Publications by authors named "Jens P Bankstahl"

62 Publications

Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length.

Geroscience 2021 Jan 31. Epub 2021 Jan 31.

Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Straße 1, 30625, Hannover, Germany.

Ageing provokes a plethora of molecular, cellular and physiological deteriorations, including heart failure, neurodegeneration, metabolic maladaptation, telomere attrition and hair loss. Interestingly, on the molecular level, the capacity to induce autophagy, a cellular recycling and cleaning process, declines with age across a large spectrum of model organisms and is thought to be responsible for a subset of age-induced changes. Here, we show that a 6-month administration of the natural autophagy inducer spermidine in the drinking water to aged mice is sufficient to significantly attenuate distinct age-associated phenotypes. These include modulation of brain glucose metabolism, suppression of distinct cardiac inflammation parameters, decreased number of pathological sights in kidney and liver and decrease of age-induced hair loss. Interestingly, spermidine-mediated age protection was associated with decreased telomere attrition, arguing in favour of a novel cellular mechanism behind the anti-ageing effects of spermidine administration.
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http://dx.doi.org/10.1007/s11357-020-00310-0DOI Listing
January 2021

TSPO PET Identifies Different Anti-inflammatory Minocycline Treatment Response in Two Rodent Models of Epileptogenesis.

Neurotherapeutics 2020 07;17(3):1228-1238

Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany.

Epileptogenesis-associated brain inflammation might be a promising target to prevent or attenuate epileptogenesis. Positron emission tomography (PET) imaging targeting the translocator protein (TSPO) was applied here to quantify effects of different dosing regimens of the anti-inflammatory drug minocycline during the latent phase in two rodent models of epileptogenesis. After induction of epileptogenesis by status epilepticus (SE), rats were treated with minocycline for 7 days (25 or 50 mg/kg) and mice for 5 or 10 days (50 or 100 mg/kg). All animals were subjected to scans at 1 and 2 weeks post-SE. Radiotracer distribution was analyzed and statistical parametric mapping (SPM) was performed, as well as histological analysis of astroglial activation and neuronal cell loss. Atlas-based analysis of [F]GE180 PET in rats revealed a dose-dependent regional decrease of TSPO expression at 2 weeks post-SE. Results of SPM analysis depicted a treatment effect already at 1 week post-SE in rats treated with the higher minocycline dose. In mice, TSPO PET imaging did not reveal any treatment effects whereas histology identified only a treatment-related reduction in dispersion of dentate gyrus neurons. TSPO PET served as an auspicious tool for temporal monitoring and quantification of anti-inflammatory effects during epileptogenesis. Importantly, the findings underline the need to applying more than one animal model to avoid missing treatment effects. For future studies, the setup is ready to be applied in combination with seizure monitoring to investigate the relationship between individual early treatment response and disease outcome.
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http://dx.doi.org/10.1007/s13311-020-00834-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609777PMC
July 2020

Proof-of-concept that network pharmacology is effective to modify development of acquired temporal lobe epilepsy.

Neurobiol Dis 2020 02 1;134:104664. Epub 2019 Nov 1.

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, 30559 Hannover, Germany; Center for Systems Neuroscience, 30559 Hannover, Germany. Electronic address:

Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed network-based approaches to prevent epileptogenesis. For proof of concept we combined two drugs (levetiracetam and topiramate) for which in silico analysis of drug-protein interaction networks indicated a synergistic effect on a large functional network of epilepsy-relevant proteins. Using the intrahippocampal kainate mouse model of temporal lobe epilepsy, the drug combination was administered during the latent period before onset of spontaneous recurrent seizures (SRS). When SRS were periodically recorded by video-EEG monitoring after termination of treatment, a significant decrease in incidence and frequency of SRS was determined, indicating antiepileptogenic efficacy. Such efficacy was not observed following single drug treatment. Furthermore, a combination of levetiracetam and phenobarbital, for which in silico analysis of drug-protein interaction networks did not indicate any significant drug-drug interaction, was not effective to modify development of epilepsy. Surprisingly, the promising antiepileptogenic effect of the levetiracetam/topiramate combination was obtained in the absence of any significant neuroprotective or anti-inflammatory effects as indicated by multimodal brain imaging and histopathology. High throughput RNA-sequencing (RNA-seq) of the ipsilateral hippocampus of mice treated with the levetiracetam/topiramate combination showed that several genes that have been linked previously to epileptogenesis, were significantly differentially expressed, providing interesting entry points for future mechanistic studies. Overall, we have discovered a novel combination treatment with promise for prevention of epilepsy.
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http://dx.doi.org/10.1016/j.nbd.2019.104664DOI Listing
February 2020

Ex vivo characterization of neuroinflammatory and neuroreceptor changes during epileptogenesis using candidate positron emission tomography biomarkers.

Epilepsia 2019 11 1;60(11):2325-2333. Epub 2019 Oct 1.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.

Objective: Identification of patients at risk of developing epilepsy before the first spontaneous seizure may promote the development of preventive treatment providing opportunity to stop or slow down the disease.

Methods: As development of novel radiotracers and on-site setup of existing radiotracers is highly time-consuming and expensive, we used dual-centre in vitro autoradiography as an approach to characterize the potential of innovative radiotracers in the context of epilepsy development. Using brain slices from the same group of rats, we aimed to characterise the evolution of neuroinflammation and expression of inhibitory and excitatory neuroreceptors during epileptogenesis using translational positron emission tomography (PET) tracers; F-flumazenil ( F-FMZ; GABA receptor), F-FPEB (metabotropic glutamate receptor 5; mGluR5), F-flutriciclamide (translocator protein; TSPO, microglia activation) and F-deprenyl (monoamine oxidase B, astroglia activation). Autoradiography images from selected time points after pilocarpine-induced status epilepticus (SE; baseline, 24 and 48 hours, 5, 10 and 15 days and 6 and 12-14 weeks after SE) were normalized to a calibration curve, co-registered to an MRI-based 2D region-of-interest atlas, and activity concentration (Bq/mm ) was calculated.

Results: In epileptogenesis-associated brain regions, F-FMZ and F-FPEB showed an early decrease after SE. F-FMZ decrease was maintained in the latent phase and further reduced in the chronic epileptic animals, while F-FPEB signal recovered from day 10, reaching baseline levels in chronic epilepsy. F-flutriciclamide showed an increase of activated microglia at 24 hours after SE, peaking at 5-15 days and decreasing during the chronic phase. On the other hand, F-deprenyl autoradiography showed late astrogliosis, peaking in the chronic phase.

