40 results on '"Heiko Backes"'
Search Results
2. COORDINATED INTERPLAY BETWEEN AGRP AND POMC NEURONS MODULATES SYSTEMIC METABOLISM
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Alain De Solis, Almudena Del Rio-Martin, Jan Radermacher, Weiyi Chen, Lukas Steuernagel, Corinna Bauder, Fynn Eggersmann, Ronald Morgan, Anna-Lena Cremer, Michael Sue, Stephan Vollmar, Heiko Backes, Kamal Rahmouni, Peter Kloppenburg, and Jens Brüning
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
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3. Sorafenib and everolimus in patients with advanced solid tumors and KRAS‐mutated NSCLC: A phase I trial with early pharmacodynamic FDG‐PET assessment
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Lucia Nogova, Christian Mattonet, Matthias Scheffler, Max Taubert, Masyar Gardizi, Martin L. Sos, Sebastian Michels, Rieke N. Fischer, Meike Limburg, Diana S.Y. Abdulla, Thorsten Persigehl, Carsten Kobe, Sabine Merkelbach‐Bruse, Jeremy Franklin, Heiko Backes, Roland Schnell, Dirk Behringer, Britta Kaminsky, Martina Eichstaedt, Christoph Stelzer, Martina Kinzig, Fritz Sörgel, Yingying Tian, Lisa Junge, Ahmed A. Suleiman, Sebastian Frechen, Dennis Rokitta, Dongsheng Ouyang, Uwe Fuhr, Reinhard Buettner, and Jürgen Wolf
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FDG‐PET ,KRAS mutation ,non‐small‐cell lung cancer ,pharmacodynamics ,pharmacokinetics ,Phase‐I trial ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF‐MEK‐ERK and PI3K‐AKT‐mTOR. Methods Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5‐10.0 mg/d in a 14‐day run‐in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS‐mutated non–small‐cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG‐PET. Efficacy was assessed by CT scans every 6 weeks of combination. Results Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose‐limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG‐PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. Conclusions Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG‐PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS‐mutant solid tumors.
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- 2020
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4. Time-dependent assessment of stimulus-evoked regional dopamine release
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Rachel N. Lippert, Anna Lena Cremer, Sharmili Edwin Thanarajah, Clio Korn, Thomas Jahans-Price, Lauren M. Burgeno, Marc Tittgemeyer, Jens C. Brüning, Mark E. Walton, and Heiko Backes
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Science - Abstract
It has proven difficult to measure the release of neurotransmitters, such as dopamine, in the human brain. Here, the authors introduce and validate a new method that infers dopamine release based on minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride.
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- 2019
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5. [11C]raclopride and extrastriatal binding to D2/3 receptors
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Heiko Backes
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Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2020
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6. Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption
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Kornelia Johann, Anna Lena Cremer, Alexander W. Fischer, Markus Heine, Eva Rial Pensado, Julia Resch, Sebastian Nock, Samuel Virtue, Lisbeth Harder, Rebecca Oelkrug, Mariana Astiz, Georg Brabant, Amy Warner, Antonio Vidal-Puig, Henrik Oster, Anita Boelen, Miguel López, Joerg Heeren, Jeffrey W. Dalley, Heiko Backes, and Jens Mittag
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Biology (General) ,QH301-705.5 - Abstract
Summary: Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor β and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents. : Thyroid hormone induces browning of white fat, but it is unclear whether this contributes to thermogenesis. Here, Johann et al. show that thyroid-hormone-induced beige fat is metabolically inactive due to lack of central stimulation and that the metabolic and thermogenic effects of the hormone are independent of UCP1. Keywords: brown adipose tissue, beige adipose tissue, uncoupling protein 1, thyroid hormone receptor, body temperature, norepinephrine, sympathetic nervous system, metabolism, beta3-adrenergic receptor, pyrexia, hyperthermia, glucose tolerance
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- 2019
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7. Mismatch responses in the awake rat: evidence from epidural recordings of auditory cortical fields.
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Fabienne Jung, Klaas Enno Stephan, Heiko Backes, Rosalyn Moran, Markus Gramer, Tetsuya Kumagai, Rudolf Graf, Heike Endepols, and Marc Tittgemeyer
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Medicine ,Science - Abstract
Detecting sudden environmental changes is crucial for the survival of humans and animals. In the human auditory system the mismatch negativity (MMN), a component of auditory evoked potentials (AEPs), reflects the violation of predictable stimulus regularities, established by the previous auditory sequence. Given the considerable potentiality of the MMN for clinical applications, establishing valid animal models that allow for detailed investigation of its neurophysiological mechanisms is important. Rodent studies, so far almost exclusively under anesthesia, have not provided decisive evidence whether an MMN analogue exists in rats. This may be due to several factors, including the effect of anesthesia. We therefore used epidural recordings in awake black hooded rats, from two auditory cortical areas in both hemispheres, and with bandpass filtered noise stimuli that were optimized in frequency and duration for eliciting MMN in rats. Using a classical oddball paradigm with frequency deviants, we detected mismatch responses at all four electrodes in primary and secondary auditory cortex, with morphological and functional properties similar to those known in humans, i.e., large amplitude biphasic differences that increased in amplitude with decreasing deviant probability. These mismatch responses significantly diminished in a control condition that removed the predictive context while controlling for presentation rate of the deviants. While our present study does not allow for disambiguating precisely the relative contribution of adaptation and prediction error processing to the observed mismatch responses, it demonstrates that MMN-like potentials can be obtained in awake and unrestrained rats.
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- 2013
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8. Patient-Tailored, Imaging-Guided, Long-Term Temozolomide Chemotherapy in Patients with Glioblastoma
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Norbert Galldiks, Lutz W. Kracht, Lothar Burghaus, Roland T. Ullrich, Heiko Backes, Anna Brunn, Wolf-Dieter Heiss, and Andreas H. Jacobs
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Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
We present two patients with glioblastoma with an unusually stable clinical course and long-term survival who were treated after surgery and radiotherapy with adjuvant temozolomide (TMZ) chemotherapy for 17 and 20 cycles, respectively. Afterward, adjuvant TMZ chemotherapy was discontinued in one patient and the dosage of TMZ was reduced in the other. In addition to clinical status and magnetic resonance imaging, the biologic activity of the tumors was monitored by repeated methyl- 11 C-l-methionine (MET) and 3′-deoxy-3′- 18 F-fluorothymidine (FLT) positron emission tomography (PET) studies in these patients. In these patients, repeated MET-and FLT-PET imaging documented complete response to the initial treatment regimen, including resection, radiation, and TMZ, and during the course of the disease, recurrent, uncontrollable tumor activity. Continuation or dose escalation of TMZ in both patients was shown to be ineffective to overcome the metabolic activity of the tumor. Our data suggest that repeated MET- and FLT-PET imaging provide information on the biologic activity of a tumor that is highly useful to monitor and detect changes in activity.
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- 2010
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9. Early detection of erlotinib treatment response in NSCLC by 3'-deoxy-3'-[F]-fluoro-L-thymidine ([F]FLT) positron emission tomography (PET).
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Roland T Ullrich, Thomas Zander, Bernd Neumaier, Mirjam Koker, Takeshi Shimamura, Yannic Waerzeggers, Christa L Borgman, Samir Tawadros, Hongfeng Li, Martin L Sos, Heiko Backes, Geoffrey I Shapiro, Jürgen Wolf, Andreas H Jacobs, Roman K Thomas, and Alexandra Winkeler
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Medicine ,Science - Abstract
BACKGROUND: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. METHODOLOGY/PRINCIPAL FINDINGS: We performed a systematic comparison of 3'-Deoxy-3'-[(18)F]-fluoro-L-thymidine ([(18)F]FLT) and 2-[(18)F]-fluoro-2-deoxy-D-glucose ([(18)F]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [(18)F]FLT uptake after only two days of treatment, [(18)F]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [(18)F]FLT PET but not [(18)F]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [(18)F]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [(18)F]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. CONCLUSIONS: [(18)F]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [(18)F]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.
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- 2008
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10. Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery
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Helene Luise Walter, Anton Pikhovych, Heike Endepols, Steffen Rotthues, Johannes Bärmann, Heiko Backes, Mathias Hoehn, Dirk Wiedermann, Bernd Neumaier, Gereon Rudolf Fink, Maria Adele Rueger, and Michael Schroeter
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Stroke ,Mice ,Humans ,Animals ,Recovery of Function ,Longitudinal Studies ,Cerebral Infarction ,General Medicine ,Transcranial Direct Current Stimulation ,Brain Ischemia - Abstract
Background Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity. Objective In a longitudinal study, we employed tDCS in the subacute and chronic phase after experimental focal cerebral ischemia in mice to explore the relationship between functional recovery and cellular processes. Methods Mice received photothrombosis in the right motor cortex, verified by Magnetic Resonance Imaging. A composite neuroscore quantified subsequent functional deficits. Mice received tDCS daily: either 5 sessions from day 5 to 9, or 10 sessions with days 12 to 16 in addition. TDCS with anodal or cathodal polarity was compared to sham stimulation. Further imaging to assess proliferation and neuroinflammation was performed by immunohistochemistry at different time points and Positron Emission Tomography at the end of the observation time of 3 weeks. Results Cathodal tDCS at 198 kC/m2 (220 A/m2) between days 5 and 9 accelerated functional recovery, increased neurogenesis, decreased microglial activation, and mitigated CD16/32-expression associated with M1-phenotype. Anodal tDCS exerted similar effects on neurogenesis and microglial polarization but not on recovery of function or microglial activation. TDCS on days 12 to 16 after stroke did not induce any further effects, suggesting that the therapeutic time window was closed by then. Conclusion Overall, data suggest that non-invasive neuromodulation by tDCS impacts neurogenesis and microglial activation as critical cellular processes influencing functional recovery during the early phase of regeneration from focal cerebral ischemia.
