| 1. |
- de Rojas, I., et al.
(författare)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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| 5. |
- Bellenguez, C, et al.
(författare)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Tidskriftsartikel (refereegranskat)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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| 9. |
- Jansen, Iris E, et al.
(författare)
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Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.
- 2022
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 144:5, s. 821-842
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n=8074; replication n=5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
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| 10. |
- Forstner, O., et al.
(författare)
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Isobar suppression in AMS using laser photodetachment
- 2008
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Ingår i: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. ; 266:19-20, s. 4565-4568
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Tidskriftsartikel (refereegranskat)abstract
- We are investigating the possibility of using laser photodetachment of negative atomic and molecular ions as an additional isobaric selection filter in accelerator mass spectrometry. The aim of this study is to find a possibility to further improve the detection limit for long-lived heavy radionuclides at AMS facilities. We will focus on the astrophysical relevant radionuclide 182Hf, which is one of the isotopes measured with the 3 MV tandem AMS facility VERA (Vienna Environmental Research Accelerator) at the University of Vienna. Laser-induced isobar suppression is also of importance for radioactive-beam facilities. The present detection limit for measuring the isotope ratio 182Hf/Hf at VERA is 1×10-11. The limiting factor is the strong background of the stable isobar 182W. Currently this background is suppressed using suitable molecular ions in the injection stage. Selective laser photodetachment of the negative ions at the injector can lead to an additional suppression of the interfering isobar. Test experiments have been carried out at the negative ion laser spectroscopy setup at Göteborg University. In a small ion beam apparatus pulsed tunable laser radiation is used to measure the photodetachment cross-section of different atomic and molecular negative ions. We will present studies of the photodetachment process for various tungsten and hafnium molecules with the aim to find a selective isobaric suppression scheme using laser photodetachment spectroscopy in combination with AMS.
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| 11. |
- Forstner, Oliver, et al.
(författare)
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Reassessment of 182Hf AMS measurements at VERA
- 2011
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Ingår i: Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. - : Elsevier BV. - 0168-583X. ; 269:24, s. 3180-3182
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Tidskriftsartikel (refereegranskat)abstract
- The radioisotope 182Hf (t1/2 = 8.9 Ma) is of great interest for astrophysical applications as a chronometer for the early solar system or as possible live supernova remnant on earth. However, AMS measurements of 182Hf are seriously influenced by the presence of the stable isobar 182W, which cannot be separated at typical AMS energies. Previous studies revealed a possible suppression of 182W against 182Hf by extracting the negatively charged pentafluoride from the ion source, leading to a detection limit for 182Hf/180Hf in the order of 10−11. However, this suppression behavior is in contrast to theoretical calculations of the electron affinity and recent measurements using SIMS instruments, where the achieved suppression cannot be reproduced. The aim of our study is to determine the effects of ion source background as well as further investigate the suppression of tungsten against hafnium by extracting negatively charged fluoride ions from different sample materials. The previously reported suppression factor of about 6000 could be increased to 36000 by careful tuning of the ion source using HfF4 as sample material. The trend of the theoretical electron affinities could be reproduced using atomic tungsten and hafnium instead of HfF4 as sample material. This supports the assumption that the major contribution of the tungsten background is not sputtered from the target matrix but comes from somewhere else in the ion source. Measurements from the second ion source show a higher background of tungsten and a lower suppression factor, i.e. careful design of the ion source is crucial. Moving the sputter beam over the target surface extending over the wheel holding the targets revealed the highest tungsten background was detected outside the sputter target position. Further investigations are necessary to locate the origin of the tungsten background in the ion source. Possible sources are the material used for the ion source construction or contaminations in the cesium used for sputtering.
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| 13. |
- Martschini, M., et al.
(författare)
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AMS of Cl-36 with the VERA 3 MV tandem accelerator
- 2013
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Ingår i: Nuclear Instruments & Methods in Physics Research Section B-Beam Interactions with Materials and Atoms. - : Elsevier BV. - 0168-583X. ; 294, s. 115-120
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Tidskriftsartikel (refereegranskat)abstract
- Recent progress with compact ionization chambers has opened new possibilities for isobar Refraining from the additional use of degrader foils has the benefit of high transmission to the detector Precision and accuracy have been thoroughly assessed over the last two years. Since drifts in the Recently we also explored novel techniques for additional sulfur suppression already in the ion source.
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| 16. |
- Rojo, R, et al.
(författare)
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Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3215-
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Tidskriftsartikel (refereegranskat)abstract
- The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.