Significance: Autoradiography revealed different evolution of the selected targets during epileptogenesis. Our results suggest an advantage of combined imaging of inter-related targets like glutamate and GABA receptors, or microglia and astrocyte activation, in order to identify important interactions, especially when using PET imaging for the evaluation of novel treatments.
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http://dx.doi.org/10.1111/epi.16353DOI Listing
November 2019

Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis.

Haematologica 2020 04 9;105(4):1147-1157. Epub 2019 Jul 9.

Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany

Hereditary pulmonary alveolar proteinosis due to GM-CSF receptor deficiency (herPAP) constitutes a life-threatening lung disease characterized by alveolar deposition of surfactant protein secondary to defective alveolar macrophage function. As current therapeutic options are primarily symptomatic, we have explored the potential of hematopoietic stem cell-based gene therapy. Using mice, a model closely reflecting the human herPAP disease phenotype, we here demonstrate robust pulmonary engraftment of an alveolar macrophage population following intravenous transplantation of lentivirally corrected hematopoietic stem and progenitor cells. Engraftment was associated with marked improvement of critical herPAP disease parameters, including bronchoalveolar fluid protein, cholesterol and cytokine levels, pulmonary density on computed tomography scans, pulmonary deposition of Periodic Acid-Schiff material as well as respiratory mechanics. These effects were stable for at least nine months. With respect to engraftment and alveolar macrophage differentiation kinetics, we demonstrate the rapid development of CD11c/SiglecF cells in the lungs from a CD11c/SiglecF progenitor population within four weeks after transplantation. Based on these data, we suggest hematopoietic stem cell-based gene therapy as an effective and cause-directed treatment approach for herPAP.
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http://dx.doi.org/10.3324/haematol.2018.214866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109724PMC
April 2020

Anesthesia and Preconditioning Induced Changes in Mouse Brain [F] FDG Uptake and Kinetics.

Mol Imaging Biol 2019 12;21(6):1089-1096

Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Purpose: 2-Deoxy-2-[F]fluoro-D-glucose ([F]FDG) has been widely used for imaging brain metabolism. Tracer injection in anesthetized animals is a prerequisite for performing dynamic positron emission tomography (PET) scanning. Since preconditioning, as well as anesthesia, has been described to potentially influence brain [F] FDG levels, this study evaluated how these variables globally and regionally affect both [F] FDG uptake and kinetics in murine brain.

Procedures: Sixty-minute dynamic [F] FDG PET scans were performed in adult male C57BL/6 mice anesthetized with isoflurane [control (in 100 % O), in medical air, in 100 % O + insulin pre-treatment, and in 100 % O after 18 h fasting], ketamine/xylazine, sevoflurane, and chloral hydrate. An additional group was scanned after awake uptake. Blood glucose levels were determined, and data was analyzed by comparing percent injected dose per cc tissue (%ID/cc) and glucose influx rate and metabolic rate (MRGlu) calculated by Patlak plot.

Results: Ketamine/xylazine and chloral hydrate anesthesia induced a lower whole-brain uptake of [F] FDG (2.86 ± 0.67 %ID/cc, p < 0.001; 4.25 ± 0.28 %ID/cc, p = 0.0179, respectively) compared to isoflurane anesthesia (5.04 ± 0.19 %ID/cc). In addition, protocols affected differently distribution of [F] FDG uptake in brain regions. Ketamine/xylazine reduced [F] FDG influx rate in murine brain (0.0135 ± 0.0009 vs 0.0247 ± 0.0014 ml/g/min; p < 0.005) and chloral hydrate increased MRGlu (66.72 ± 3.75 vs 41.55 ± 3.06 μmol/min/100 ml; p < 0.01) compared to isoflurane. Insulin-pretreated animals showed a higher influx rate (0.0477 ± 0.0101 ml/min/g; p < 0.05) but a reduced MRGlu (21.92 ± 3.12 μmol/min/100 ml; p < 0.01). Blood glucose levels were negatively correlated to [F] FDG uptake and influx rate, but positively correlated to MRGlu.

Conclusions: Choice of anesthesia and pre-conditioning affect not only [F] FDG uptake but also kinetics and regional distribution in the mouse brain. Both anesthesia and pre-conditioning should be carefully considered in the interpretation of [F] FDG studies due to its great influence on the uptake and distribution of the tracer along the brain regions.
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http://dx.doi.org/10.1007/s11307-019-01314-9DOI Listing
December 2019

Reproducibility and Comparability of Preclinical PET Imaging Data: A Multicenter Small-Animal PET Study.

J Nucl Med 2019 10 8;60(10):1483-1491. Epub 2019 Mar 8.

Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard-Karls University Tübingen, Tübingen, Germany.

The standardization of preclinical imaging is a key factor to ensure the reliability, reproducibility, validity, and translatability of preclinical data. Preclinical standardization has been slowly progressing in recent years and has mainly been performed within a single institution, whereas little has been done in regards to multicenter standardization between facilities. This study aimed to investigate the comparability among preclinical imaging facilities in terms of PET data acquisition and analysis. In the first step, basic PET scans were obtained in 4 different preclinical imaging facilities to compare their standard imaging protocol for F-FDG. In the second step, the influence of the personnel performing the experiments and the experimental equipment used in the experiment were compared. In the third step, the influence of the image analysis on the reproducibility and comparability of the acquired data was determined. Distinct differences in the uptake behavior of the 4 standard imaging protocols were determined for the investigated organs (brain, left ventricle, liver, and muscle) due to different animal handling procedures before and during the scans (e.g., fasting vs. nonfasting, glucose levels, temperature regulation vs. constant temperature warming). Significant differences in the uptake behavior in the brain were detected when the same imaging protocol was used but executed by different personnel and using different experimental animal handling equipment. An influence of the person analyzing the data was detected for most of the organs, when the volumes of interest were manually drawn by the investigators. Coregistration of the PET to an MR image and drawing the volume of interest based on anatomic information yielded reproducible results among investigators. It has been demonstrated that there is a huge demand for standardization among multiple institutions.
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http://dx.doi.org/10.2967/jnumed.118.221994DOI Listing
October 2019

Multimodal and Multiscale Analysis Reveals Distinct Vascular, Metabolic and Inflammatory Components of the Tissue Response to Limb Ischemia.

Theranostics 2019 1;9(1):152-166. Epub 2019 Jan 1.

Vascular Medicine Research, Dept. of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany.

Ischemia triggers a complex tissue response involving vascular, metabolic and inflammatory changes.

Methods: We combined hybrid SPECT/CT or PET/CT nuclear imaging studies of perfusion, metabolism and inflammation with multicolor flow cytometry-based cell population analysis to comprehensively analyze the ischemic tissue response and to elucidate the cellular substrate of noninvasive molecular imaging techniques in a mouse model of hind limb ischemia.

