36 research outputs found

    [18F]F-DED PET imaging of reactive astrogliosis in neurodegenerative diseases: preclinical proof of concept and first-in-human data

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    ObjectivesReactive gliosis is a common pathological hallmark of CNS pathology resulting from neurodegeneration and neuroinflammation. In this study we investigate the capability of a novel monoamine oxidase B (MAO-B) PET ligand to monitor reactive astrogliosis in a transgenic mouse model of Alzheimer`s disease (AD). Furthermore, we performed a pilot study in patients with a range of neurodegenerative and neuroinflammatory conditions.MethodsA cross-sectional cohort of 24 transgenic (PS2APP) and 25 wild-type mice (age range: 4.3-21.0 months) underwent 60 min dynamic [F-18]fluorodeprenyl-D2 ([F-18]F-DED), static 18 kDa translocator protein (TSPO, [F-18]GE-180) and beta-amyloid ([F-18]florbetaben) PET imaging. Quantification was performed via image derived input function (IDIF, cardiac input), simplified non-invasive reference tissue modelling (SRTM2, DVR) and late-phase standardized uptake value ratios (SUVr). Immunohistochemical (IHC) analyses of glial fibrillary acidic protein (GFAP) and MAO-B were performed to validate PET imaging by gold standard assessments. Patients belonging to the Alzheimer's disease continuum (AD, n = 2), Parkinson's disease (PD, n = 2), multiple system atrophy (MSA, n = 2), autoimmune encephalitis (n = 1), oligodendroglioma (n = 1) and one healthy control underwent 60 min dynamic [F-18]F-DED PET and the data were analyzed using equivalent quantification strategies.ResultsWe selected the cerebellum as a pseudo-reference region based on the immunohistochemical comparison of age-matched PS2APP and WT mice. Subsequent PET imaging revealed that PS2APP mice showed elevated hippocampal and thalamic [F-18]F-DED DVR when compared to age-matched WT mice at 5 months (thalamus: + 4.3%;p = 0.048), 13 months (hippocampus: + 7.6%, p = 0.022) and 19 months (hippocampus: + 12.3%, p < 0.0001;thalamus: + 15.2%, p < 0.0001). Specific [F-18]F-DED DVR increases of PS2APP mice occurred earlier when compared to signal alterations in TSPO and beta-amyloid PET and [F-18]F-DED DVR correlated with quantitative immunohistochemistry (hippocampus: R = 0.720, p < 0.001;thalamus: R = 0.727, p = 0.002). Preliminary experience in patients showed [F-18]F-DED V-T and SUVr patterns, matching the expected topology of reactive astrogliosis in neurodegenerative (MSA) and neuroinflammatory conditions, whereas the patient with oligodendroglioma and the healthy control indicated [F-18]F-DED binding following the known physiological MAO-B expression in brain.Conclusions[F-18]F-DED PET imaging is a promising approach to assess reactive astrogliosis in AD mouse models and patients with neurological diseases

    Candidate Gene Screen in the Red Flour Beetle Tribolium Reveals Six3 as Ancient Regulator of Anterior Median Head and Central Complex Development

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    Several highly conserved genes play a role in anterior neural plate patterning of vertebrates and in head and brain patterning of insects. However, head involution in Drosophila has impeded a systematic identification of genes required for insect head formation. Therefore, we use the red flour beetle Tribolium castaneum in order to comprehensively test the function of orthologs of vertebrate neural plate patterning genes for a function in insect head development. RNAi analysis reveals that most of these genes are indeed required for insect head capsule patterning, and we also identified several genes that had not been implicated in this process before. Furthermore, we show that Tc-six3/optix acts upstream of Tc-wingless, Tc-orthodenticle1, and Tc-eyeless to control anterior median development. Finally, we demonstrate that Tc-six3/optix is the first gene known to be required for the embryonic formation of the central complex, a midline-spanning brain part connected to the neuroendocrine pars intercerebralis. These functions are very likely conserved among bilaterians since vertebrate six3 is required for neuroendocrine and median brain development with certain mutations leading to holoprosencephaly

    Causality in mean and variance between ISE 100 and S&P 500: Turkcell case

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    WOS: 000290800600018The article examines the causality between US stock market and Turkish stock market by using two-step method which is developed by Hong ( 2001). The returns of Turkcell securities that are traded as American Depository Receipt in the New York Stock Exchange and ISE 100 are used. The causality test results indicate that S&P 500 affects ISE 100 and Turkcell returns, moreover, Turkcell returns influence each other. Consequently, it can be seen that there is a spillover effect from US stock market to Turkish stock market

    The effects of least-to-most prompting procedure in teaching basic tennis skills to children with autism

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    In the present study, the effects of a least-to-most prompting procedure in teaching basic tennis skills (i.e. tennis ball dribble, air dribble and dribble the lines drills) to children with autism were investigated. A single-subject multiple-probe design with probe conditions across behaviors was used. Participants were four male children with autism, aged 7-9 years. Data were collected over the course of 6 weeks, five times a week, an hour per session. Inter-observer reliability data of the study was determined as 93% on probes and 100% on teaching sessions for participant one, 96% on probes and 100% on teaching sessions for participant two, 90% on probes and 100% on teaching sessions for participant three, and 93% on probes and 100% on teaching sessions for participant four. Procedural reliability showed that the trainer implemented the planned steps with 100% accuracy for all participants. Results revealed that least to most prompting was an effective instructional approach and all subjects increased their basic tennis skills considerably during intervention

    The effect of zymosan and the protective effect of various antioxidants on fracture healing in rats

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    Aim To investigate the effects of free oxygen radicals and various antioxidants on bone healing after experimental formation of fracture
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