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- 2022
11. Sorafenib and everolimus in patients with advanced solid tumors and KRAS‐mutated NSCLC: A phase I trial with early pharmacodynamic FDG‐PET assessment
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Dennis Rokitta, Max Taubert, Britta Kaminsky, Martin L. Sos, Reinhard Buettner, Carsten Kobe, Diana S.Y. Abdulla, Christian Mattonet, Lucia Nogova, Martina Eichstaedt, Dirk Behringer, Sabine Merkelbach-Bruse, Sebastian Michels, Dongsheng Ouyang, Lisa Junge, Meike Limburg, Sebastian Frechen, Masyar Gardizi, Jürgen Wolf, Jeremy Franklin, Matthias Scheffler, Uwe Fuhr, Heiko Backes, Rieke Fischer, Thorsten Persigehl, Yingying Tian, Roland Schnell, Christoph Stelzer, Martina Kinzig, Fritz Sörgel, and Ahmed Abbas Suleiman
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Male ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,medicine.disease_cause ,Gastroenterology ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Antineoplastic Combined Chemotherapy Protocols ,non‐small‐cell lung cancer ,Original Research ,Phase‐I trial ,solid tumors ,Middle Aged ,Sorafenib ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Oncology ,030220 oncology & carcinogenesis ,Female ,KRAS ,pharmacokinetics ,medicine.drug ,Adult ,medicine.medical_specialty ,FDG‐PET ,Combination therapy ,lcsh:RC254-282 ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Pharmacokinetics ,Fluorodeoxyglucose F18 ,Internal medicine ,pharmacodynamics ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Everolimus ,Progression-free survival ,Lung cancer ,neoplasms ,Aged ,business.industry ,Clinical Cancer Research ,KRAS mutation ,medicine.disease ,030104 developmental biology ,Positron-Emission Tomography ,Pharmacodynamics ,business - Abstract
Background Treatment of patients with solid tumors and KRAS mutations remains disappointing. One option is the combined inhibition of pathways involved in RAF‐MEK‐ERK and PI3K‐AKT‐mTOR. Methods Patients with relapsed solid tumors were treated with escalating doses of everolimus (E) 2.5‐10.0 mg/d in a 14‐day run‐in phase followed by combination therapy with sorafenib (S) 800 mg/d from day 15. KRAS mutational status was assessed retrospectively in the escalation phase. Extension phase included KRAS‐mutated non–small‐cell lung cancer (NSCLC) only. Pharmacokinetic analyses were accompanied by pharmacodynamics assessment of E by FDG‐PET. Efficacy was assessed by CT scans every 6 weeks of combination. Results Of 31 evaluable patients, 15 had KRAS mutation, 4 patients were negative for KRAS mutation, and the KRAS status remained unknown in 12 patients. Dose‐limiting toxicity (DLT) was not reached. The maximum tolerated dose (MTD) was defined as 7.5 mg/d E + 800 mg/d S due to toxicities at previous dose level (10 mg/d E + 800 mg/d S) including leucopenia/thrombopenia III° and pneumonia III° occurring after the DLT interval. The metabolic response rate in FDG‐PET was 17% on day 5 and 20% on day 14. No patient reached partial response in CT scan. Median progression free survival (PFS) and overall survival (OS) were 3.25 and 5.85 months, respectively. Conclusions Treatment of patients with relapsed solid tumors with 7.5 mg/d E and 800 mg/d S is safe and feasible. Early metabolic response in FDG‐PET was not confirmed in CT scan several weeks later. The combination of S and E is obviously not sufficient to induce durable responses in patients with KRAS‐mutant solid tumors., The study investigated the combination of sorafenib and everolimus in patients with solid tumors (dose escalation part) and KRAS mutated NSCLC (expansion part). Although the trial showed manageable safety profile of sorafenib and everolimus, it failed in providing long terms responses for patients with solid tumors and KRAS mutated NSCLC. The novelty of the study was the early pharmacodynamics assessment using FDG‐PET implemented in a phase‐I.
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- 2020
12. Avian neurons consume three times less glucose than mammalian neurons
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Kaya von Eugen, Heike Endepols, Alexander Drzezga, Bernd Neumaier, Onur Güntürkün, Heiko Backes, and Felix Ströckens
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Neurons ,Mammals ,bird ,brain ,Brain ,General Biochemistry, Genetics and Molecular Biology ,Birds ,Glucose ,metabolism [Glucose] ,PET ,metabolism [Brain] ,Fluorodeoxyglucose F18 ,metabolism [Neurons] ,ddc:570 ,energy consumption ,evolution ,Animals ,metabolism [Birds] ,General Agricultural and Biological Sciences ,metabolism - Abstract
Brains are among the most energetically costly tissues in the mammalian body.1 This is predominantly caused by expensive neurons with high glucose demands.2 Across mammals, the neuronal energy budget appears to be fixed, possibly posing an evolutionary constraint on brain growth.3-6 Compared to similarly sized mammals, birds have higher numbers of neurons, and this advantage conceivably contributes to their cognitive prowess.7 We set out to determine the neuronal energy budget of birds to elucidate how they can metabolically support such high numbers of neurons. We estimated glucose metabolism using positron emission tomography (PET) and 2-[18F]fluoro-2-deoxyglucose ([18F]FDG) as the radiotracer in awake and anesthetized pigeons. Combined with kinetic modeling, this is the gold standard to quantify cerebral metabolic rate of glucose consumption (CMRglc).8 We found that neural tissue in the pigeon consumes 27.29 ± 1.57 μmol glucose per 100 g per min in an awake state, which translates into a surprisingly low neuronal energy budget of 1.86 × 10-9 ± 0.2 × 10-9 μmol glucose per neuron per minute. This is approximately 3 times lower than the rate in the average mammalian neuron.3 The remarkably low neuronal energy budget explains how pigeons, and possibly other avian species, can support such high numbers of neurons without associated metabolic costs or compromising neuronal signaling. The advantage in neuronal processing of information at a higher efficiency possibly emerged during the distinct evolution of the avian brain.
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- 2022
13. Gut-brain communication by distinct sensory neurons differently controls feeding and glucose metabolism
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F. Thomas Wunderlich, Diba Borgmann, Henning Fenselau, Nasim Biglari, Elisa Ciglieri, Marc Tittgemeyer, Claus Brandt, Anna Lena Cremer, Heiko Backes, and Jens C. Brüning
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Male ,0301 basic medicine ,Physiology ,Stimulation ,Cell Communication ,nodose ganglion ,Receptors, G-Protein-Coupled ,0302 clinical medicine ,Dorsal root ganglion ,Brain-Gut Axis ,media_common ,Neurons ,2. Zero hunger ,gut-brain axis ,digestive, oral, and skin physiology ,Brain ,intersectional genetics ,Chemogenetics ,appetite ,medicine.anatomical_structure ,dorsal root ganglion ,Sensory Receptor Cells ,glucose metabolism ,media_common.quotation_subject ,Gut–brain axis ,Mice, Transgenic ,Sensory system ,Wnt1 Protein ,Biology ,Glucagon-Like Peptide-1 Receptor ,Article ,03 medical and health sciences ,vagus nerve ,medicine ,Animals ,Humans ,Molecular Biology ,Homeodomain Proteins ,Afferent Pathways ,Parabrachial Nucleus ,Appetite Regulation ,Appetite ,Cell Biology ,Gastrointestinal Microbiome ,Vagus nerve ,Glucose ,sensory neurons ,030104 developmental biology ,Dre-recombinase ,chemogenetics ,Energy Metabolism ,Neuroscience ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Summary Sensory neurons relay gut-derived signals to the brain, yet the molecular and functional organization of distinct populations remains unclear. Here, we employed intersectional genetic manipulations to probe the feeding and glucoregulatory function of distinct sensory neurons. We reconstruct the gut innervation patterns of numerous molecularly defined vagal and spinal afferents and identify their downstream brain targets. Bidirectional chemogenetic manipulations, coupled with behavioral and circuit mapping analysis, demonstrated that gut-innervating, glucagon-like peptide 1 receptor (GLP1R)-expressing vagal afferents relay anorexigenic signals to parabrachial nucleus neurons that control meal termination. Moreover, GLP1R vagal afferent activation improves glucose tolerance, and their inhibition elevates blood glucose levels independent of food intake. In contrast, gut-innervating, GPR65-expressing vagal afferent stimulation increases hepatic glucose production and activates parabrachial neurons that control normoglycemia, but they are dispensable for feeding regulation. Thus, distinct gut-innervating sensory neurons differentially control feeding and glucoregulatory neurocircuits and may provide specific targets for metabolic control., Graphical abstract, Highlights • Intersectional mapping of sensory neurons identifies distinct gut innervation patterns • Gut-innervating GLP1R+ vagal afferents relay anorexigenic signals to brainstem neurons • Gut-innervating GPR65+ vagal afferent stimulation increases hepatic glucose production • GLP1R+ vagal afferent activity is required to control glycemia during feeding, Borgmann et al. devise an intersectional genetic approach to probe the contribution of molecularly defined sensory neurons in gut-brain communication. They identify that distinct gut-innervating vagal afferents differentially control food intake and peripheral glucose metabolism, and engage distinct downstream circuits in the brain.
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- 2021
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14. PNOC
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Alexander, Jais, Lars, Paeger, Tamara, Sotelo-Hitschfeld, Stephan, Bremser, Melanie, Prinzensteiner, Paul, Klemm, Vasyl, Mykytiuk, Pia J M, Widdershooven, Anna Juliane, Vesting, Katarzyna, Grzelka, Marielle, Minère, Anna Lena, Cremer, Jie, Xu, Tatiana, Korotkova, Bradford B, Lowell, Hanns Ulrich, Zeilhofer, Heiko, Backes, Henning, Fenselau, F Thomas, Wunderlich, Peter, Kloppenburg, and Jens C, Brüning
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obesity ,Pro-Opiomelanocortin ,food intake ,prepronociceptin ,acute high-fat-diet feeding ,Hyperphagia ,Diet, High-Fat ,Weight Gain ,Article ,Mice ,nociceptin ,Animals ,arcuate nucleus ,GABAergic Neurons ,Protein Precursors ,hypothalamus ,neuropeptide ,orphanin FQ ,Neurons ,digestive, oral, and skin physiology ,Arcuate Nucleus of Hypothalamus ,Neural Inhibition ,Feeding Behavior ,Optogenetics ,PNOC neurons ,nervous system ,Receptors, Opioid ,Septal Nuclei ,hormones, hormone substitutes, and hormone antagonists - Abstract
Summary Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOCARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia., Graphical Abstract, Highlights • Acute high-fat-diet feeding activates PNOC neurons in the arcuate nucleus (ARC) • GABAergic PNOCARC neurons inhibit anorexigenic POMC neurons • Optogenetic activation of PNOCARC neurons promotes feeding • Ablation of PNOCARC neurons protects from obesity, Calorie-rich diets induce hyperphagia and promote obesity. Here, Jais et al. report that short-term high-fat-diet (HFD) feeding in mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). They characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia.