Results: Comparative analysis of tissue perfusion with [Tc]-Sestamibi and arterial influx with [Tc]-labeled albumin microspheres by SPECT/CT revealed a distinct pattern of response to vascular occlusion: an early ischemic period of matched suppression of tissue perfusion and arterial influx, a subacute ischemic period of normalized arterial influx but impaired tissue perfusion, and a protracted post-ischemic period of hyperdynamic arterial and normalized tissue perfusion, indicating coordination of macrovascular and microvascular responses. In addition, the subacute period showed increased glucose uptake by [F]-FDG PET/CT scanning as the metabolic response of viable tissue to hypoperfusion. This was associated with robust macrophage infiltration by flow cytometry, and glucose uptake studies identified macrophages as major contributors to glucose utilization in ischemic tissue. Furthermore, imaging with the TSPO ligand [F]-GE180 showed a peaked response during the subacute phase due to preferential labeling of monocytes and macrophages, while imaging with [Ga]-RGD, an integrin ligand, showed prolonged post-ischemic upregulation, which was attributed to labeling of macrophages and endothelial cells by flow cytometry.

Conclusion: Combined nuclear imaging and cell population analysis reveals distinct components of the ischemic tissue response and associated cell subsets, which could be targeted for therapeutic interventions.
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http://dx.doi.org/10.7150/thno.27175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332799PMC
December 2019

Divergent metabolic substrate utilization in brain during epileptogenesis precedes chronic hypometabolism.

J Cereb Blood Flow Metab 2020 01 30;40(1):204-213. Epub 2018 Oct 30.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.

Alterations in metabolism during epileptogenesis may be a therapy target. Recently, an increase in amino acid transport into the brain was proposed to play a role in epileptogenesis. We aimed to characterize alterations of substrate utilization during epileptogenesis and in chronic epilepsy. The lithium-pilocarpine post status epilepticus (SE) rat model was used. We performed longitudinal O-(2-[(18)F]fluoroethyl)-l-tyrosine (F-FET) and F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) and calculated F-FET volume of distribution (V) and F-FDG uptake. Correlation analyses were performed with translocator protein-PET defined neuroinflammation from previously acquired data. We found reduced F-FET V at 48 h after SE (amygdala: -30.2%,  = 0.014), whereas F-FDG showed increased glucose uptake 4 and 24 h after SE (hippocampus: + 43.6% and +42.5%, respectively;  < 0.001) returning to baseline levels thereafter. In chronic epileptic animals, we found a reduction in F-FET and F-FDG in the hippocampus. No correlation was found for F-FET or F-FDG to microglial activation at seven days post SE. Whereas metabolic alterations do not reflect higher metabolism associated to activated microglia, they might be partially driven by chronic neuronal loss. However, both metabolisms diverge during early epileptogenesis, pointing to amino acid turnover as a possible biomarker and/or therapeutic target for epileptogenesis.
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http://dx.doi.org/10.1177/0271678X18809886DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928550PMC
January 2020

Visualization of the auditory pathway in rats with 18F-FDG PET activation studies based on different auditory stimuli and reference conditions including cochlea ablation.

PLoS One 2018 2;13(10):e0205044. Epub 2018 Oct 2.

Cluster of Excellence Hearing4all, Hannover Medical School, Hannover, Germany.

Activation studies with positron emission tomography (PET) in auditory implant users explained some of the mechanisms underlying the variability of achieved speech comprehension. Since future developments of auditory implants will include studies in rodents, we aimed to inversely translate functional PET imaging to rats. In normal hearing rats, activity in auditory and non-auditory regions was studied using 18F-fluorodeoxyglucose (18F-FDG) PET with 3 different acoustic conditions: sound attenuated laboratory background, continuous white noise and rippled noise. Additionally, bilateral cochlea ablated animals were scanned. 3D image data were transferred into a stereotaxic standard space and evaluated using volume of interest (VOI) analyses and statistical parametric mapping (SPM). In normal hearing rats alongside the auditory pathway consistent activations of the nucleus cochlearis (NC), olivary complex (OC) and inferior colliculus (IC) were seen comparing stimuli with background. In this respect, no increased activation could be detected in the auditory cortex (AC), which even showed deactivation with white noise stimulation. Nevertheless, higher activity in the AC in normal hearing rats was observed for all 3 auditory conditions against the cochlea ablated status. Vice versa, in ablated status activity in the olfactory nucleus (ON) was higher compared to all auditory conditions in normal hearing rats. Our results indicate that activations can be demonstrated in normal hearing animals based on 18F-FDG PET in nuclei along the central auditory pathway with different types of noise stimuli. However, in the AC missing activation with respect to the background advises the need for more rigorous background noise attenuation for non-invasive reference conditions. Finally, our data suggest cross-modal activation of the olfactory system following cochlea ablation-underlining, that 18F-FDG PET appears to be well suited to study plasticity in rat models for cochlear implantation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205044PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168174PMC
March 2019

Immunohistochemical detection of chemokine receptor 4 expression in chronic osteomyelitis confirms specific uptake in 68Ga-Pentixafor-PET/CT.

Nuklearmedizin 2018 Sep 28;57(5):198-203. Epub 2018 Sep 28.

Previous findings of our group showed the chemokine receptor CXCR4 as a suitable target in PET/CT-imaging of axial bone infections, early postoperative osteomyelitis and periprosthetic infections. The aim of this study was to verify specific uptake of Ga-Pentixafor in chronic osteomyelitis.

Methods: 29 consecutive patients who underwent Ga-Pentixafor-PET/CT with clinically suspected osteomyelitis were evaluated retrospectively. Bone tissues of 6 patients were available and evaluated by immunohistochemical staining for CXCR4 and autoradiography with Ga-Pentixafor. Staining was performed with an anti-CXCR4 antibody. In order to detect lymphocytic infiltration and CXCR4-expressing lymphocytes double immunofluorescence with an anti-CD3 and anti-CXCR4 antibody was performed.

Results: Ga-Pentixafor-PET/ CT was true positive in 16 and true negative in 13 patients. In available bone tissue samples, immunohistochemical staining of CXCR4 expression and autoradiography with Ga-Pentixafor was highly positive. Double immunofluorescence was able to detect CXCR4-expressing T-lymphocytes within all bone samples while a control sample of noninfected tibial bone was negative for CXCR4.

Conclusion: Ga-Pentixafor-PET/CT specifically shows CXCR4-expressing immune cells in chronic osteomyelitis and is therefore a suitable method for imaging chronic infection of the skeleton.Der Chemokinrezeptor CXCR4 konnte in einer Pilotstudie unserer Arbeitsgruppe als geeignete Zielstruktur zur PET/CT-Bildgebung von frühen postoperativen und periprothetischen Osteomyelitiden sowie Osteomyelitiden im Stammskelett identifiziert werden. In dieser Studie haben wir untersucht, ob Ga-Pentixafor spezifisch CXCR4-exprimierende Entzündungszellen in einer chronischen Osteomyelitis darstellen kann.

