Stefan; Montaner, Joan (Brain and Behavior, 2023)
Introduction: Therapeutic hypothermia is a promising candidate for stroke treatment although its efficacy has not yet been demonstrated in patients. Changes in blood molecules could act as surrogate markers to evaluate the efficacy and safety of therapeutic cooling. Methods: Blood samples from 54 patients included in the EuroHYP-1 study (27 treated with hypothermia, and 27 controls) were obtained at baseline, 24 ± 2 h, and 72 ± 4 h. The levels of a panel of 27 biomarkers, including matrix metalloproteinases and cardiac and inflammatory markers, were measured. Results: Metalloproteinase-3 (MMP-3), fatty-acid-binding protein (FABP), and interleukin-8 (IL-8) increased over time in relation to the hypothermia treatment. Statistically significant correlations between the minimum temperature achieved by each patient in the hypothermia group and the MMP-3 level measured at 72 h, FABP level measured at 24 h, and IL-8 levels measured at 24 and 72 h were found. No differential biomarker levels were observed in patients with poor or favorable outcomes according to modified Rankin Scale scores. Conclusion: Although the exact roles of MMP3, FABP, and IL-8 in hypothermia-treated stroke patients are not known, further exploration is needed to confirm their roles in brain ischemia.
CRIS-Team Scopus Importer:2023-09-29
Keywords: biomarkers; hypothermia; ischemia; stroke

Blood Pressure and Anticoagulation Reversal Management during Off-Hours in Oral Anticoagulation-Associated Intracerebral Hemorrhage - Mrochen, Anne; Sprügel, Maximilian; Gerner, Stefan; Sembill, Jochen; Lang, Stefan; Lücking, Hannes; Kuramatsu, Joji; Huttner, Hagen (Cerebrovascular Diseases, 2020)
Background: Prevention of hematoma enlargement in oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) focuses on blood pressure (BP) reduction and OAC reversal. We investigated whether treatment efficiency and clinical outcomes differ between OAC-ICH patients admitted outside versus during regular working hours. Methods: Based on pooled data of multicenter cohort studies, we grouped OAC-ICH patients (vitamin K antagonist [VKA], non-vitamin K oral anticoagulant [NOAC]) according to on-vs. off-hour admission. Primary outcome was the functional outcome using the modified Rankin scale (mRS) dichotomized into favorable (mRS 0-3) and unfavorable (mRS 4-6) and mortality at 3 months. Secondary outcome measures included the occurrence of hematoma enlargement, the proportions of patients with systolic BP <140 mm Hg and with anticoagulation treatment achieving international normalized ratio (INR) levels <1.3 at 4 h. Propensity score matching (PSM) was performed to account for imbalances in baseline characteristics. Results: The study population consisted of 76/126 NOAC-ICH patients and 1,005/1,470 VKA patients presenting during off-hours. Functional outcome and mortality rates were not significantly different among PSM patients with VKA-ICH and NOAC-ICH during on-vs. off-hours (mRS 4-6 VKA-ICH: On-hour: 239/357 [66.9%] vs. 253/363 [69.7%] off-hour; p = 0.43; NOAC-ICH: On-hour 26/42 [61.9%] vs. off-hour: 37/57 [64.9%]; p = 0.76; mRS 6 VKA-ICH: On-hour: 127/357 [35.6%] vs. off-hour: 148/363 [40.8%]; p = 0.15;-NOAC-ICH: On-hour 17/42 [40.5%] vs. off-hour: 16/57 [28.1%]; p = 0.20). There were no differences detectable regarding the secondary outcome measures (i.e., hematoma enlargement, the proportion of patients who achieved systolic BP levels <140 mm Hg at 4 h as well as anticoagulation treatment achieving INR levels <1.3 at 4 h) in OAC patients. Conclusion: Our study implies that BP reduction and anticoagulation reversal management are well established and associated with similar rates of hematoma enlargement and clinical outcomes in on-vs. off-hour admitted OAC-ICH patients.
CRIS-Team Scopus Importer:2020-05-12
Keywords: Clinical outcome; Intracerebral hemorrhage; Non-vitamin K oral anticoagulant; Off-hour; Oral anticoagulation; Vitamin K antagonist