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- 2020
15. [11C]raclopride and extrastriatal binding to D2/3 receptors
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Heiko Backes
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Raclopride ,Cognitive Neuroscience ,Brain ,Reproducibility of Results ,Pharmacology ,Biology ,11c raclopride ,lcsh:RC321-571 ,Neurology ,medicine ,Humans ,Carbon Radioisotopes ,Receptor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,medicine.drug - Published
- 2019
16. Thyroid-Hormone-Induced Browning of White Adipose Tissue Does Not Contribute to Thermogenesis and Glucose Consumption
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Lisbeth Harder, Amy Warner, Sebastian Nock, Eva Rial Pensado, Jens Mittag, Rebecca Oelkrug, Heiko Backes, Georg Brabant, Jeffrey W. Dalley, Anna Lena Cremer, Alexander W. Fischer, Anita Boelen, Antonio Vidal-Puig, Henrik Oster, Samuel Virtue, Miguel López, Joerg Heeren, Markus Heine, Kornelia Johann, Mariana Astiz, Julia Resch, Vidal-Puig, Antonio [0000-0003-4220-9577], Dalley, Jeffrey [0000-0002-2282-3660], Apollo - University of Cambridge Repository, Universidade de Santiago de Compostela. Centro de Investigación en Medicina Molecular e Enfermidades Crónicas, Universidade de Santiago de Compostela. Departamento de Fisioloxía, Endocrinology Laboratory, and AGEM - Endocrinology, metabolism and nutrition
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0301 basic medicine ,Male ,Sympathetic nervous system ,beige adipose tissue ,glucose tolerance ,White adipose tissue ,Brown adipose tissue ,Norepinephrine ,Mice ,0302 clinical medicine ,Adipose Tissue, Brown ,pyrexia ,Body temperature ,lcsh:QH301-705.5 ,Thyroid hormone receptor ,Glucose tolerance ,Thermogenesis ,hyperthermia ,Thermogenin ,medicine.anatomical_structure ,Pyrexia ,Hyperthermia ,medicine.medical_specialty ,Thyroid Hormones ,uncoupling protein 1 ,Adipose Tissue, White ,General Biochemistry, Genetics and Molecular Biology ,norepinephrine ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,beta3-adrenergic receptor ,Muscle, Skeletal ,sympathetic nervous system ,Beta3-adrenergic receptor ,business.industry ,Uncoupling protein 1 ,thyroid hormone receptor ,brown adipose tissue ,Adipose Tissue, Beige ,medicine.disease ,Beige adipose tissue ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,Metabolism ,Glucose ,lcsh:Biology (General) ,Receptors, Adrenergic, beta-3 ,business ,body temperature ,metabolism ,030217 neurology & neurosurgery ,Hormone - Abstract
Regulation of body temperature critically depends on thyroid hormone (TH). Recent studies revealed that TH induces browning of white adipose tissue, possibly contributing to the observed hyperthermia in hyperthyroid patients and potentially providing metabolic benefits. Here, we show that browning by TH requires TH-receptor β and occurs independently of the sympathetic nervous system. The beige fat, however, lacks sufficient adrenergic stimulation and is not metabolically activated despite high levels of uncoupling protein 1 (UCP1). Studies at different environmental temperatures reveal that TH instead causes hyperthermia by actions in skeletal muscle combined with a central body temperature set-point elevation. Consequently, the metabolic and thermogenic effects of systemic hyperthyroidism were maintained in UCP1 knockout mice, demonstrating that neither beige nor brown fat contributes to the TH-induced hyperthermia and elevated glucose consumption, and underlining that the mere presence of UCP1 is insufficient to draw conclusions on the therapeutic potential of browning agents This work was supported by grants of the Deutsche Forschungsgemeinschaft (MI1242/2-2 and 3-2 Heisenberg Program and MI1242/4-1 and 5-1 SPP1629 “Thyroid TransAct” to J.M.; AS547-1/1 to M.A.; GRK1957 “Adipocyte-Brain-Crosstalk”), Young Active Research in Endocrinology, Bioscientifica Trust (BT-000011), and European Society for Endocrinology to K.J. A.V.-P. and S.V. were funded by the BHF (RG/18/7/33636). M.L. was funded by Xunta de Galicia (2016-PG068) and Ministerio de Economía y Competitividad (MINECO) (SAF2015-71026-R). H.O. is a Lichtenberg Fellow of the Volkswagen Stiftung SI
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- 2019
17. Time-dependent assessment of stimulus-evoked regional dopamine release
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Lauren M. Burgeno, Sharmili Edwin Thanarajah, Jens C. Brüning, Clio Korn, Mark E. Walton, Rachel N. Lippert, Marc Tittgemeyer, Anna Lena Cremer, Thomas Jahans-Price, and Heiko Backes
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0301 basic medicine ,Male ,Time Factors ,Science ,Dopamine ,General Physics and Astronomy ,02 engineering and technology ,Stimulus (physiology) ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Eating ,Mice ,Radioligand Assay ,Radioligand ,medicine ,Animals ,Humans ,lcsh:Science ,Dopamine metabolism ,Electrodes ,Raclopride ,Neurons ,Multidisciplinary ,Chemistry ,Dopaminergic ,Brain ,General Chemistry ,Human brain ,021001 nanoscience & nanotechnology ,Electric Stimulation ,Temporal Lobe ,030104 developmental biology ,medicine.anatomical_structure ,Positron-Emission Tomography ,lcsh:Q ,Female ,0210 nano-technology ,Neuroscience ,Extracellular dopamine ,medicine.drug - Abstract
To date, the spatiotemporal release of specific neurotransmitters at physiological levels in the human brain cannot be detected. Here, we present a method that relates minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride directly to subsecond dopamine release events. We show theoretically that synaptic dopamine release induces low frequency temporal variations of extrasynaptic extracellular dopamine levels, at time scales of one minute, that can evoke detectable temporal variations in the [11C]raclopride signal. Hence, dopaminergic activity can be monitored via temporal fluctuations in the [11C]raclopride PET signal. We validate this theory using fast-scan cyclic voltammetry and [11C]raclopride PET in mice during chemogenetic activation of dopaminergic neurons. We then apply the method to data from human subjects given a palatable milkshake and discover immediate and—for the first time—delayed food-induced dopamine release. This method enables time-dependent regional monitoring of stimulus-evoked dopamine release at physiological levels., It has proven difficult to measure the release of neurotransmitters, such as dopamine, in the human brain. Here, the authors introduce and validate a new method that infers dopamine release based on minute-by-minute fluctuations of the positron emission tomography (PET) radioligand [11C]raclopride.
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- 2019
18. Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity
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Heiko Backes, Markus Schwaninger, Jens Alber, Bhagirath Chaurasia, Jan Mauer, Sophie M. Steculorum, Carola Förster, Julia Goldau, André Kleinridders, Sebastian Theurich, Maite Solas, Napoleone Ferrara, Alexander Jais, Brigitte Hampel, Gerard Karsenty, Jens C. Brüning, and Sabine A. Eming
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,Glucose uptake ,Neurodegenerative ,Cardiovascular ,Medical and Health Sciences ,Mice ,chemistry.chemical_compound ,Cognition ,2.1 Biological and endogenous factors ,Myeloid Cells ,Aetiology ,Cognitive decline ,Glucose Transporter Type 1 ,Diabetes ,Fatty Acids ,Brain ,Biological Sciences ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Blood-Brain Barrier ,medicine.medical_specialty ,1.1 Normal biological development and functioning ,Biology ,Diet, High-Fat ,Blood–brain barrier ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Underpinning research ,Internal medicine ,Acquired Cognitive Impairment ,medicine ,Animals ,Obesity ,Neuroinflammation ,Nutrition ,Neurosciences ,Glucose transporter ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Endothelial Cells ,nutritional and metabolic diseases ,Brain Disorders ,Diet ,High-Fat ,Glucose ,030104 developmental biology ,Endocrinology ,chemistry ,biology.protein ,Dementia ,GLUT1 ,Developmental Biology - Abstract
High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not inlean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associatedmacrophage activation a homeostatic role torestore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.
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- 2016
19. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue
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Katharina Timper, Heiko Backes, Philipp Hammerschmidt, Stephan Bremser, Thomas Benzing, Andreas Klein, Sophie M. Steculorum, Linda Engström Ruud, Peter Frommolt, Jens C. Brüning, Martin E. Hess, Johan Ruud, Jan Mauer, Donald A. Morgan, Paul Brinkkötter, Peter Kloppenburg, Ismene Karakasilioti, F. Thomas Wunderlich, Merly C. Vogt, Kamal Rahmouni, Eva Tsaousidou, and Lars Paeger
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0301 basic medicine ,medicine.medical_specialty ,Glucose uptake ,Adipose tissue ,Myostatin ,Carbohydrate metabolism ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Insulin resistance ,Adipose Tissue, Brown ,Internal medicine ,Brown adipose tissue ,medicine ,Glucose homeostasis ,Animals ,Agouti-Related Protein ,Neurons ,biology ,Appetite Regulation ,Biochemistry, Genetics and Molecular Biology(all) ,digestive, oral, and skin physiology ,Feeding Behavior ,medicine.disease ,Optogenetics ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Glucose ,nervous system ,biology.protein ,Neuron ,Insulin Resistance ,Transcriptome ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.