Methoden: Es erfolgte eine retrospektive Auswertung von 29 Patienten mit klinischem Verdacht einer chronischen Osteomyelitis, die mittels Ga-Pentixafor-PET/CT untersucht wurden. Hiervon lagen uns in 6 Fällen Knochengewebe zur immunhistochemischen und autoradiographischen Evaluation vor. Die Immunhistochemie wurde mit einem anti-CXCR4 Antikörper durchgeführt. Des Weiteren wurden ein anti-CD3 und der anti-CXCR4-Antikörper zur Detektion CXCR4-exprimierender Lymphozyten am Ort der Entzündung mittels Doppel- Immunfluoreszenz verwendet.

Ergebnisse: Die Ga-Pentixafor-PET/CT war bei 16 Patienten richtig positiv und bei 13 Patienten richtig negativ. Die Färbungen der verfügbaren Knochenpräparate waren sowohl in der Immunhistochemie als auch in der Autoradiographie deutlich positiv. In der Immunfluoreszenz konnten zudem CXCR4-exprimierende Lymphozyten am Ort der Entzündung in allen Proben nachgewiesen werden. Die Kontrolle eines Präparats einer nicht infizierten distalen Tibia zeigte dagegen keine CXCR4-oder CD3-Expression.

Fazit: Mit der Ga-Pentixafor-PET/CT können spezifisch CXCR4-exprimierende Lymphozyten am Ort der Entzündung nachgewiesen werden. Die Ga-Pentixafor-PET/CT stellt eine geeignete Methode in der Diagnostik chronischer Osteomyeltiden dar.
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http://dx.doi.org/10.3413/Nukmed-0971-18-04DOI Listing
September 2018

iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice.

Stem Cell Reports 2018 09 9;11(3):696-710. Epub 2018 Aug 9.

Research Group Reprogramming and Gene Therapy, Hannover Medical School (MHH), Hannover, Germany; Institute of Experimental Hematology, MHH, Hannover Medical School, Carl-Neuberg-Str.1, 30625 Hannover, Germany; Cluster of Excellence REBIRTH, MHH, Hannover, Germany.

Induced pluripotent stem cell (iPSC)-derived hematopoietic cells represent a highly attractive source for cell and gene therapy. Given the longevity, plasticity, and self-renewal potential of distinct macrophage subpopulations, iPSC-derived macrophages (iPSC-Mφ) appear of particular interest in this context. We here evaluated the airway residence, plasticity, and therapeutic efficacy of iPSC-Mφ in a murine model of hereditary pulmonary alveolar proteinosis (herPAP). We demonstrate that single pulmonary macrophage transplantation (PMT) of 2.5-4 × 10 iPSC-Mφ yields efficient airway residence with conversion of iPSC-Mφ to an alveolar macrophage (AMφ) phenotype characterized by a distinct surface marker and gene expression profile within 2 months. Moreover, PMT significantly improves alveolar protein deposition and other critical herPAP disease parameters. Thus, our data indicate iPSC-Mφ as a source of functional macrophages displaying substantial plasticity and therapeutic potential that upon pulmonary transplantation will integrate into the lung microenvironment, adopt an AMφ phenotype and gene expression pattern, and profoundly ameliorate pulmonary disease phenotypes.
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http://dx.doi.org/10.1016/j.stemcr.2018.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135208PMC
September 2018

Targeting Chemokine Receptor CXCR4 and Translocator Protein for Characterization of High-Risk Plaque in Carotid Stenosis Ex Vivo.

Stroke 2018 08;49(8):1988-1991

From the Department of Neurology (G.M.G., H.W., K.W.).

Background and Purpose- This pilot study aims to demonstrate the feasibility of targeting molecular characteristics of high-risk atherosclerotic plaque in symptomatic and asymptomatic carotid stenosis (CS), that is, upregulation of the translocator protein (TSPO) and the chemokine receptor type 4 (CXCR4), by means of molecular imaging. Methods- In a translational setting, specimens of carotid plaques of patients with symptomatic and asymptomatic CS obtained by carotid endarterectomy were analyzed for the presence of TSPO and CXCR4 by autoradiography, using the positron emission tomography tracers F-GE180 and Ga-Pentixafor and evaluated by histopathology. In addition, Ga-Pentixafor positron emission tomography/computed tomography was performed in a patient with high-grade CS. Results- Distinct patterns of upregulation of TSPO (F-GE180 uptake) and CXCR4 (Ga-Pentixafor uptake) were identified in carotid plaque by autoradiography. The spatial distribution was associated with specific histological hallmarks that are established features of high-risk plaque: TSPO upregulation correlated with activated macrophages infiltration, whereas CXCR4 upregulation also corresponded to areas of intraplaque hemorrhage. Ga-Pentixafor uptake was significantly higher in plaques of symptomatic compared with asymptomatic CS. Clinical positron emission tomography revealed marked Ga-Pentixafor uptake in carotid plaque of a patient with high-grade CS. Conclusions- Clinical imaging of molecular signatures of high-risk atherosclerotic plaque is feasible and may become a promising diagnostic tool for comprehensive characterization of carotid disease. This methodology provides a platform for future studies targeting carotid plaque.
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http://dx.doi.org/10.1161/STROKEAHA.118.021070DOI Listing
August 2018

Imaging of chemokine receptor CXCR4 expression in culprit and nonculprit coronary atherosclerotic plaque using motion-corrected [Ga]pentixafor PET/CT.

Eur J Nucl Med Mol Imaging 2018 10 3;45(11):1934-1944. Epub 2018 Jul 3.

Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.

Purpose: The chemokine receptor CXCR4 is a promising target for molecular imaging of CXCR4 cell types, e.g. inflammatory cells, in cardiovascular diseases. We speculated that a specific CXCR4 ligand, [Ga]pentixafor, along with novel techniques for motion correction, would facilitate the in vivo characterization of CXCR4 expression in small culprit and nonculprit coronary atherosclerotic lesions after acute myocardial infarction by motion-corrected targeted PET/CT.

Methods: CXCR4 expression was analysed ex vivo in separately obtained arterial wall specimens. [Ga]Pentixafor PET/CT was performed in 37 patients after stent-based reperfusion for a first acute ST-segment elevation myocardial infarction. List-mode PET data were reconstructed to five different datasets using cardiac and/or respiratory gating. Guided by CT for localization, the PET signals of culprit and various groups of nonculprit coronary lesions were analysed and compared.