Brain MRI Lesions are Related to Bowel Incontinence in Multiple Sclerosis - Fröhlich, Katharina; Linker, Ralf; Engelhorn, Tobias; Dörfler, Arnd; Lee, De-Hyung; Huhn, Konstantin; Schwab, Stefan; Hilz, Max-Josef; Seifert, Frank; Winder, Klemens (Journal of Neuroimaging, 2018)
BACKGROUND AND PURPOSE: Bowel incontinence in multiple sclerosis might be associated with specific lesion sites. This study intended to determine associations between bowel incontinence and cerebral multiple sclerosis lesions using a voxel-wise lesion symptom mapping analysis. METHODS: We conducted a retrospective study of multiple sclerosis patients with self-reported bowel incontinence and matched controls. Lesions were manually outlined on T2-weighted MRI scans and transformed into stereotaxic space. We performed a voxel-wise subtraction analysis subtracting the lesion overlap of patients without from patients with bowel incontinence. Finally, we compared the absence or presence of bowel incontinence between patients with and without lesions in a given voxel using the Liebermeister test. RESULTS: A total of 51 patients were included in the study. The analysis yielded associations between bowel incontinence and lesions in the supramarginal gyrus of the left secondary somatosensory cortex and another lesion cluster in the right parahippocampal gyrus and amygdala. CONCLUSIONS: Our analysis indicates associations between bowel incontinence and lesions in the left supramarginal gyral area contributing to integrating anorectal-visceral sensation and in the right parahippocampal gyrus and amygdala contributing to generating visceral autonomic arousal states. Moreover, our results suggest left hemispheric dominance of sensory visceral integration, while limbic areas of the right hemisphere seem to contribute to the autonomic component of the defecation process. A limitation of our study is the retrospective evaluation of the bowel incontinence status based on medical records. Further research should evaluate the bowel incontinence status in multiple sclerosis patients prospectively to overcome the limitations of the current study.
EVALuna2:36318

Brain Preservation and Cryonics Through the Lens of Moral Psychology - German, Alexander; Tretter, Max (Neuroethics, 2025)
Structural brain preservation (SBP) and classical cryonics are techniques aimed at preserving the human brain for potential future applications. Reluctant public discourse around these techniques may be explained with intuitive aversions identified by moral psychology. In the first part of the paper, we conjecture the existence of a self-sustaining cycle of moral condemnation of SBP and classical cryonics due to quick, affect-laden moral intuitions. In the second part, we propose an alternative framing of SBP and classical cryonics through a thought experiment featuring a time machine metaphor called "Schrödinger’s chrono-cat", which might avoid triggering aversive moral intuitions and foster public discourse. We discuss the limitations of this framing and its consequence
Keywords: Brain preservation; Cryonics; Moral psychology; Dual-process theory; Disgust; Purity; Mortality salience effects; Smart heuristics

Brain tissues have single-voxel signatures in multi-spectral MRI - German, Alexander; Mennecke, Angelika; Martin, Jan; Hanspach, Jannis; Liebert, Andrzej; Herrler, Jürgen; Kuder, Tristan Anselm; Schmidt, Manuel; Nagel, Armin Michael; Uder, Michael; Dörfler, Arnd; Winkler, Jürgen; et al. (NeuroImage, 2021)
Since the seminal works by Brodmann and contemporaries, it is well-known that different brain regions exhibit unique cytoarchitectonic and myeloarchitectonic features. Transferring the approach of classifying brain tissues – and other tissues – based on their intrinsic features to the realm of magnetic resonance (MR) is a longstanding endeavor. In the 1990s, atlas-based segmentation replaced earlier multi-spectral classification approaches because of the large overlap between the class distributions. Here, we explored the feasibility of performing global brain classification based on intrinsic MR features, and used several technological advances: ultra-high field MRI, q-space trajectory diffusion imaging revealing voxel-intrinsic diffusion properties, chemical exchange saturation transfer and semi-solid magnetization transfer imaging as a marker of myelination and neurochemistry, and current neural network architectures to analyze the data. In particular, we used the raw image data as well to increase the number of input features. We found that a global brain classification of roughly 97 brain regions was feasible with gross classification accuracy of 60%; and that mapping from voxel-intrinsic MR data to the brain region to which the data belongs is possible. This indicates the presence of unique MR signals of different brain regions, similar to their cytoarchitectonic and myeloarchitectonic fingerprints.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Brain; Data Analysis; High-Field Imaging; Machine Learning; MRI; Segmentation