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- 2016
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20. PNOCARC Neurons Promote Hyperphagia and Obesity upon High-Fat-Diet Feeding
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F. Thomas Wunderlich, Heiko Backes, Paul Klemm, Peter Kloppenburg, Hanns Ulrich Zeilhofer, Melanie Prinzensteiner, Jie Xu, Vasyl Mykytiuk, Henning Fenselau, Lars Paeger, Pia J.M. Widdershooven, Katarzyna Grzelka, Anna Lena Cremer, Bradford B. Lowell, Jens C. Brüning, Tatiana Korotkova, Anna Juliane Vesting, Stephan Bremser, Tamara Sotelo-Hitschfeld, Alexander Jais, Marielle Minére, and University of Zurich
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0301 basic medicine ,medicine.medical_specialty ,Population ,10050 Institute of Pharmacology and Toxicology ,Neuropeptide ,610 Medicine & health ,Optogenetics ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Arcuate nucleus ,Internal medicine ,medicine ,education ,2. Zero hunger ,education.field_of_study ,Arc (protein) ,General Neuroscience ,digestive, oral, and skin physiology ,Stria terminalis ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,nervous system ,Hypothalamus ,570 Life sciences ,biology ,Neuron ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery - Abstract
Calorie-rich diets induce hyperphagia and promote obesity, although the underlying mechanisms remain poorly defined. We find that short-term high-fat-diet (HFD) feeding of mice activates prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC). PNOCARC neurons represent a previously unrecognized GABAergic population of ARC neurons distinct from well-defined feeding regulatory AgRP or POMC neurons. PNOCARC neurons arborize densely in the ARC and provide inhibitory synaptic input to nearby anorexigenic POMC neurons. Optogenetic activation of PNOCARC neurons in the ARC and their projections to the bed nucleus of the stria terminalis promotes feeding. Selective ablation of these cells promotes the activation of POMC neurons upon HFD exposure, reduces feeding, and protects from obesity, but it does not affect food intake or body weight under normal chow consumption. We characterize PNOCARC neurons as a novel ARC neuron population activated upon palatable food consumption to promote hyperphagia. ISSN:0896-6273 ISSN:1097-4199
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- 2020
21. Regulation of cerebral metabolism during cortical spreading depression
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Markus Gramer, Heiko Backes, Delphine Feuerstein, Paula Gabel, Masatoshi Takagaki, Rudolf Graf, and Tetsuya Kumagai
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0301 basic medicine ,Male ,medicine.medical_specialty ,Microdialysis ,positron emission tomography ,Models, Neurological ,Spreading depression ,Neuroimaging ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Extracellular ,Animals ,Lactic Acid ,Rats, Wistar ,Cerebral Cortex ,lactate ,Glycogen ,Cortical Spreading Depression ,Original Articles ,Cortex (botany) ,Lactic acid ,030104 developmental biology ,Endocrinology ,Ion homeostasis ,medicine.anatomical_structure ,Glucose ,Neurology ,chemistry ,Cerebral cortex ,Cortical spreading depression ,glycogen ,Positron-Emission Tomography ,rapid sampling microdialysis ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,Energy Metabolism ,Neuroscience ,030217 neurology & neurosurgery - Abstract
We analyzed the metabolic response to cortical spreading depression that drastically increases local energy demand to restore ion homeostasis. During single and multiple cortical spreading depressions in the rat cortex, we simultaneously monitored extracellular levels of glucose and lactate using rapid sampling microdialysis and glucose influx using 18 F-fluorodeoxyglucose positron emission tomography while tracking cortical spreading depression using laser speckle imaging. Combining the acquired data with steady-state requirements we developed a mass-conserving compartment model including neurons and glia that was consistent with the observed data. In summary, our findings are: (1) Early breakdown of glial glycogen provides a major source of energy during increased energy demand and leaves 80% of blood-borne glucose to neurons. (2) Lactate is used solely by neurons and only if extracellular lactate levels are >80% above normal. (3) Although the ratio of oxygen and glucose consumption transiently reaches levels 90%) of the overall energy supply is from oxidative metabolism. (4) During cortical spreading depression, brain release of lactate exceeds its consumption suggesting that lactate is only a circumstantial energy substrate. Our findings provide a general scenario for the metabolic response to increased cerebral energy demand.
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- 2015
22. Detecting tissue deterioration after brain injury: regional blood flow level versus capacity to raise blood flow
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Markus Gramer, Rudolf Graf, Heike Endepols, Stefan Vollmar, Masatoshi Takagaki, Andrew Manning, Antony J Strong, Toshiki Yoshimine, Delphine Feuerstein, and Heiko Backes
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Male ,Neuroimaging ,upstream blood supply ,Vasoactive ,Medicine ,cortical spreading depolarization ,Animals ,Humans ,Cerebral perfusion pressure ,Rats, Wistar ,business.industry ,Cortical Spreading Depression ,Brain ,Laser Speckle Imaging ,Blood flow ,Rats ,Neurology ,Cerebral blood flow ,Cortical spreading depression ,Brain Injuries ,Cerebrovascular Circulation ,Original Article ,Neurology (clinical) ,High incidence ,Cardiology and Cardiovascular Medicine ,business ,Neuroscience ,circulatory and respiratory physiology ,focal cerebral ischemia - Abstract
Regional cerebral blood flow ( rCBF) is spatially and temporally adjusted to local energy needs. This coupling involves dilation of vessels both at the site of metabolite exchange and upstream of the activated region. Deficits in upstream blood supply limit the ‘capacity to raise rCBF’ in response to functional activation and therefore compromise brain function. We here demonstrate in rats that the ‘capacity to raise rCBF’ can be determined from real-time measurements of rCBF using laser speckle imaging during an energy challenge induced by cortical spreading depolarizations (CSDs). Cortical spreading depolarizations (CSDs) occur with high incidence in stroke and various other brain injuries and cause large metabolic changes. Various conditions of cerebral perfusion were induced, either by modifying microvascular tone, or by altering upstream blood supply independently. The increase in rCBF per unit of time in response to CSD was linearly correlated to the upstream blood supply. In an experimental model of stroke, we found that this marker of the capacity to raise rCBF which, in pathologic tissue may be additionally limited by impaired vasoactive signaling, was a better indicator of the functional status of cerebral tissue than local rCBF levels.
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- 2014
23. Glucose consumption of inflammatory cells masks metabolic deficits in the brain
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Rudolf Graf, Mathias Hoehn, Bernd Neumaier, Anne Ladwig, Gereon R. Fink, Heiko Backes, Michael Schroeter, Maria Adele Rueger, Maureen Walberer, and Heike Endepols
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Male ,0301 basic medicine ,Positron emission tomography ,medicine.medical_specialty ,Pathology ,FDG ,Cognitive Neuroscience ,Ischemia ,Inflammation ,Carbohydrate metabolism ,Article ,Brain Ischemia ,Brain ischemia ,03 medical and health sciences ,0302 clinical medicine ,Neuroinflammation ,Internal medicine ,Image Processing, Computer-Assisted ,medicine ,Animals ,ddc:610 ,Rats, Wistar ,Membrane potential ,Glucose metabolism ,Microglia ,business.industry ,Brain ,Blood flow ,Cerebral ischemia ,medicine.disease ,Magnetic Resonance Imaging ,Rats ,3. Good health ,Glucose ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Neurology ,Positron-Emission Tomography ,medicine.symptom ,Energy Metabolism ,business ,[11C]PK11195 ,030217 neurology & neurosurgery - Abstract
Inflammatory cells such as microglia need energy to exert their functions and to maintain their cellular integrity and membrane potential. Subsequent to cerebral ischemia, inflammatory cells infiltrate tissue with limited blood flow where neurons and astrocytes died due to insufficient supply with oxygen and glucose. Using dual tracer positron emission tomography (PET), we found that concomitant with the presence of inflammatory cells, transport and consumption of glucose increased up to normal levels but returned to pathological levels as soon as inflammatory cells disappeared. Thus, inflammatory cells established sufficient glucose supply to satisfy their energy demands even in regions with insufficient supply for neurons and astrocytes to survive. Our data suggest that neurons and astrocytes died from oxygen deficiency and inflammatory cells metabolized glucose non-oxidatively in regions with residual availability. As a consequence, glucose metabolism of inflammatory cells can mask metabolic deficits in neurodegenerative diseases. We further found that the PET tracer did not bind to inflammatory cells in severely hypoperfused regions and thus only a part of the inflammation was detected. We conclude that glucose consumption of inflammatory cells should be taken into account when analyzing disease-related alterations of local cerebral metabolism., Highlights • Inflammatory cells consume high amounts of glucose in supply-limited brain regions. • Glucose metabolism of inflammatory cells masks metabolic deficits in the brain. • In vivo markers only reach inflammatory cells in regions with residual blood supply. • Measuring inflammation and metabolism provide complementary information.
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- 2016
24. Potential of Early [ 18 F]-2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography for Identifying Hypoperfusion and Predicting Fate of Tissue in a Rat Embolic Stroke Model
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Heike Endepols, Gereon R. Fink, Bernd Neumaier, Mathias Hoehn, Rudolf Graf, Maria Adele Rueger, Maureen Walberer, Heiko Backes, and Michael Schroeter
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medicine.medical_specialty ,Ischemia ,Brain Ischemia ,Fluorodeoxyglucose F18 ,Internal medicine ,medicine.artery ,Occlusion ,medicine ,Animals ,Rats, Wistar ,Stroke ,Advanced and Specialized Nursing ,medicine.diagnostic_test ,business.industry ,Penumbra ,Brain ,Infarction, Middle Cerebral Artery ,medicine.disease ,Rats ,Disease Models, Animal ,Cerebral blood flow ,Positron emission tomography ,Cerebrovascular Circulation ,Positron-Emission Tomography ,Middle cerebral artery ,Cardiology ,Neurology (clinical) ,Radiology ,Cardiology and Cardiovascular Medicine ,business ,Perfusion - Abstract
Background and Purpose— Experimental stroke models are essential to study in vivo pathophysiological processes of focal cerebral ischemia. In this study, an embolic stroke model in rats was applied (1) to characterize early development of regional cerebral blood flow and metabolism with positron emission tomography (PET) using [ 15 O]H 2 O and [ 18 F]-2-fluoro-2-deoxy-D-glucose (FDG); and (2) to identify potential parameters for predicting tissue fate. Methods— Remote occlusion of the middle cerebral artery was induced in 10 Wistar rats by injection of 4 TiO 2 macrospheres. Sequential [ 15 O]H 2 O-PET (baseline, 5, 30, 60 minutes after middle cerebral artery occlusion) and FDG-PET measurements (75 minutes after middle cerebral artery occlusion) were performed. [ 15 O]H 2 O-PET data and FDG kinetic parameters were compared with MRIs and histology at 24 hours. Results— Regional cerebral blood flow decreased substantially within 30 minutes after middle cerebral artery occlusion (41% to 58% of baseline regional cerebral blood flow; P K1 of FDG in all animals ( r =0.86±0.09; P K1 and net influx rate constant Ki of FDG. The infarct volume predicted by FDG-PET (375.8±102.3 mm 3 ) correlated significantly with the infarct size determined by MRI after 24 hours (360.8±93.7 mm 3 ; r =0.85). Conclusions— Hypoperfused tissue can be identified by decreased K1 of FDG. Acute ischemic tissue can be well characterized using K1 and Ki allowing for discrimination between infarct core and early viable tissue. Because FDG-PET is widely spread, our findings can be easily translated into clinical application for early diagnoses of ischemia.