Results: Ex vivo, CXCR4 was upregulated in atherosclerotic lesions, and mainly colocalized with CD68 inflammatory cells. In vivo, elevated CXCR4 expression was detected in culprit and nonculprit lesions, and the strongest CXCR4 PET signal (median SUV 1.96; interquartile range, IQR, 1.55-2.31) was observed in culprit coronary artery lesions. Stented nonculprit lesions (median SUV 1.45, IQR 1.23-1.88; P = 0.048) and hot spots in naive remote coronary segments (median SUV 1.34, IQR 1.23-1.74; P = 0.0005) showed significantly lower levels of CXCR4 expression. Dual cardiac/respiratory gating provided the strongest CXCR4 PET signal and the highest lesion detectability.

Conclusion: We demonstrated the basic feasibility of motion-corrected targeted PET/CT imaging of CXCR4 expression in coronary artery lesions, which was triggered by vessel wall inflammation but also by stent-induced injury. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of coronary atherosclerotic plaque.
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http://dx.doi.org/10.1007/s00259-018-4076-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6132552PMC
October 2018

Blood-Brain Barrier Leakage during Early Epileptogenesis Is Associated with Rapid Remodeling of the Neurovascular Unit.

eNeuro 2018 May-Jun;5(3). Epub 2018 May 30.

Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstr. 19, Leipzig, 04103, Germany.

Increased permeability of the blood-brain barrier (BBB) following cerebral injury results in regional extravasation of plasma proteins and can critically contribute to the pathogenesis of epilepsy. Here, we comprehensively explore the spatiotemporal evolution of a main extravasation component, albumin, and illuminate associated responses of the neurovascular unit (NVU) contributing to early epileptogenic neuropathology. We applied translational MR imaging and complementary immunohistochemical analyses in the widely used rat pilocarpine post-status epilepticus (SE) model. The observed rapid BBB leakage affected major epileptogenesis-associated brain regions, peaked between 1 and 2 d post-SE, and rapidly declined thereafter, accompanied by cerebral edema generally following the same time course. At peak of BBB leakage, serum albumin colocalized with NVU constituents, such as vascular components, neurons, and brain immune cells. Surprisingly, astroglial markers did not colocalize with albumin, and aquaporin-4 (AQP4) was clearly reduced in areas of leaky BBB, indicating a severe disturbance of astrocyte-mediated endothelial-neuronal coupling. In addition, a distinct adaptive reorganization process of the NVU vasculature apparently takes place at sites of albumin presence, substantiated by reduced immunoreactivity of endothelial and changes in vascular basement membrane markers. Taken together, degenerative events at the level of the NVU, affecting vessels, astrocytes, and neurons, seem to outweigh reconstructive processes. Considering the rapidly occurring BBB leakage and subsequent impairment of the NVU, our data support the necessity of a prompt BBB-restoring treatment as one component of rational therapeutic intervention to prevent epileptogenesis and the development of other detrimental sequelae of SE.
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http://dx.doi.org/10.1523/ENEURO.0123-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975718PMC
January 2019

[ F]GE180 positron emission tomographic imaging indicates a potential double-hit insult in the intrahippocampal kainate mouse model of temporal lobe epilepsy.

Epilepsia 2018 03 24;59(3):617-626. Epub 2018 Jan 24.

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany.

Objective: Accumulating evidence suggests that brain inflammation, elicited by epileptogenic insults, is involved in epilepsy development. Noninvasive nuclear imaging of brain inflammation in animal models of epileptogenesis represents a diagnostic in vivo approach with potential for direct translation into the clinic. Here, we investigated up-regulation of the translocator protein (TSPO) indicative of microglial activation by serial [ F]GE180 positron emission tomographic (PET) imaging in a mouse model of temporal lobe epilepsy.

Methods: As epileptogenic insult, a status epilepticus (SE) was induced in mice by intrahippocampal injection of kainate. Post-SE mice injected with kainate and sham-injected mice were subjected to [ F]GE180 PET scans before SE and at 2 days, 5-7 days, 2 weeks, 3 weeks, 7 weeks, and 14 weeks postinsult. For data evaluation, brain regions ipsilateral and contralateral to the injection site were outlined by coregistration with a standard mouse brain atlas, and percentage of injected dose per cubic centimeter was calculated. In addition, a statistical parametric mapping analysis, comparing post-SE mice to baseline, sham mice to baseline, and post-SE to sham mice was performed.

Results: Following SE, elevations in [ F]GE180 uptake were most prominent in the ipsilateral hippocampus, occurring between 2 days and at least 7 weeks after SE, with a peak at 5-7 days after SE. In the contralateral hippocampus and other epilepsy-associated brain regions, increased tracer uptake was observed with a similar time profile but to a lesser extent. Moderate enhancement of tracer uptake was also evident in mice after sham surgery.

Significance: TSPO in vivo imaging reliably detects brain inflammation during epileptogenesis. These inflammatory processes most prominently affect the hippocampus ipsilateral to the injection site. Inflammation induced by the traumatic insult associated with surgery synergistically contributes to total brain inflammation and may also contribute to epileptogenesis. The revealed time course of neuroinflammation will help to identify appropriate time points for anti-inflammatory, potentially antiepileptogenic treatment.
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http://dx.doi.org/10.1111/epi.14009DOI Listing
March 2018

Myocardial Inflammation Predicts Remodeling and Neuroinflammation After Myocardial Infarction.

J Am Coll Cardiol 2018 01;71(3):263-275

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany. Electronic address:

Background: The local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration.

Objectives: This study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis.

Methods: After coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9).

Results: Infarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68 inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (r = -0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls.

Conclusions: The brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes.
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http://dx.doi.org/10.1016/j.jacc.2017.11.024DOI Listing
January 2018

Recent Advances in Radiotracer Imaging Hold Potential for Future Refined Evaluation of Epilepsy in Veterinary Neurology.

Front Vet Sci 2017 13;4:218. Epub 2017 Dec 13.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.

Non-invasive nuclear imaging by positron emission tomography and single photon emission computed tomography has significantly contributed to epileptic focus localization in human neurology for several decades now. Offering functional insight into brain alterations, it is also of particular relevance for epilepsy research. Access to these techniques for veterinary medicine is becoming more and more relevant and has already resulted in first studies in canine patients. In view of the substantial proportion of drug-refractory epileptic dogs and cats, image-guided epileptic focus localization will be a prerequisite for selection of patients for surgical focus resection. Moreover, radiotracer imaging holds potential for a better understanding of the pathophysiology of underlying epilepsy syndromes as well as to forecast disease risk after epileptogenic brain insults. Importantly, recent advances in epilepsy research demonstrate the suitability and value of several novel radiotracers for non-invasive assessment of neuroinflammation, blood-brain barrier alterations, and neurotransmitter systems. It is desirable that veterinary epilepsy patients will also benefit from these promising developments in the medium term. This paper reviews the current use of radiotracer imaging in the veterinary epilepsy patient and suggests possible future directions for the technique.
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http://dx.doi.org/10.3389/fvets.2017.00218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733338PMC
December 2017

Metyrapone prevents acute glucose hypermetabolism and short-term brain damage induced by intrahippocampal administration of 4-aminopyridine in rats.

