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| 3. |
- 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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| 6. |
- 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. |
- Fernandez-Klett, F, et al.
(författare)
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Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke
- 2013
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Ingår i: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. - : SAGE Publications. - 1559-7016. ; 33:3, s. 428-439
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Tidskriftsartikel (refereegranskat)abstract
- Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)+ and CD105+ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ+ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.
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| 11. |
- 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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| 13. |
- Kleineidam, Luca, et al.
(författare)
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Midlife occupational cognitive requirements protect cognitive function in old age by increasing cognitive reserve
- 2022
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Ingår i: Frontiers in Psychology. - : Frontiers Media SA. - 1664-1078. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Several lifestyle factors promote protection against Alzheimer's disease (AD) throughout a person's lifespan. Although such protective effects have been described for occupational cognitive requirements (OCR) in midlife, it is currently unknown whether they are conveyed by brain maintenance (BM), brain reserve (BR), or cognitive reserve (CR) or a combination of them. Methods: We systematically derived hypotheses for these resilience concepts and tested them in the population-based AgeCoDe cohort and memory clinic-based AD high-risk DELCODE study. The OCR score (OCRS) was measured using job activities based on the O*NET occupational classification system. Four sets of analyses were conducted: (1) the interaction of OCR and APOE-ε4 with regard to cognitive decline (N = 2,369, AgeCoDe), (2) association with differentially shaped retrospective trajectories before the onset of dementia of the Alzheimer's type (DAT; N = 474, AgeCoDe), (3) cross-sectional interaction of the OCR and cerebrospinal fluid (CSF) AD biomarkers and brain structural measures regarding memory function (N = 873, DELCODE), and (4) cross-sectional and longitudinal association of OCR with CSF AD biomarkers and brain structural measures (N = 873, DELCODE). Results: Regarding (1), higher OCRS was associated with a reduced association of APOE-ε4 with cognitive decline (mean follow-up = 6.03 years), consistent with CR and BR. Regarding (2), high OCRS was associated with a later onset but subsequently stronger cognitive decline in individuals converting to DAT, consistent with CR. Regarding (3), higher OCRS was associated with a weaker association of the CSF Aβ42/40 ratio and hippocampal volume with memory function, consistent with CR. Regarding (4), OCR was not associated with the levels or changes in CSF AD biomarkers (mean follow-up = 2.61 years). We found a cross-sectional, age-independent association of OCRS with some MRI markers, but no association with 1-year-change. OCR was not associated with the intracranial volume. These results are not completely consistent with those of BR or BM. Discussion: Our results support the link between OCR and CR. Promoting and seeking complex and stimulating work conditions in midlife could therefore contribute to increased resistance to pathologies in old age and might complement prevention measures aimed at reducing pathology.
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| 14. |
- 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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| 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. |
- Baumeister, Hannah, et al.
(författare)
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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings
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Ingår i: Brain : a journal of neurology. - 1460-2156. ; 147:7, s. 2400-2413
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Tidskriftsartikel (refereegranskat)abstract
- Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.
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| 19. |
- Holtmann, M, et al.
(författare)
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Severe affective and behavioral dysregulation in youths is associated with a proinflammatory state
- 2013
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Ingår i: Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie. - : Hogrefe Publishing Group. - 1422-4917 .- 1664-2880. ; 41:6, s. 393-399
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Tidskriftsartikel (refereegranskat)abstract
- Objective: A heritable behavioral phenotype, the so-called Dysregulation Profile (DP), characterized by extreme scores on the syndrome scales Anxious/Depressed (A/D), Attention Problems (AP), and Aggressive Behavior (AGG), has been identified on the Child Behavior Checklist (CBCL). It characterizes children with severe affective and behavioral dysregulation. The present study examined possible alterations of the inflammatory system in CBCL-DP using a clinical sample of n = 133 children and adolescents. Method: Participants with the CBCL-DP scoring ≥ 2.5 SDs above average constituted the CBCL-DP subgroup (n = 51). Those with CBCL-DP scores of 1 SD or less above average were regarded as controls (n = 82). Groups were compared in terms of serum levels of C-reactive protein (CRP) and albumin. Results: Participants showing the CBCL-DP exhibited increased CRP and decreased albumin levels compared to controls. CRP was correlated with AGG, AP, and the CBCL-DP total score. A negative correlation was observed between albumin and AGG, AP, the CBCL-DP score, and A/D. These associations could not be attributed to differences in age, sex, weight, socioeconomic status, global functioning, or duration of illness. Conclusions: This is the first study to demonstrate associations between the CBCL-DP and a proinflammatory state. Limitations include the lack of a healthy control group, the use of a single measurement of inflammatory markers, and the lack of follow-up data. Future research should address whether inflammatory diathesis in these children confers increased susceptibility to later development of cardiovascular disease and other medical morbidities.
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| 20. |
- 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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