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- 2012
25. Analysis of the Growth Dynamics of Angiogenesis-Dependent and -Independent Experimental Glioblastomas by Multimodal Small-Animal PET and MRI
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Hrvoje Miletic, Krishna M. Talasila, Jian Wang, Frits Thorsen, Rolf Bjerkvig, Mathias Hoehn, Thomas Viel, Bernd Neumaier, Parisa Monfared, Alexandra Winkeler, Narve Brekka, Yannic Waerzeggers, Jan F. Jikeli, Heiko Backes, Daniel Stieber, Andreas H. Jacobs, Bertrand Tavitian, and Simone P. Niclou
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Pathology ,medicine.medical_specialty ,Angiogenesis ,Neovascularization ,03 medical and health sciences ,Rats, Nude ,0302 clinical medicine ,Methionine ,In vivo ,Fluorodeoxyglucose F18 ,Glioma ,medicine ,Image Processing, Computer-Assisted ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Paraffin Embedding ,medicine.diagnostic_test ,Neovascularization, Pathologic ,business.industry ,Brain Neoplasms ,Magnetic resonance imaging ,medicine.disease ,Phenotype ,Immunohistochemistry ,Magnetic Resonance Imaging ,Xenograft Model Antitumor Assays ,Dideoxynucleosides ,Rats ,Ki-67 Antigen ,Positron emission tomography ,Blood-Brain Barrier ,030220 oncology & carcinogenesis ,Data Interpretation, Statistical ,Positron-Emission Tomography ,Disease Progression ,medicine.symptom ,Radiopharmaceuticals ,business ,Glioblastoma ,030217 neurology & neurosurgery ,Neoplasm Transplantation - Abstract
The hypothesis of this study was that distinct experimental glioblastoma phenotypes resembling human disease can be noninvasively distinguished at various disease stages by imaging in vivo. Methods: Cultured spheroids from 2 human glioblastomas were implanted into the brains of nude rats. Glioblastoma growth dynamics were followed by PET using 18F-FDG, 11C-methyl-l-methionine (11C-MET), and 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and by MRI at 3–6 wk after implantation. For image validation, parameters were coregistered with immunohistochemical analysis. Results: Two tumor phenotypes (angiogenic and infiltrative) were obtained. The angiogenic phenotype showed high uptake of 11C-MET and 18F-FLT and relatively low uptake of 18F-FDG. 11C-MET was an early indicator of vessel remodeling and tumor proliferation. 18F-FLT uptake correlated to positive Ki67 staining at 6 wk. T1- and T2-weighted MR images displayed clear tumor delineation with strong gadolinium enhancement at 6 wk. The infiltrative phenotype did not accumulate 11C-MET and 18F-FLT and impaired the 18F-FDG uptake. In contrast, the Ki67 index showed a high proliferation rate. The extent of the infiltrative tumors could be observed by MRI but with low contrast. Conclusion: For angiogenic glioblastomas, noninvasive assessment of tumor activity corresponds well to immunohistochemical markers, and 11C-MET was more sensitive than 18F-FLT at detecting early tumor development. In contrast, infiltrative glioblastoma growth in the absence of blood–brain barrier breakdown is difficult to noninvasively follow by existing imaging techniques, and a negative 18F-FLT PET result does not exclude the presence of proliferating glioma tissue. The angiogenic model may serve as an advanced system to study imaging-guided antiangiogenic and antiproliferative therapies.
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- 2012
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26. ATPS-21MONITORING OF LOCAL TREATMENT EFFECTS WITH TEMOZOLOMIDE IN AN ORTHOTOPIC MURINE GLIOBLASTOMA MODEL
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Roland Goldbrunner, Heiko Backes, Marco Timmer, Heike Endepols, and Andrea Faymonville
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Temozolomide ,Tumor size ,business.industry ,medicine.disease ,Text mining ,Internal medicine ,Glioma ,medicine ,Stereotactic injection ,Distribution (pharmacology) ,Neurology (clinical) ,U87 ,business ,Abstracts from the 20th Annual Scientific Meeting of the Society for Neuro-Oncology ,medicine.drug ,Glioblastoma - Abstract
INTRODUCTION: Locally administered agents against malignant gliomas demand sophisticated metabolic imaging to monitor local and systemic treatment effects in animal models. The purpose of this feasibility study was to create an animal model suitable to represent the effect of locally delivered, soluble temozolomide in orthotopically implanted gliomas using micro-[18F] FLT-PET for high quality metabolic information with a distinct resolution for observation of treatment effects. METHODS: U87 glioma cells were stereotactically implanted in 48 female T-cell deficient athymic nude rats (RNU). Tumor existence and proliferation was proven by [18F] FLT-PET and microMRI. Rats were allocated to four treatment groups. Group one and two received a one-time intratumoral stereotactic injection of soluble temozolomide (TMZ) (group 1: 0.03mg; group 2: 0.015mg). Group three was administered systemic TMZ for 2 days (5mg). Group four served as untreated control group. Treatment was performed on day 15 post implantation. FLT-PET and MRI were performed 7 and 14 days after treatment. Animals showing signs of neurological impairment or reduced general health were immediately examined by MRI and sacrificed according to the animal ethical guidelines. RESULTS: The tumor take rate was 100 percent. Characteristically, U87 tumor cell formation was rather solid. Tumor size (MRI) and proliferation rate (PET) were congruent in all groups prior to treatment. Post treatment, FLT-PET was more specific for tumor growth compared to MRI. Tumor proliferation rates were significantly lower in the local treatment groups. MRI confirmed intratumoral TMZ fluid distribution which decreased within 7 days. CONCLUSION: Our orthotopic rat glioma model proved to be feasible and efficient for the performance of local therapy studies. Sophisticated Micro-PET offers distinct monitoring of tumor proliferation and supplements MR tumor imaging very well. The FLT-PET tracer is most suitable for the monitoring of local treatment effects of TMZ.
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- 2015
27. Effort-Based Decision Making in the rat: An [18F]Fluorodeoxyglucose Micro Positron Emission Tomography Study
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Heike Endepols, Susanne Sommer, Wolfgang Hauber, Heiko Backes, Rudolf Graf, and Dirk Wiedermann
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Male ,Elementary cognitive task ,Decision Making ,Infralimbic cortex ,Prefrontal Cortex ,Nucleus accumbens ,Gyrus Cinguli ,Nucleus Accumbens ,Task (project management) ,Reward ,Fluorodeoxyglucose F18 ,medicine ,Animals ,Prefrontal cortex ,Anterior cingulate cortex ,medicine.diagnostic_test ,General Neuroscience ,Cognition ,Articles ,Rats ,medicine.anatomical_structure ,Positron emission tomography ,Positron-Emission Tomography ,Conditioning, Operant ,Psychology ,Neuroscience - Abstract
Decision making refers to the process by which subjects choose between competing courses of action based on the expected costs and benefits of their consequences. Lesion studies in rats suggest that the anterior cingulate cortex and the nucleus accumbens are key structures of a neural system that subserves effort-based decision making. Little is known about brain activation associated with effort-based decisions in intact rats. Using an open hypothesis approach, we used 2-deoxy-2[(18)F]fluoro-d-glucose positron emission tomography (FDG-PET) to assess regional metabolic changes in two conditions of an effort-based decision making task. In the “same effort” condition, male rats could choose between two response options associated with the same effort but different reward sizes, i.e., decision making was simply a function of reward size. By contrast, in the “different effort” condition, an integration of different efforts and reward sizes associated with the two response options was necessary before making a decision. Separate PET scans were performed from each condition. Subtractive analysis revealed that metabolic activity was increased in the different effort relative to the same effort condition in the left anterior cingulate, left orbitofrontal and prelimbic cortex region. Metabolic activity was decreased in the infralimbic cortex and septum region. Our findings suggest that making decisions on how much effort to invest to obtain greater rewards evokes changes of metabolic activity in multiple brain areas associated with cognitive, limbic, motor and autonomic functions. This study demonstrates that FDG-PET provides a tool to determine in rats regional brain metabolic activity in cognitive tasks.