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| 17. |
- Bainbridge, Wilma A., et al.
(författare)
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Memorability of photographs in subjective cognitive decline and mild cognitive impairment : Implications for cognitive assessment
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 610-618
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Impaired long-term memory is a defining feature of mild cognitive impairment (MCI). We tested whether this impairment is item specific, limited to some memoranda, whereas some remain consistently memorable. Methods: We conducted item-based analyses of long-term visual recognition memory. Three hundred ninety-four participants (healthy controls, subjective cognitive decline [SCD], and MCI) in the multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) were tested with images from a pool of 835 photographs. Results: We observed consistent memorability for images in healthy controls, SCD, and MCI, predictable by a neural network trained on another healthy sample. Looking at memorability differences between groups, we identified images that could successfully categorize group membership with higher success and a substantial image reduction than the original image set. Discussion: Individuals with SCD and MCI show consistent memorability for specific items, while other items show significant diagnosticity. Certain stimulus features could optimize diagnostic assessment, while others could support memory.
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| 18. |
- Martschini, M., et al.
(författare)
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Selective laser photodetachment of intense atomic and molecular negative ion beams with the ILIAS RFQ ion beam cooler
- 2017
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Ingår i: International Journal of Mass Spectrometry. - : Elsevier BV. - 1387-3806. ; 415, s. 9-17
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Tidskriftsartikel (refereegranskat)abstract
- The Ion Laser InterAction Setup (ILIAS) project at the University of Vienna aims at the exploration of negative ion beam filtering by selective laser photodetachment for applications in accelerator mass spectrometry (AMS). A gas-filled radio frequency quadrupole (RFQ) is used to decelerate and cool negative atomic and molecular ion beams with intensities of up to several-hundred nA, and overlap them collinearly with a continuous wave (cw) laser beam. Ion-laser interaction times ranging from 500 mu s to several ms allow for highly efficient, selective photodetachment depletion of disturbing ion species within these beams. The elemental selectivity of this technique is based on the differences in electron affinities, and therefore does not depend on relative differences in atomic numbers. It may therefore provide sufficient isobar suppression for new trace isotopes, which are not accessible with existing AMS techniques. The ILIAS RFQ cooler was characterized at a purpose-built test bench with respect to ion beam transmission, ion cooling capabilities and ion residence times as a function of injected ion current to assess its suitability for future AMS use. A Cu-63(-) test beam of 600 nA was photodetached with more than 99.999% efficiency with a 532 nm laser at 10.8 W power. At the same time, ions of interest having electron affinities higher than the photon energy passed the cooler unaffected. Total ion losses were thus found to be below 50% of the sputter source output. Finally, first photodetachment experiments in connection with Al-26 detection demonstrated selective isobar suppression of MgO- vs. AlO- by more than 4 orders of magnitude. Currently, the RFQ cooler is moved to a new injector beamline at the Vienna Environmental Research Accelerator (VERA) for first applications of this novel technique at a state-of-the-art AMS facility. (C) 2016 Elsevier B.V. All rights reserved.
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| 19. |
- Martschini, M., et al.
(författare)
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The ILIAMS project - An RFQ ion beam cooler for selective laser photodetachment at VERA
- 2019
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Ingår i: Nuclear Instruments & Methods in Physics Research Section B-Beam Interactions with Materials and Atoms. - : Elsevier BV. - 0168-583X. ; 456, s. 213-217
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Tidskriftsartikel (refereegranskat)abstract
- Selective laser photodetachment of anions is a novel technique for isobar suppression in Accelerator Mass Spectrometry (AMS). Ion-laser interaction times on the order of ms required for near-complete isobar suppression are achieved by retarding the ions in a gas-filled radio frequency quadrupole cooler. Inside this RFQ, the cooled anion beam is overlapped collinearly with an intense cw-laser beam. Within the Ion Laser InterAction Mass Spectrometry (ILIAMS) project at the University of Vienna, a dedicated injector beamline has been coupled to the VERA-AMS facility to explore and develop this method. In this work, experimental investigations on ion beam transmission, stability and elemental selectivity of the new setup are presented. A 532 nm laser at 10 W transmitted power provides suppression factors larger than ten orders of magnitude for S- and MgO- under AMS conditions with simultaneous beam transmission for the ions of interest of up to 80%. The excellent ion identification capabilities of the subsequent AMS system also facilitate the study of destruction and formation of molecular anions inside the ion cooler. These kinetic and chemical reactions with the buffer gas provide additional elemental selectivity in certain cases, whereas others constitute a source of background.
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