| 11. |
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| 12. |
- Kessler, Richard, et al.
(författare)
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First-Year Sloan Digital Sky Survey-II Supernova Results : Hubble Diagram and Cosmological Parameters
- 2009
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Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 185:1, s. 32-84
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Tidskriftsartikel (refereegranskat)abstract
- We present measurements of the Hubble diagram for 103 Type Ia supernovae (SNe) with redshifts 0.04 < z < 0.42, discovered during the first season (Fall 2005) of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey. These data fill in the redshift "desert" between low- and high-redshift SN Ia surveys. Within the framework of the MLCS2K2 light-curve fitting method, we use the SDSS-II SN sample to infer the mean reddening parameter for host galaxies, RV = 2.18 ± 0.14stat ± 0.48syst, and find that the intrinsic distribution of host-galaxy extinction is well fitted by an exponential function, P(AV ) = exp(-AV /τV), with τV = 0.334 ± 0.088 mag. We combine the SDSS-II measurements with new distance estimates for published SN data from the ESSENCE survey, the Supernova Legacy Survey (SNLS), the Hubble Space Telescope (HST), and a compilation of Nearby SN Ia measurements. A new feature in our analysis is the use of detailed Monte Carlo simulations of all surveys to account for selection biases, including those from spectroscopic targeting. Combining the SN Hubble diagram with measurements of baryon acoustic oscillations from the SDSS Luminous Red Galaxy sample and with cosmic microwave background temperature anisotropy measurements from the Wilkinson Microwave Anisotropy Probe, we estimate the cosmological parameters w and ΩM, assuming a spatially flat cosmological model (FwCDM) with constant dark energy equation of state parameter, w. We also consider constraints upon ΩM and ΩΛ for a cosmological constant model (ΛCDM) with w = -1 and non-zero spatial curvature. For the FwCDM model and the combined sample of 288 SNe Ia, we find w = -0.76 ± 0.07(stat) ± 0.11(syst), ΩM = 0.307 ± 0.019(stat) ± 0.023(syst) using MLCS2K2 and w = -0.96 ± 0.06(stat) ± 0.12(syst), ΩM = 0.265 ± 0.016(stat) ± 0.025(syst) using the SALT-II fitter. We trace the discrepancy between these results to a difference in the rest-frame UV model combined with a different luminosity correction from color variations; these differences mostly affect the distance estimates for the SNLS and HST SNe. We present detailed discussions of systematic errors for both light-curve methods and find that they both show data-model discrepancies in rest-frame U band. For the SALT-II approach, we also see strong evidence for redshift-dependence of the color-luminosity parameter (β). Restricting the analysis to the 136 SNe Ia in the Nearby+SDSS-II samples, we find much better agreement between the two analysis methods but with larger uncertainties: w = -0.92 ± 0.13(stat)+0.10 -0.33(syst) for MLCS2K2 and w = -0.92 ± 0.11(stat)+0.07 -0.15 (syst) for SALT-II.
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| 13. |
- Portelius, Erik, 1977, et al.
(författare)
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Amyloid-β(1-15/16) as a marker for γ-secretase inhibition in Alzheimer's disease.
- 2012
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 31:2, s. 335-41
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-β (Aβ) producing enzymes are key targets for disease-modifying Alzheimer's disease (AD) therapies since Aβ trafficking is at the core of AD pathogenesis. Development of such drugs might benefit from the identification of markers indicating in vivo drug effects in the central nervous system. We have previously shown that Aβ(1-15) is produced by concerted β-and α-secretase cleavage of amyloid-β protein precursor (AβPP). Here, we test the hypothesis that this pathway is more engaged upon γ-secretase inhibition in humans, and cerebrospinal fluid (CSF) levels of Aβ(1-15/16) represent a biomarker for this effect. Twenty healthy men were treated with placebo (n = 5) or the γ-secretase inhibitor semagacestat (100 mg [n = 5], 140 mg [n = 5], or 280 mg [n = 5]). CSF samples were collected hourly over 36 hours and 10 time points were analyzed by immunoassay for Aβ(1-15/16), Aβ(x-38), Aβ(x-40), Aβ(x-42), sAβPPα, and sAβPPβ. The CSF concentration of Aβ(1-15/16) showed a dose-dependent response over 36 hours. In the 280 mg treatment group, a transient increase was seen with a maximum of 180% relative to baseline at 9 hours post administration of semagacestat. The concentrations of Aβ(x-38), Aβ(x-40), and Aβ(x-42) decreased the first 9 hours followed by increased concentrations after 36 hours relative to baseline. No significant changes were detected for CSF sAβPPα and sAβPPβ. Our data shows that CSF levels of Aβ(1-15/16) increase during treatment with semagacestat supporting its feasibility as a pharmacodynamic biomarker for drug candidates aimed at inhibiting γ-secretase-mediated AβPP-processing.