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- 2010
28. Noninvasive quantification of 18F-FLT human brain PET for the assessment of tumour proliferation in patients with high-grade glioma
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Lutz W. Kracht, Andreas H. Jacobs, Bernd Neumaier, Heiko Backes, Klaus Wienhard, and Roland T. Ullrich
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Pathology ,medicine.medical_specialty ,Models, Biological ,Kinetic modelling ,Quantification ,Glioma ,Proliferation rate ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,In patient ,Cell Proliferation ,Retrospective Studies ,High-Grade Glioma ,medicine.diagnostic_test ,Brain Neoplasms ,business.industry ,Brain ,Reproducibility of Results ,Input function ,Arteries ,General Medicine ,Human brain ,medicine.disease ,Dideoxynucleosides ,Kinetics ,PET ,medicine.anatomical_structure ,Radiology Nuclear Medicine and imaging ,Positron emission tomography ,Positron-Emission Tomography ,18F-FLT ,Original Article ,business ,Blood sampling - Abstract
Purpose Compartmental modelling of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) PET-derived kinetics provides a method for noninvasive assessment of the proliferation rate of gliomas. Such analyses, however, require an input function generally derived by serial blood sampling and counting. In the current study, 18F-FLT kinetic parameters obtained from image-derived input functions were compared with those from input functions derived from arterialized blood samples. Methods Based on the analysis of 11 patients with glioma (WHO grade II–IV) a procedure for the automated extraction of an input function from 18F-FLT brain PET data was derived. The time–activity curve of the volume of interest with the maximum difference in 18F-FLT uptake during the first 5 min after injection and the period from 60 to 90 min was corrected for partial-volume effects and in vivo metabolism of 18F-FLT. For each patient a two-compartment kinetic model was applied to the tumour tissue using the image-derived input function. The resulting kinetic rate constants K1 (transport across the blood–brain barrier) and Ki (metabolic rate constant or net influx constant) were compared with those obtained from the same data using the input function derived from blood samples. Additionally, the metabolic rate constant was correlated with the frequency of tumour cells stained with Ki-67, a widely used immunohistochemical marker of cell proliferation. Results The rate constants from kinetic modelling were comparable when the blood sample-derived input functions were replaced by the image-derived functions (K1,img and K1,sample, r = 0.95, p
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- 2009
29. Glioma Proliferation as Assessed by 3‘-Fluoro-3’-Deoxy-<scp>l</scp>-Thymidine Positron Emission Tomography in Patients with Newly Diagnosed High-Grade Glioma
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Hrvoje Miletic, Kristina Kesper, Bernd Neumaier, Roland T. Ullrich, Wolf-Dieter Heiss, Klaus Wienhard, Andreas H. Jacobs, Hongfeng Li, Heiko Backes, and Lutz W. Kracht
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Adult ,Male ,Fluorine Radioisotopes ,Cancer Research ,Pathology ,medicine.medical_specialty ,Proliferation index ,Standardized uptake value ,Methionine ,In vivo ,Glioma ,medicine ,Humans ,Tissue Distribution ,Proliferation Marker ,Carbon Radioisotopes ,Aged ,Cell Proliferation ,medicine.diagnostic_test ,Brain Neoplasms ,Chemistry ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Magnetic Resonance Imaging ,Molecular biology ,Dideoxynucleosides ,In vitro ,Ki-67 Antigen ,Oncology ,Positron emission tomography ,Positron-Emission Tomography ,Female ,Radiopharmaceuticals ,Immunostaining - Abstract
Purpose: The aim of this study was to investigate the relationship between the in vivo derived kinetic parameters of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and the proliferation rate measured in vitro by Ki-67 staining in patients with newly diagnosed high-grade gliomas. Experimental Design: Thirteen patients with newly diagnosed high-grade gliomas were investigated with 18F-FLT and methyl-11C- l-methionine (11C-MET) positron emission tomography (PET) and T1-, Gd-T1–, and T2-weighted magnetic resonance imaging on consecutive days. Tracer kinetic parameters of 18F-FLT as well as the standardized uptake value and the tumor-to-background (T/B) ratio of 18F-FLT and 11C-MET were determined. Data of kinetic modeling, standardized uptake value, and T/B values derived from 18F-FLT-PET were compared with T/B values derived from 11C-MET-PET and to the in vitro proliferation marker Ki-67. Results: A significant correlation was observed between the metabolic rate constant Ki and the proliferation index as measured by Ki-67 immunostaining [Ki, r = 0.79 (P = 0.004)]. Also, the phosphorylation rate constant k3 correlated with Ki-67 [k3, r = 0.76 (P = 0.006)], whereas the rate constant for transport through the blood brain barrier K1 showed a weaker correlation with Ki-67 [K1, r = 0.62 (P = 0.044)]. No significant correlation between 11C-MET and 18F-FLT uptake ratios and Ki-67 was observed. Conclusions: This study shows that kinetic analysis of 18F-FLT tracer uptake is essential for the in vivo assessment of tumor proliferation in high-grade gliomas, whereas uptake ratios of 11C-MET and 18F-FLT failed to correlate with the in vitro determined proliferation marker. Thus, kinetic analysis of 18F-FLT might provide an accurate method for the assessment of early response to glioma treatment in the future.
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- 2008
30. Longitudinal assessment of infarct progression, brain metabolism and behavior following anterior cerebral artery occlusion in rats
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Günter Mies, Bernd Neumaier, Heike Endepols, Heiko Backes, Uwe Himmelreich, Rudolf Graf, and Hanna Mertgens
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Brain Infarction ,Male ,Positron emission tomography ,Time Factors ,Anterior Cerebral Artery ,Neuroscience(all) ,Spatial memory ,Cerebral glucose metabolism ,Executive functions ,Isotopes ,Fluorodeoxyglucose F18 ,medicine.artery ,Occlusion ,Anterior cerebral artery ,medicine ,Animals ,Anterior cerebral artery occlusion ,Longitudinal Studies ,Stroke ,Diaschisis ,Behavior ,Endothelin-1 ,business.industry ,Mental Disorders ,General Neuroscience ,Brain ,Infarction, Middle Cerebral Artery ,Spontaneous alternation ,Cerebral blood flow ,medicine.disease ,Magnetic Resonance Imaging ,Rats ,Disease Models, Animal ,Cerebrovascular Circulation ,Positron-Emission Tomography ,Anesthesia ,Disease Progression ,Autoradiography ,business ,Antipyrine ,Decision-making - Abstract
BACKGROUND: Stroke patients suffering from occlusion of the anterior cerebral artery (ACAo) develop cognitive and executive deficits. Experimental models to investigate such functional impairments and recovery are rare and not satisfyingly validated. NEW METHOD: We stereotactically injected the vasoconstrictor endothelin-1 (ET-1) close to the ACA of rats and assessed magnitude and course of CBF reduction using [(14)C]iodoantipyrine autoradiography and [(15)O]H2O-PET. [(18)F]FDG-PET and T2-weighted MRI determined regional metabolic and structural alterations. To test cognitive and executive functions, we analyzed decision-making in a food-carrying task, spatial working memory in a spontaneous alternation task and anxiety in an elevated plus maze test before and 1 month after ACAo. RESULTS: CBF decreased immediately after ET-1 injection, started to recover 1-2h and returned to control 4h thereafter. Metabolic and structural lesions developed permanently in the ACA territory. Hypometabolism occurring bilaterally in the piriform region may reflect diaschisis. Behavioral testing after ACAo revealed context-dependent changes in decision making, exploratory activity and walking speed, as well as decreased anxiety and spatial working memory. COMPARISON WITH EXISTING METHOD(S): Aside from modeling a known entity of stroke patients, ACAo in rats allows to longitudinally study deterioration of cognitive and executive function without major interference by disturbed primary motor function. It complements therefore stroke research since common models using middle cerebral artery occlusion (MCAo) all affect motor function severely. CONCLUSION: The established ACAo model in rats effectively reflects deficits characteristic for ACA stroke in humans. It is furthermore highly suitable for longitudinal assessment of cognitive and executive functions. publisher: Elsevier articletitle: Longitudinal assessment of infarct progression, brain metabolism and behavior following anterior cerebral artery occlusion in rats journaltitle: Journal of Neuroscience Methods articlelink: http://dx.doi.org/10.1016/j.jneumeth.2014.11.003 content_type: article copyright: Copyright © 2014 The Authors. Published by Elsevier B.V. ispartof: Journal of Neuroscience Methods vol:253 pages:279-291 ispartof: location:Netherlands status: published
- Published
- 2015
31. Titan's Magnetic Field Signature During the First Cassini Encounter
- Author
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Nicolas André, Krishan K. Khurana, Heiko Backes, Michele K. Dougherty, Chris S. Arridge, Nicholas Achilleos, Alexandre Wennmacher, Geraint H. Jones, Christopher T. Russell, Cesar Bertucci, and Fritz M. Neubauer
- Subjects
Physics ,Multidisciplinary ,Extraterrestrial Environment ,Atmosphere ,Magnetosphere ,Astronomy ,Champ magnetique ,Close encounter ,Astrobiology ,Magnetic field ,Magnetics ,symbols.namesake ,Saturn ,Field orientation ,Physics::Space Physics ,symbols ,Astrophysics::Earth and Planetary Astrophysics ,Spacecraft ,Ionosphere ,Titan (rocket family) - Abstract
The magnetic field signature obtained by Cassini during its first close encounter with Titan on 26 October 2004 is presented and explained in terms of an advanced model. Titan was inside the saturnian magnetosphere. A magnetic field minimum before closest approach marked Cassini's entry into the magnetic ionopause layer. Cassini then left the northern and entered the southern magnetic tail lobe. The magnetic field before and after the encounter was approximately constant for ∼20 Titan radii, but the field orientation changed exactly at the location of Titan's orbit. No evidence of an internal magnetic field at Titan was detected.
- Published
- 2005
32. Device for simultaneous positron emission tomography, laser speckle imaging and RGB reflectometry: validation and application to cortical spreading depression and brain ischemia in rats
- Author
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Tetsuja Kumagai, Markus Gramer, Matthias Kohl-Bareis, Stefan Vollmar, Heiko Backes, Delphine Feuerstein, André Steimers, Rudolf Graf, Michael Sué, and Masatoshi Takagaki
- Subjects
medicine.medical_specialty ,Cognitive Neuroscience ,Brain mapping ,Sensitivity and Specificity ,Brain Ischemia ,Photometry ,medicine ,Animals ,Tissue Distribution ,Brain Mapping ,Microscopy, Confocal ,medicine.diagnostic_test ,Chemistry ,Cortical Spreading Depression ,Brain ,Reproducibility of Results ,Laser Speckle Imaging ,Depolarization ,Blood flow ,Oxygenation ,Equipment Design ,Voltage-Sensitive Dye Imaging ,Surgery ,Rats ,Equipment Failure Analysis ,Oxygen ,Glucose ,Neurology ,Cerebral blood flow ,Positron emission tomography ,Cortical spreading depression ,Cerebrovascular Circulation ,Positron-Emission Tomography ,Colorimetry ,Biomedical engineering - Abstract
Brain function critically relies on the supply with energy substrates (oxygen and glucose) via blood flow. Alterations in energy demand as during neuronal activation induce dynamic changes in substrate fluxes and blood flow. To study the complex system that regulates cerebral metabolism requires the combination of methods for the simultaneous assessment of multiple parameters. We developed a multimodal imaging device to combine positron emission tomography (PET) with laser speckle imaging (LSI) and RGB reflectometry (RGBR). Depending on the radiotracer, PET provides 3-dimensional quantitative information of specific molecular processes, while LSI and RGBR measure cerebral blood flow (CBF) and hemoglobin oxygenation at high temporal and spatial resolution. We first tested the functional capability of each modality within our system and showed that interference between the modalities is negligible. We then cross-calibrated the system by simultaneously measuring absolute CBF using (15)O-H2O PET (CBF(PET)) and the inverse correlation time (ICT), the LSI surrogate for CBF. ICT and CBF(PET) correlated in multiple measurements in individuals as well as across different animals (R(2)=0.87, n=44 measurements) indicating that ICT can be used for absolute quantitative assessment of CBF. To demonstrate the potential of the combined system, we applied it to cortical spreading depression (CSD), a wave of transient cellular depolarization that served here as a model system for neurovascular and neurometabolic coupling. We analyzed time courses of hemoglobin oxygenation and CBF alterations coupled to CSD, and simultaneously measured regional uptake of (18)F-2-fluoro-2-deoxy-D-glucose ((18)F-FDG) used as a radiotracer for regional glucose metabolism, in response to a single CSD and to a cluster of CSD waves. With this unique combination, we characterized the changes in cerebral metabolic rate of oxygen (CMRO2) in real-time and showed a correlation between (18)F-FDG uptake and the number of CSD waves that passed the local tissue. Finally, we examined CSD spontaneously occurring during focal ischemia also referred to as peri-infarct depolarization (PID). In the vicinity of the ischemic territory, we observed PIDs that were characterized by reduced CMRO2 and increased oxygen extraction fraction (OEF), indicating a limitation of oxygen supply. Simultaneously measured PET showed an increased (18)F-FDG uptake in these regions. Our combined system proved to be a novel tool for the simultaneous study of dynamic spatiotemporal alterations of cortical blood flow, oxygen metabolism and glucose consumption under normal and pathologic conditions.