Break-out session highlights - Myhr, Kjell-Morten; Maeurer, Mathias; Martinez Gines, Marisa; Esposito, Federica; Linker, Ralf (Neurodegenerative Disease Management, 2017)
A popular feature of the Multiple Sclerosis Experts Summit is interactive break-out sessions to discuss various aspects of multiple sclerosis (MS), including MS spasticity and general management of MS patients. The format encourages participation and active discussion, thus providing attendees with the opportunity to exchange their experiences of the day-to-day management of MS in clinical practice. Following feedback provided by each session leader, key messages are summarized and presented in a plenary session by the Summit chair. Topics covered in this year's country break-out sessions included: triggering factors for MS; decision-making in MS and the importance of patients' risk perception; assessment and management of MS spasticity.
EVALuna2:36329

Breastfeeding in Mothers with Multiple Sclerosis: The German Experience - Aigner, Stefanie; Huhn, Konstantin; Cepek, Lukas; Hellwig, Kerstin; Nickel, Florian; Bayas, Antonios (Breastfeeding Medicine, 2023)
Background: Many female people with multiple sclerosis (pwMS) are in childbearing age; however, only few data exist about the situation of breastfeeding in pwMS.Objective: Our study analyzed breastfeeding rate and duration, reasons for weaning, and the impact of disease severity on successful breastfeeding in pwMS.Methods: The study included pwMS giving birth within 3 years before study participation. Data were collected by structured questionnaire.Results: Compared to published data, we found a significant difference (p = 0.0007) between the nursing rate in the general population (96.6%) and females with MS (85.9%). However, a higher rate of exclusive breastfeeding could be observed in our study population for 5-6 months in 40.6% of pwMS versus 9% for 6 months in the general population. In contrast, total breastfeeding duration in our study population was shorter (18.8% for 11-12 months) than in the general population (41.1% for 12 months). Reasons for weaning were predominantly (68.7%) related to breastfeeding barriers based on MS. No significant impact of prepartum or postpartum education on the breastfeeding rate could be observed. Prepartum relapse rate and prepartum disease-modifying drugs had no effect on breastfeeding success.Conclusion: Our survey provides an insight into the situation of breastfeeding in pwMS in Germany.
CRIS-Team WoS Importer:2023-03-17

Burden of infectious disease studies in Europe and the United Kingdom: a review of methodological design choices - Charalampous, Periklis; Haagsma, Juanita A.; Jakobsen, Lea S.; Gorasso, Vanessa; Noguer, Isabel; Padron-Monedero, Alicia; Sarmiento, Rodrigo; Santos, João Vasco; Mcdonald, Scott A.; Plass, Dietrich; Wyper, Grant M.A.; Assunção, Ricardo; et al. (EPIDEMIOL INFECT, 2023)
This systematic literature review aimed to provide an overview of the characteristics and methods used in studies applying the Disability-Adjusted Life Years (DALY) concept for infectious diseases within European Union (EU)/European Economic Area (EEA)/European Free Trade Association (EFTA) countries and the United Kingdom. Electronic databases and grey literature were searched for articles reporting the assessment of DALY and its components. We considered studies in which researchers performed DALY calculations using primary epidemiological data input sources. We screened 3,053 studies of which 2,948 were excluded and 105 studies met our inclusion criteria. Of these studies, 22 were multi-country and 83 were single-country studies, of which 46 were from the Netherlands. Food- and water-borne diseases were the most frequently studied infectious diseases. Between 2015 and 2022, the number of burden of infectious disease studies was 1.6 times higher compared to that published between 2000 and 2014. Almost all studies (97%) estimated DALYs based on the incidence- and pathogen-based approach and without social weighting functions; however, there was less methodological consensus with regards to the disability weights and life tables that were applied. The number of burden of infectious disease studies undertaken across Europe has increased over time. Development and use of guidelines will promote performing burden of infectious disease studies and facilitate comparability of the results.
CRIS-Team Scopus Importer:2023-01-20
Keywords: Burden of disease; disability-adjusted life years; infectious diseases; methodology; systematic review