Neurochem Int 2018 02 2;113:92-106. Epub 2017 Dec 2.

Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII n° 1, 28040 Madrid, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto Tecnológico PET, C/ Manuel Bartolomé Cossío n° 10, 28040 Madrid, Spain.

Intracerebral administration of the potassium channel blocker 4-aminopyridine (4-AP) triggers neuronal depolarization and intense acute seizure activity followed by neuronal damage. We have recently shown that, in the lithium-pilocarpine rat model of status epilepticus (SE), a single administration of metyrapone, an inhibitor of the 11β-hydroxylase enzyme, had protective properties of preventive nature against signs of brain damage and neuroinflammation. Herein, our aim was to investigate to which extent, pretreatment with metyrapone (150 mg/kg, i.p.) was also able to prevent eventual changes in the acute brain metabolism and short-term neuronal damage induced by intrahippocampal injection of 4-AP (7 μg/5 μl). To this end, regional brain metabolism was assessed by 2-deoxy-2-[F]fluoro-d-glucose ([F]FDG) positron emission tomography (PET) during the ictal period. Three days later, markers of neuronal death and hippocampal integrity and apoptosis (Nissl staining, NeuN and active caspase-3 immunohistochemistry), neurodegeneration (Fluoro-Jade C labeling), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and microglia-mediated neuroinflammation (in vitro [F]GE180 autoradiography) were evaluated. 4-AP administration acutely triggered marked brain hypermetabolism within and around the site of injection as well as short-term signs of brain damage and inflammation. Most important, metyrapone pretreatment was able to reduce ictal hypermetabolism as well as all the markers of brain damage except microglia-mediated neuroinflammation. Overall, our study corroborates the neuroprotective effects of metyrapone against multiple signs of brain damage caused by seizures triggered by 4-AP. Ultimately, our data add up to the consistent protective effect of metyrapone pretreatment reported in other models of neurological disorders of different etiology.
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http://dx.doi.org/10.1016/j.neuint.2017.11.018DOI Listing
February 2018

Neuroinflammation imaging markers for epileptogenesis.

Epilepsia 2017 07;58 Suppl 3:11-19

Departments of Pediatrics, Anatomy/Neurobiology, Neurology, University of California-Irvine, Irvine, California, U.S.A.

Epilepsy can be a devastating disorder. In addition to debilitating seizures, epilepsy can cause cognitive and emotional problems with reduced quality of life. Therefore, the major aim is to prevent the disorder in the first place: identify, detect, and reverse the processes responsible for its onset, and monitor and treat its progression. Epilepsy often occurs following a latent period of months to years (epileptogenesis) as a consequence of a brain insult, such as head trauma, stroke, or status epilepticus. Although this latent period clearly represents a therapeutic window, we are not able to stratify patients at risk for long-term epilepsy, which is prerequisite for preventative clinical trials. Moreover, because of the length of the latent period, an early biomarker for treatment response would be of high value. Finally, mechanistic biomarkers of epileptogenesis may provide more profound insight in the process of disease development.
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http://dx.doi.org/10.1111/epi.13778DOI Listing
July 2017

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression.

JCI Insight 2017 May 18;2(10). Epub 2017 May 18.

Division of Molecular Cardiology, Department of Cardiology and Angiology, and.

Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme. As tumor cells consume glucose in an insulin-independent manner, they shift glucose away from cardiomyocytes. Since cardiomyocytes in both tumor models remained insulin responsive, low-dose insulin supplementation by subcutaneous implantation of insulin-releasing pellets improved cardiac glucose uptake, atrophy, and function, with no adverse side effects. In addition, by redirecting glucose to the heart in addition to other organs, the systemic insulin treatment lowered glucose usage by the tumor and thereby decreased tumor growth and volume. Insulin corrected the cancer-induced reduction in cardiac Akt activation and the subsequent overactivation of the proteasome and autophagy. Thus, cancer-induced systemic insulin depletion contributes to cardiac wasting and failure and may promote tumor growth. Low-dose insulin supplementation attenuates these processes and may be supportive in cardio-oncologic treatment concepts.
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http://dx.doi.org/10.1172/jci.insight.93098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436547PMC
May 2017

Metyrapone prevents brain damage induced by status epilepticus in the rat lithium-pilocarpine model.

Neuropharmacology 2017 Sep 8;123:261-273. Epub 2017 May 8.

Unidad de Cartografía Cerebral, Instituto Pluridisciplinar, Universidad Complutense de Madrid, Paseo Juan XXIII nº 1, 28040 Madrid, Spain; Departamento de Fisiología, Facultad de Medicina, Universidad Complutense de Madrid, Plaza Ramón y Cajal s/n, 28040 Madrid, Spain; Instituto Tecnológico PET, C/ Manuel Bartolomé Cossío nº 10, 28040 Madrid, Spain.

The status epilepticus (SE) induced by lithium-pilocarpine is a well characterized rodent model of the human temporal lobe epilepsy (TLE) which is accompanied by severe brain damage. Stress and glucocorticoids markedly contribute to exacerbate neuronal damage induced by seizures but the underlying mechanisms are poorly understood. Herein we sought to investigate whether a single administration of metyrapone (150 mg/kg, i.p.), an 11β-hydroxylase inhibitor, enzyme involved in the peripheral and central synthesis of corticosteroids, had neuroprotective properties in this model. Two experiments were carried out. In exp. 1, metyrapone was administered 3 h before pilocarpine injection whereas in exp. 2, metyrapone administration took place at the onset of the SE. In both experiments, 3 days after the insult, brain metabolism was assessed by in vivo 2-deoxy-2-[F]fluoro-d-glucose ([F]FDG) positron emission tomography (PET). Brains were processed for analyses of markers of hippocampal integrity (Nissl staining), neurodegeneration (Fluoro-Jade C), astrogliosis (glial fibrillary acidic protein (GFAP) immunohistochemistry) and, for a marker of activated microglia by in vitro autoradiography with the TSPO (18 kDa translocator protein) radioligand [F]GE180. The SE resulted in a consistent hypometabolism in hippocampus, cortex and striatum and neuronal damage, hippocampal neurodegeneration, neuronal death and gliosis. Interestingly, metyrapone had neuroprotective effects when administered before, but not after the insult. In summary, we conclude that metyrapone administration prior but not after the SE protected from brain damage induced by SE in the lithium-pilocarpine model. Therefore, it seems that the effect of metyrapone is preventive in nature and likely related to its antiseizure properties.
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http://dx.doi.org/10.1016/j.neuropharm.2017.05.007DOI Listing
September 2017

Preparation and Ga-radiolabeling of porous zirconia nanoparticle platform for PET/CT-imaging guided drug delivery.