- Published
- 2013
33. Imaging microglial activation and glucose consumption in a mouse model of Alzheimer's disease
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Mathias Hoehn, Andreas H. Jacobs, Heiko Backes, Michael T. Heneka, Sara Rapic, Parisa Monfared, Annemie Van der Linden, Stefan Vollmar, Thomas Viel, Bernd Neumaier, and Markus P. Kummer
- Subjects
Aging ,Pathology ,positron emission tomography ,microglia ,Amyloid beta-Protein Precursor ,Mice ,0302 clinical medicine ,Carbon Radioisotopes ,0303 health sciences ,Brain Mapping ,CD11b Antigen ,Microglia ,medicine.diagnostic_test ,General Neuroscience ,Brain ,medicine.anatomical_structure ,Positron emission tomography ,PPAR-gamma ,Immunohistochemistry ,medicine.symptom ,Alzheimer’s disease ,medicine.drug ,Genetically modified mouse ,medicine.medical_specialty ,Inflammation ,Mice, Transgenic ,transgenic mice ,03 medical and health sciences ,In vivo ,Alzheimer Disease ,Fluorodeoxyglucose F18 ,Internal medicine ,medicine ,Presenilin-1 ,Animals ,Humans ,Neuroinflammation ,030304 developmental biology ,PK11195 ,Analysis of Variance ,Amyloid beta-Peptides ,business.industry ,Isoquinolines ,molecular imaging ,Disease Models, Animal ,Endocrinology ,Glucose ,inflammation ,Positron-Emission Tomography ,Mutation ,Neurology (clinical) ,Human medicine ,Geriatrics and Gerontology ,business ,Pioglitazone ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
In Alzheimer's disease (AD), persistent microglial activation as sign of chronic neuroinflammation contributes to disease progression. Our study aimed to in vivo visualize and quantify microglial activation in 13- to 15-month-old AD mice using [C-11]-(R)-PK11195 and positron emission tomography (PET). We attempted to modulate neuroinflammation by subjecting the animals to an anti-inflammatory treatment with pioglitazone (5-weeks' treatment, 5-week wash-out period). [C-11]-(R)-PK11195 distribution volume values in AD mice were significantly higher compared with control mice after the wash-out period at 15 months, which was supported by immunohistochemistry data. However, [C-11]-(R)-PK11195 mu PET could not demonstrate genotype-or treatment-dependent differences in the 13- to 14-month-old animals, suggesting that microglial activation in AD mice at this age and disease stage is too mild to be detected by this imaging method. (C) 2013 Elsevier Inc. All rights reserved.
- Published
- 2012
34. Non-invasive imaging of endogenous neural stem cell mobilization in vivo using Positron Emission Tomography
- Author
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Heiko Backes, Roland T. Ullrich, Michael Schroeter, Beata Emig, Marie-Lune Simard, Bernd Neumaier, Rudolf Graf, Mathias Hoehn, Gereon R. Fink, Maria Adele Rueger, and Maureen Walberer
- Subjects
Pathology ,pharmacology [Fibroblast Growth Factor 2] ,metabolism [Stem Cells] ,Hippocampus ,Endogeny ,Brain Ischemia ,ddc:590 ,Cell Movement ,Lateral Ventricles ,physiology [Stem Cells] ,Insulin ,alovudine ,drug effects [Cell Movement] ,Cells, Cultured ,pharmacology [Insulin] ,Neurons ,pharmacology [Membrane Proteins] ,medicine.diagnostic_test ,drug effects [Lateral Ventricles] ,Chemistry ,Stem Cells ,General Neuroscience ,methods [Positron-Emission Tomography] ,Intracellular Signaling Peptides and Proteins ,Brain ,Articles ,physiology [Neurons] ,physiopathology [Brain Ischemia] ,Neural stem cell ,medicine.anatomical_structure ,metabolism [Neurons] ,Positron emission tomography ,metabolism [Dideoxynucleosides] ,drug effects [Brain] ,Fibroblast Growth Factor 2 ,physiology [Cell Movement] ,Noninvasive imaging ,medicine.medical_specialty ,metabolism [Brain Ischemia] ,Ischemia ,Subventricular zone ,Biology ,physiology [Brain] ,embryology [Brain] ,In vivo ,Physiology (medical) ,medicine ,Animals ,delta protein ,Cell Proliferation ,drug effects [Cell Proliferation] ,physiology [Lateral Ventricles] ,Dentate gyrus ,Membrane Proteins ,medicine.disease ,Dideoxynucleosides ,Rats ,metabolism [Brain] ,Positron-Emission Tomography ,radionuclide imaging [Brain] ,Neurology (clinical) ,Neuroscience - Abstract
Neural stem cells reside in two major niches in the adult brain [i.e., the subventricular zone (SVZ) and the dentate gyrus of the hippocampus]. Insults to the brain such as cerebral ischemia result in a physiological mobilization of endogenous neural stem cells. Since recent studies showed that pharmacological stimulation can be used to expand the endogenous neural stem cell niche, hope has been raised to enhance the brain's own regenerative capacity. For the evaluation of such novel therapeutic approaches, longitudinal and intraindividual monitoring of the endogenous neural stem cell niche would be required. However, to date no conclusive imaging technique has been established. We used positron emission tomography (PET) and the radiotracer 3′-deoxy-3′-[18F]fluoro-l-thymidine ([18F]FLT) that enables imaging and measuring of proliferation to noninvasively detect endogenous neural stem cells in the normal and diseased adult rat brainin vivo. This method indeed visualized neural stem cell niches in the living rat brain, identified as increased [18F]FLT-binding in the SVZ and the hippocampus. Focal cerebral ischemia and subsequent damage of the blood–brain barrier did not interfere with the capability of [18F]FLT-PET to visualize neural stem cell mobilization. Moreover, [18F]FLT-PET allowed for anin vivoquantification of increased neural stem cell mobilization caused by pharmacological stimulation or by focal cerebral ischemia. The data suggest that noninvasive longitudinal monitoring and quantification of endogenous neural stem cell activation in the brain is feasible and that [18F]FLT-PET could be used to monitor the effects of drugs aimed at expanding the neural stem cell niche.
- Published
- 2012
35. Whiskers area as extracerebral reference tissue for quantification of rat brain metabolism using (18)F-FDG PET: application to focal cerebral ischemia
- Author
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Rudolf Graf, Klaus Wienhard, Heiko Backes, Günter Mies, Bernd Neumaier, Heike Endepols, and Maureen Walberer
- Subjects
Blood Glucose ,Diagnostic Imaging ,Male ,Pathology ,medicine.medical_specialty ,Central nervous system ,Ischemia ,Brain Ischemia ,In vivo ,Fluorodeoxyglucose F18 ,TRACER ,medicine ,Animals ,Radiology, Nuclear Medicine and imaging ,Rats, Wistar ,Whole blood ,Chemistry ,Brain ,Metabolism ,medicine.disease ,Rats ,Kinetics ,medicine.anatomical_structure ,Glucose ,Positron-Emission Tomography ,Vibrissae ,Reference Region ,Radiopharmaceuticals ,Biomedical engineering ,Blood sampling - Abstract
Diseases and dysfunction of the central nervous system are often associated with regional changes in cerebral glucose metabolism, which can be measured in vivo by PET using 18F-FDG as the tracer. For quantification, the arterial tracer input function must be determined. For rodents in particular, direct measurement of blood radioactivity concentration is scarcely feasible for follow-up of individual animals because of the invasiveness of blood sampling. We show that the whiskers area of the rat9s muzzle serves as an extracerebral reference region. The derived model also takes into account local variations of the lumped constant, which is crucial in pathologic tissue. Methods: In 11 rats, the reference tissue kinetic parameters were determined from PET data and measured whole blood radioactivity concentration. Parametric images of cerebral kinetic rate constants were calculated using the directly measured input function, the reference tissue time–activity curve with individually fitted reference kinetic parameters, and the reference time–activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals. The need for kinetic modeling in disease models is demonstrated in 5 rats subjected to acute focal cerebral ischemia. 18F-FDG metabolism and transport rate constants and local cerebral glucose metabolic rates were calculated. Results: Cerebral kinetic constants derived from the 3 methods corresponded closely. The maximum difference in whole-brain kinetic parameters observed between the directly measured input function and the reference tissue time–activity curve with individually fitted reference kinetic parameters was less than 5%. Taking fixed reference parameters (the reference time–activity curve with fixed reference kinetic parameters calculated from the fitted parameters averaged over all animals) still provided whole-brain kinetic parameters with an accuracy of approximately 90%. In the rats subjected to focal cerebral ischemia, 18F-FDG kinetic parameters in healthy tissue were not significantly different from whole-brain kinetic parameters in naive rats. The ischemic region was characterized by preserved glucose metabolism, although 18F-FDG uptake was elevated significantly—that is, the lumped constant in the ischemic region was different from that of healthy brain tissue. Conclusion: The method presented here allows for the quantitative noninvasive determination of cerebral glucose consumption in rats, takes into account local variations of the lumped constant, and is suitable for follow-up measurements of individuals.