Burst Motor Cortex Stimulation Evokes Sustained Suppression of Thalamic Stroke Pain: A Narrative Review and Single-Case Overview - Nuessel, Martin; Hamperl, Melanie; Maslarova, Anna; Chaudhry, Shafqat R.; Kohn, Julia; Stadlbauer, Andreas; Buchfelder, Michael; Kinfe, Thomas Mehari (Pain and Therapy, 2020)
Chronic refractory central post-stroke pain (CPSP), one of the most disabling consequences of cerebral stroke, occurs in up to 10% of patients with CPSP. Because a considerable proportion of these patients with chronic pain remain resistant to pharmacological and behavioral therapies, adjunctive invasive and non-invasive brain stimulation therapies are needed. We performed a review of human studies applying burst and conventional motor cortex stimulation (burstMCS and cMCS, respectively) for chronic pain states, on the basis of data sources identified through searches of PubMed, MEDLINE/OVID, and SCOPUS, as well as manual searches of the bibliographies of known primary and review articles. Our aim was to review and discuss clinical data on the indications of burstMCS for various chronic pain states originating from central stroke (excluding trigeminal facial pain). In addition, we assessed the efficacy and safety of burst versus cMCS for central post-stroke pain with an extended follow-up of 5 years in a 60-year-old man. According to our review, uncontrolled observational human cohort studies and one RCT using cMCS waveforms have revealed a meaningful clinical response; however, these studies lacked placebo groups and extended observation periods. In our case report, we found that 3 months of adjunctive cMCS reduced pain levels [visual analog scale (VAS) pre: 9/10 versus VAS post 7/10], whereas the pain decreased further under burstMCS (VAS pre: 7/10 versus VAS post: 2/10); the study involved a follow-up of 5 years and the following parameters: burst rate 40 Hz (500 Hz), 1-1.75 mA, 1 ms, bipolar configuration. To date, only limited evidence exists for the efficacy and safety of burst motor cortex stimulation for the treatment of refractory chronic pain. BurstMCS resulted in significantly decreased post-stroke pain observed after 5 years of cMCS. The available literature suggests similar efficacy as that of conventional (tonic) motor cortex stimulation, although the results are preliminary. Mechanistically, the precise mechanism of action is not fully understood. However, burstMCS may interact with the nociceptive thalamic-cingulate and descending spinal pain networks. To determine the potential utility of this treatment, large-scale sham-controlled trials comparing cMCS and burstMCS are highly recommended.
CRIS-Team WoS Importer:2021-01-01

C9ORF72-ALS: P62- and ubiquitin-aggregation pathology in skeletal muscle - Türk, Matthias; Haaker, Gerrit; Winter, Lilli; Just, Walter; Nickel, Franziska; Linker, Ralf; Chevessier, Frederic; Schröder, Rolf (Muscle & Nerve, 2014)
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Cancer-Type Organic Anion Transporting Polypeptide 1B3 Is Localized in Lysosomes and Mediates Resistance against Kinase Inhibitors - Haberkorn, Bastian; Oswald, Stefan; Kehl, Niklas; Geßner, Arne; Taudte, Verena; Dobert, Jan; Zunke, Friederike; Fromm, Martin; König, Jörg (Molecular Pharmacology, 2022)
Cancer-type organic anion transporting polypeptide 1B3 (CtOATP1B3), a splice variant of the hepatic uptake transporter OATP1B3 (liver-type), is expressed in several tumor entities, including colorectal carcinoma (CRC) and breast cancer. In CRC, high OATP1B3 expression has been associated with reduced progression-free and overall survival. Several kinase inhibitors used for antitumor treatment are substrates and/or inhibitors of OATP1B3 (e.g., encorafenib, vemurafenib). The functional importance of CtOATP1B3 has not been elucidated so far. Human embryonic kidney 293 cells stably overexpressing Ct-OATP1B3 protein were established and compared with control cells. Confocal laser scanning microscopy, immunoblot, and proteomics-based expression analysis demonstrated that Ct-OATP1B3 protein is intracellularly localized in lysosomes of stably transfected cells. Cytotoxicity experiments showed that cells recombinantly expressing the Ct-OATP1B3 protein were more resistant against the kinase inhibitor encorafenib compared with control cells [e.g., encorafenib (100 mM) survival rates: 89.5% versus 52.8%]. In line with these findings, colorectal cancer DLD1 cells endogenously expressing Ct-OATP1B3 protein had poorer survival rates when the OATP1B3 substrate bromosulfophthalein (BSP) was coincubated with encorafenib or vemurafenib compared with the incubation with the kinase inhibitor alone. This indicates a competitive inhibition of Ct-OATP1B3–mediated uptake into lysosomes by BSP. Accordingly, mass spectrometry-based drug analysis of lysosomes showed a reduced lysosomal accumulation of encorafenib in DLD1 cells additionally exposed to BSP. These results demonstrate that Ct-OATP1B3 protein is localized in the lysosomal membrane and can mediate transport of certain kinase inhibitors into lysosomes, revealing a new mechanism of resistance.
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