J Pharm Biomed Anal 2017 Apr 18;137:146-150. Epub 2017 Jan 18.

Department of Nuclear Medicine, Hannover Medical School, Carl-Neuberg Str 1, 30627 Hannover, Germany.

This paper describes the preparation of gallium-68 (Ga) isotope labeled porous zirconia (ZrO) nanoparticle (NP) platform of nearly 100nm diameter and its first pharmacokinetic and biodistribution evaluation accomplished with a microPET/CT (μPet/CT) imaging system. Objectives of the investigations were to provide a nanoparticle platform which can be suitable for specific delivery of various therapeutic drugs using surface attached specific molecules as triggering agents, and at the same time, suitable for positron emission tomography (PET) tracing of the prospective drug delivery process. Radiolabeling was accomplished using DOTA bifunctional chelator. DOTA was successfully adsorbed onto the surface of nanoparticles, while the Ga-radiolabeling method proved to be simple and effective. In the course of biodistribution studies, the Ga-labeled DOTA-ZrNPs showed proper radiolabeling stability in their original suspension and in blood serum. μPet/CT imaging studies confirmed a RES-biodistribution profile indicating stable nano-sized labeled particles in vivo. Results proved that the new method offers the opportunity to examine further specifically targeted and drug payload carrier variants of zirconia NP systems using PET/CT imaging.
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http://dx.doi.org/10.1016/j.jpba.2017.01.028DOI Listing
April 2017

Common data elements and data management: Remedy to cure underpowered preclinical studies.

Epilepsy Res 2017 01 22;129:87-90. Epub 2016 Nov 22.

Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Electronic address:

Lack of translation of data obtained in preclinical trials to clinic has kindled researchers to develop new methodologies to increase the power and reproducibility of preclinical studies. One approach relates to harmonization of data collection and analysis, and has been used for a long time in clinical studies testing anti-seizure drugs. EPITARGET is a European Union FP7-funded research consortium composed of 18 partners from 9 countries. Its main research objective is to identify biomarkers and develop treatments for epileptogenesis. As the first step of harmonization of procedures between laboratories, EPITARGET established working groups for designing project-tailored common data elements (CDEs) and case report forms (CRFs) to be used in data collection and analysis. Eight major modules of CRFs were developed, presenting >1000 data points for each animal. EPITARGET presents the first single-project effort for harmonization of preclinical data collection and analysis in epilepsy research. EPITARGET is also anticipating the future challenges and requirements in a larger-scale preclinical harmonization of epilepsy studies, including training, data management expertise, cost, location, data safety and continuity of data repositories during and after funding period, and incentives motivating for the use of CDEs.
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http://dx.doi.org/10.1016/j.eplepsyres.2016.11.010DOI Listing
January 2017

Isoflurane prevents acquired epilepsy in rat models of temporal lobe epilepsy.

Ann Neurol 2016 12;80(6):896-908

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.

Objective: Acquired epilepsy is a devastating long-term risk of various brain insults, including trauma, stroke, infections, and status epilepticus (SE). There is no preventive treatment for patients at risk. Attributable to the complex alterations involved in epileptogenesis, it is likely that multitargeted approaches are required for epilepsy prevention. We report novel preclinical findings with isoflurane, which exerts various nonanesthetic effects that may be relevant for antiepileptogenesis.

Methods: The effects of isoflurane were investigated in two rat models of SE-induced epilepsy: intrahippocampal kainate and systemic administration of paraoxon. Isoflurane was either administered during (kainate) or after (paraoxon) induction of SE. Magnetic resonance imaging was used to assess blood-brain barrier (BBB) dysfunction. Positron emission tomography was used to visualize neuroinflammation. Long-term electrocorticographic recordings were used to monitor spontaneous recurrent seizures. Neuronal damage was assessed histologically.

Results: In the absence of isoflurane, spontaneous recurrent seizures were common in the majority of rats in both models. When isoflurane was administered during kainate injection, duration and severity of SE were not affected, but only few rats developed spontaneous recurrent seizures. A similar antiepileptogenic effect was found when paraoxon-treated rats were exposed to isoflurane after SE. Moreover, in the latter model, isoflurane prevented BBB dysfunction and neurodegeneration, whereas isoflurane reduced neuroinflammation in the kainate model.

Interpretation: Given that isoflurane is a widely used volatile anesthetic, and is used for inhalational long-term sedation in critically ill patients at risk to develop epilepsy, our findings hold a promising potential to be successfully translated into the clinic. Ann Neurol 2016;80:896-908.
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http://dx.doi.org/10.1002/ana.24804DOI Listing
December 2016

Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction.

Theranostics 2016 15;6(11):1768-79. Epub 2016 Jul 15.

1. Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany;

Acute tissue inflammation after myocardial infarction influences healing and remodeling and has been identified as a target for novel therapies. Molecular imaging holds promise for guidance of such therapies. The amino acid (11)C-methionine is a clinically approved agent which is thought to accumulate in macrophages, but not in healthy myocytes. We assessed the suitability of positron emission tomography (PET) with (11)C-methionine for imaging post-MI inflammation, from cell to mouse to man. Uptake assays demonstrated 7-fold higher (11)C-methionine uptake by polarized pro-inflammatory M1 macrophages over anti-inflammatory M2 subtypes (p<0.001). C57Bl/6 mice (n=27) underwent coronary artery ligation or no surgery. Serial (11)C-methionine PET was performed 3, 5 and 7d later. MI mice exhibited a perfusion defect in 32-50% of the left ventricle (LV). PET detected increased (11)C-methionine accumulation in the infarct territory at 3d (5.9±0.9%ID/g vs 4.7±0.9 in remote myocardium, and 2.6±0.5 in healthy mice; p<0.05 and <0.01 respectively), which declined by d7 post-MI (4.3±0.6 in infarct, 3.4±0.8 in remote; p=0.03 vs 3d, p=0.08 vs healthy). Increased (11)C-methionine uptake was associated with macrophage infiltration of damaged myocardium. Treatment with anti-integrin antibodies (anti-CD11a, -CD11b, -CD49d; 100µg) lowered macrophage content by 56% and (11)C-methionine uptake by 46% at 3d post-MI. A patient study at 3d after ST-elevation MI and early reperfusion confirmed elevated (11)C-methionine uptake in the hypoperfused myocardial region. Targeting of elevated amino acid metabolism in pro-inflammatory M1 macrophages enables PET imaging-derived demarcation of tissue inflammation after MI. (11)C-methionine-based molecular imaging may assist in the translation of novel image-guided, inflammation-targeted regenerative therapies.
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http://dx.doi.org/10.7150/thno.15929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997235PMC
October 2017

Multimodality imaging of blood-brain barrier impairment during epileptogenesis.