- Published
- 2011
36. Patient-Tailored, Imaging-Guided, Long-Term Temozolomide Chemotherapy in Patients with Glioblastoma
- Author
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Heiko Backes, Roland T. Ullrich, Andreas H. Jacobs, Anna Brunn, Wolf-Dieter Heiss, Norbert Galldiks, Lutz W. Kracht, and Lothar Burghaus
- Subjects
Oncology ,Adult ,medicine.medical_specialty ,Fluorine Radioisotopes ,lcsh:Medical technology ,medicine.medical_treatment ,Dacarbazine ,Biomedical Engineering ,Methionine ,Internal medicine ,medicine ,Temozolomide ,Humans ,Radiology, Nuclear Medicine and imaging ,Carbon Radioisotopes ,Radionuclide Imaging ,Antineoplastic Agents, Alkylating ,lcsh:QH301-705.5 ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Brain Neoplasms ,Magnetic resonance imaging ,Middle Aged ,Condensed Matter Physics ,Dideoxynucleosides ,Surgery ,Radiation therapy ,Regimen ,lcsh:Biology (General) ,lcsh:R855-855.5 ,Positron emission tomography ,Molecular Medicine ,Radiopharmaceuticals ,business ,Glioblastoma ,Adjuvant ,Biotechnology ,medicine.drug - Abstract
We present two patients with glioblastoma with an unusually stable clinical course and long-term survival who were treated after surgery and radiotherapy with adjuvant temozolomide (TMZ) chemotherapy for 17 and 20 cycles, respectively. Afterward, adjuvant TMZ chemotherapy was discontinued in one patient and the dosage of TMZ was reduced in the other. In addition to clinical status and magnetic resonance imaging, the biologic activity of the tumors was monitored by repeated methyl- 11 C-l-methionine (MET) and 3′-deoxy-3′- 18 F-fluorothymidine (FLT) positron emission tomography (PET) studies in these patients. In these patients, repeated MET-and FLT-PET imaging documented complete response to the initial treatment regimen, including resection, radiation, and TMZ, and during the course of the disease, recurrent, uncontrollable tumor activity. Continuation or dose escalation of TMZ in both patients was shown to be ineffective to overcome the metabolic activity of the tumor. Our data suggest that repeated MET- and FLT-PET imaging provide information on the biologic activity of a tumor that is highly useful to monitor and detect changes in activity.
- Published
- 2010
37. Neuroinflammation extends brain tissue at risk to vital peri-infarct tissue: a double tracer [11C]PK11195- and [18F]FDG-PET study
- Author
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Rudolf Graf, Maureen Walberer, Gereon R. Fink, Michael Schroeter, Bernd Neumaier, Heiko Backes, and Maria Adele Dennin
- Subjects
Brain Infarction ,Male ,Pathology ,medicine.medical_specialty ,Ischemia ,Standardized uptake value ,Brain ischemia ,Fluorodeoxyglucose F18 ,Risk Factors ,medicine.artery ,medicine ,Animals ,Carbon Radioisotopes ,Rats, Wistar ,Neuroinflammation ,medicine.diagnostic_test ,Microglia ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Isoquinolines ,Rats ,Disease Models, Animal ,medicine.anatomical_structure ,Neurology ,Positron emission tomography ,Positron-Emission Tomography ,Middle cerebral artery ,Neurology (clinical) ,Neurogenic Inflammation ,Cardiology and Cardiovascular Medicine ,business - Abstract
Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [11C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [11C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [11C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [11C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [11C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93 ± 0.49), colocalizing with a 60% increase in the [18F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct.
- Published
- 2009
38. Electron temperature of Titan's sunlit ionosphere
- Author
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Jan-Erik Wahlund, Marina Galand, Roger V. Yelle, Andrew J. Coates, and Heiko Backes
- Subjects
Physics ,Magnetosphere ,Electron ,symbols.namesake ,Geophysics ,Ionization ,Physics::Space Physics ,symbols ,General Earth and Planetary Sciences ,Electron temperature ,Astrophysics::Earth and Planetary Astrophysics ,Atmosphere of Titan ,Ionosphere ,Atomic physics ,Titan (rocket family) ,Energy source - Abstract
Titan's upper atmosphere is ionized by solar radiation and particle bombardment from Saturn's magnetosphere. The induced ionosphere plays a key role in the coupling of Titan's atmosphere with the Kronian environment. It also provides unique signatures for identifying energy sources upon Titan's upper atmosphere. Here we focus on observations from the first, close flyby by the Cassini spacecraft and assess the ionization and electron heating sources in Titan's sunlit ionosphere. We compare CAPS electron spectra with spectra produced by an electron transport model based on the INMS neutral densities and a MHD interaction model. In addition, we compare RPWS electron temperature against the models. The important terms in the electron energy equation include loss through excitation of vibrational states of N-2 and CH4, Coulomb collisions with suprathermal electrons, and thermal conduction. Our analysis highlights the important role of the magnetic field line configuration for aeronomic studies at Titan.
- Published
- 2006
39. Titan's near magnetotail from magnetic field and electron plasma observations and modeling: Cassini flybys TA, TB, and T3
- Author
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Christopher T. Russell, Fritz M. Neubauer, Joachim Saur, Krishan K. Khurana, Heiko Backes, N. André, Nicholas Achilleos, Cesar Bertucci, Michele K. Dougherty, Alexandre Wennmacher, T. Knetter, Andrew J. Coates, D. T. Young, Chris S. Arridge, Gethyn R. Lewis, Geraint H. Jones, and A. Law
- Subjects
Atmospheric Science ,Soil Science ,Magnetosphere ,Venus ,Electron ,Astrophysics ,Aquatic Science ,Oceanography ,symbols.namesake ,Geochemistry and Petrology ,Earth and Planetary Sciences (miscellaneous) ,Earth-Surface Processes ,Water Science and Technology ,Physics ,Ecology ,biology ,Paleontology ,Forestry ,Geophysics ,Plasma ,biology.organism_classification ,Magnetic field ,Space and Planetary Science ,Local time ,symbols ,Ionosphere ,Titan (rocket family) - Abstract
[1] The first close Titan encounters TA, TB, and T3 of the Cassini mission at almost the same Saturnian local time � 1030 and in the same spatial region downstream of Titan have enabled us to study the formation of the tail of its induced magnetosphere. The study is based on magnetic field and electron plasma observations as well as threedimensional modeling. Our most important findings are the following: (1) No crossings of a bow shock of Titan were observed, and all encounters occurred at high plasma b > 1 for
- Published
- 2006
40. Early Detection of Erlotinib Treatment Response in NSCLC by 3′-Deoxy-3′-[18F]-Fluoro-L-Thymidine ([18F]FLT) Positron Emission Tomography (PET)
- Author
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Hongfeng Li, Mirjam Koker, Martin L. Sos, Samir Tawadros, Christa L. Borgman, Geoffrey I. Shapiro, Jürgen Wolf, Alexandra Winkeler, Bernd Neumaier, Roman K. Thomas, Andreas H. Jacobs, Yannic Waerzeggers, Heiko Backes, Roland T. Ullrich, Thomas Zander, and Takeshi Shimamura
- Subjects
Lung Neoplasms ,Down-Regulation ,Cell Biology/Cell Signaling ,Erlotinib Hydrochloride ,Mice ,T790M ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Spect imaging ,In Situ Nick-End Labeling ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Lung cancer ,Oncology/Lung Cancer ,Early Detection of Cancer ,EGFR inhibitors ,Multidisciplinary ,biology ,business.industry ,Cell Cycle ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Dideoxynucleosides ,respiratory tract diseases ,ErbB Receptors ,Ki-67 Antigen ,Treatment Outcome ,Positron-Emission Tomography ,Quinazolines ,Cancer research ,biology.protein ,Radiology and Medical Imaging/PET and SPECT Imaging ,Adenocarcinoma ,Erlotinib ,business ,Nuclear medicine ,Research Article ,Signal Transduction ,medicine.drug - Abstract
Background: Inhibition of the epidermal growth factor receptor (EGFR) has shown clinical success in patients with advanced non-small cell lung cancer (NSCLC). Somatic mutations of EGFR were found in lung adenocarcinoma that lead to exquisite dependency on EGFR signaling; thus patients with EGFR-mutant tumors are at high chance of response to EGFR inhibitors. However, imaging approaches affording early identification of tumor response in EGFR-dependent carcinomas have so far been lacking. Methodology/Principal Findings: We performed a systematic comparison of 3′-Deoxy-3′-[\(^{18}F\)]-fluoro-L-thymidine ([\(^{18}F\)]FLT) and 2-[\(^{18}F\)]-fluoro-2-deoxy-D-glucose ([\(^{18}F\)]FDG) positron emission tomography (PET) for their potential to identify response to EGFR inhibitors in a model of EGFR-dependent lung cancer early after treatment initiation. While erlotinib-sensitive tumors exhibited a striking and reproducible decrease in [\(^{18}F\)]FLT uptake after only two days of treatment, [\(^{18}F\)]FDG PET based imaging revealed no consistent reduction in tumor glucose uptake. In sensitive tumors, a decrease in [\(^{18}F\)]FLT PET but not [\(^{18}F\)]FDG PET uptake correlated with cell cycle arrest and induction of apoptosis. The reduction in [\(^{18}F\)]FLT PET signal at day 2 translated into dramatic tumor shrinkage four days later. Furthermore, the specificity of our results is confirmed by the complete lack of [\(^{18}F\)]FLT PET response of tumors expressing the T790M erlotinib resistance mutation of EGFR. Conclusions: [\(^{18}F\)]FLT PET enables robust identification of erlotinib response in EGFR-dependent tumors at a very early stage. [\(^{18}F\)]FLT PET imaging may represent an appropriate method for early prediction of response to EGFR TKI treatment in patients with NSCLC.
- Published
- 2008
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