J Cereb Blood Flow Metab 2017 Jun 1;37(6):2049-2061. Epub 2016 Jan 1.

1 Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany.

Insult-associated blood-brain barrier leakage is strongly suggested to be a key step during epileptogenesis. In this study, we used three non-invasive translational imaging modalities, i.e. positron emission tomography, single photon emission computed tomography, and magnetic resonance imaging, to evaluate BBB leakage after an epileptogenic brain insult. Sprague-Dawley rats were scanned during early epileptogenesis initiated by status epilepticus. Positron emission tomography and single photon emission computed tomography scans were performed using the novel tracer [Ga]DTPA or [Tc]DTPA, respectively. Magnetic resonance imaging included T2 and post-contrast T1 sequence after infusion of Gd-DTPA, gadobutrol, or Gd-albumin. All modalities revealed increased blood-brain barrier permeability 48 h post status epilepticus, mainly in epileptogenesis-associated brain regions like hippocampus, piriform cortex, thalamus, or amygdala. In hippocampus, Gd-DTPA-enhanced T1 magnetic resonance imaging signal was increased by 199%, [Ga]DTPA positron emission tomography by 37%, and [Tc]DTPA single photon emission computed tomography by 56%. Imaging results were substantiated by histological detection of albumin extravasation. Comparison with quantitative positron emission tomography and single photon emission computed tomography shows that magnetic resonance imaging sequences successfully amplify the signal from a moderate amount of extravasated DTPA molecules, enabling sensitive detection of blood-brain barrier disturbance in epileptogenesis. Imaging of the disturbed blood-brain barrier will give further pathophysiologic insights, will help to stratify anti-epileptogenic treatment targeting blood-brain barrier integrity, and may serve as a prognostic biomarker.
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http://dx.doi.org/10.1177/0271678X16659672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464700PMC
June 2017

Advances in the development of biomarkers for epilepsy.

Lancet Neurol 2016 07;15(8):843-856

Laboratory for Experimental Epileptology and Cognition Research, Department of Epileptology, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. Electronic address:

Over 50 million people worldwide have epilepsy. In nearly 30% of these cases, epilepsy remains unsatisfactorily controlled despite the availability of over 20 antiepileptic drugs. Moreover, no treatments exist to prevent the development of epilepsy in those at risk, despite an increasing understanding of the underlying molecular and cellular pathways. One of the major factors that have impeded rapid progress in these areas is the complex and multifactorial nature of epilepsy, and its heterogeneity. Therefore, the vision of developing targeted treatments for epilepsy relies upon the development of biomarkers that allow individually tailored treatment. Biomarkers for epilepsy typically fall into two broad categories: diagnostic biomarkers, which provide information on the clinical status of, and potentially the sensitivity to, specific treatments, and prognostic biomarkers, which allow prediction of future clinical features, such as the speed of progression, severity of epilepsy, development of comorbidities, or prediction of remission or cure. Prognostic biomarkers are of particular importance because they could be used to identify which patients will develop epilepsy and which might benefit from preventive treatments. Biomarker research faces several challenges; however, biomarkers could substantially improve the management of people with epilepsy and could lead to prevention in the right person at the right time, rather than just symptomatic treatment.
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http://dx.doi.org/10.1016/S1474-4422(16)00112-5DOI Listing
July 2016

Serial Quantitative TSPO-Targeted PET Reveals Peak Microglial Activation up to 2 Weeks After an Epileptogenic Brain Insult.

J Nucl Med 2016 08 7;57(8):1302-8. Epub 2016 Apr 7.

Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany; and

Unlabelled: Experimental and clinical evidence suggests that neuroinflammation, triggered by epileptogenic insults, contributes to seizure development. We used translocator protein-targeted molecular imaging to obtain further insights into the role of microglial activation during epileptogenesis.

Methods: As epileptogenic insult, a status epilepticus (SE) was induced in rats by lithium pilocarpine. Rats were subjected to (11)C-PK11195 PET scans before SE; at 4 h after SE; at 1, 2, 5, 7, 14, and 22 d after SE; and at 14-16 wk after SE. For data evaluation, brain regions were outlined by coregistration with a standard rat brain atlas, and percentage injected dose/cm(3) and binding potential (simplified reference tissue model with cerebellar gray matter as a reference region) were calculated. For autoradiography and immunohistochemical evaluation, additional rats were decapitated without prior SE or 2, 5, or 14 d after SE.

Results: After SE, increases in (11)C-PK11195 uptake and binding potential were evident in epileptogenesis-associated brain regions, such as the hippocampus, thalamus, or piriform cortex, but not in the cerebellum beginning at 2-5 d and persisting at least 3 wk after SE. Maximal regional signal was observed at 1-2 wk after SE. Autoradiography confirmed the spatiotemporal profile. Immunohistochemical evaluation revealed microglial and astroglial activation as well as neuronal cell loss in epileptogenesis-associated brain regions at all investigated time points. The time course of microglial activation was consistent with that demonstrated by tracer techniques.

Conclusion: Translocator protein-targeted PET is a reliable tool for identifying brain inflammation during epileptogenesis. Neuroinflammation mainly affects brain regions commonly associated with seizure generation and spread. Definition of the time profile of neuroinflammation may facilitate the development of inflammation-targeted, antiepileptogenic therapy.
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http://dx.doi.org/10.2967/jnumed.116.172494DOI Listing
August 2016

Accurate molecular imaging of small animals taking into account animal models, handling, anaesthesia, quality control and imaging system performance.

EJNMMI Phys 2015 Dec 11;2(1):31. Epub 2015 Nov 11.

Department of Electronics and Information Systems, MEDISIP, Ghent University-iMinds Medical IT-IBiTech, De Pintelaan 185 block B, B-9000, Ghent, Belgium.

Small-animal imaging has become an important technique for the development of new radiotracers, drugs and therapies. Many laboratories have now a combination of different small-animal imaging systems, which are being used by biologists, pharmacists, medical doctors and physicists. The aim of this paper is to give an overview of the important factors in the design of a small animal, nuclear medicine and imaging experiment. Different experts summarize one specific aspect important for a good design of a small-animal experiment.
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http://dx.doi.org/10.1186/s40658-015-0135-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642455PMC
December 2015