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| 14. |
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| 15. |
- Ulrich, Jason D., et al.
(författare)
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ApoE facilitates the microglial response to amyloid plaque pathology
- 2018
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Ingår i: Journal of Experimental Medicine. - : ROCKEFELLER UNIV PRESS. - 0022-1007 .- 1540-9538. ; 215:4, s. 1047-1058
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Tidskriftsartikel (refereegranskat)abstract
- One of the hallmarks of Alzheimers disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-beta (A beta) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric A beta in the brain. In addition to influencing A beta metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1 Delta E9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe-deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct A beta morphotypes in Apoe-deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe-deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
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| 16. |
- Hasselquist, Sten, et al.
(författare)
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Exploring the stellar age distribution of the milky way bulge using APOGEE
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 901:2
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Tidskriftsartikel (refereegranskat)abstract
- We present stellar age distributions of the Milky Way bulge region using ages for ∼6000 high-luminosity (log(g)< 2.0), metal-rich ([Fe/H] ≥ -0.5) bulge stars observed by the Apache Point Observatory Galactic Evolution Experiment. Ages are derived using The Cannon label-transfer method, trained on a sample of nearby luminous giants with precise parallaxes for which we obtain ages using a Bayesian isochrone-matching technique. We find that the metal-rich bulge is predominantly composed of old stars (>8 Gyr). We find evidence that the planar region of the bulge (ZGC| 0.25 kpc) is enriched in metallicity, Z, at a faster rate (dZ/dt ∼ 0.0034 Gyr-1) than regions farther from the plane (dZ/dt ∼ 0.0013 Gyr-1 at | ZGC| > 1.00 kpc). We identify a nonnegligible fraction of younger stars (age ∼2-5 Gyr) at metallicities of +0.2 < [Fe/H] < +0.4. These stars are preferentially found in the plane (ZGC| ≤ 0.25 kpc) and at R cy ≈ 2-3 kpc, with kinematics that are more consistent with rotation than are the kinematics of older stars at the same metallicities. We do not measure a significant age difference between stars found inside and outside the bar. These findings show that the bulge experienced an initial starburst that was more intense close to the plane than far from the plane. Then, star formation continued at supersolar metallicities in a thin disk at 2 kpc ≲ R cy ≲ 3 kpc until ∼2 Gyr ago.
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| 17. |
- Horie, Kanta, et al.
(författare)
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CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer’s disease
- 2023
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Ingår i: Nature Medicine. - 1078-8956. ; 29:8, s. 1954-1963
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Tidskriftsartikel (refereegranskat)abstract
- Aggregated insoluble tau is one of two defining features of Alzheimer’s disease. Because clinical symptoms are strongly correlated with tau aggregates, drug development and clinical diagnosis need cost-effective and accessible specific fluid biomarkers of tau aggregates; however, recent studies suggest that the fluid biomarkers currently available cannot specifically track tau aggregates. We show that the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is a new cerebrospinal fluid (CSF) biomarker specific for insoluble tau aggregates and compared it to multiple other phosphorylated tau measures (p-tau181, p-tau205, p-tau217 and p-tau231) in two independent cohorts (BioFINDER-2, n = 448; and Knight Alzheimer Disease Research Center, n = 219). MTBR-tau243 was most strongly associated with tau-positron emission tomography (PET) and cognition, whereas showing the lowest association with amyloid-PET. In combination with p-tau205, MTBR-tau243 explained most of the total variance in tau-PET burden (0.58 ≤ R 2 ≤ 0.75) and the performance in predicting cognitive measures (0.34 ≤ R 2 ≤ 0.48) approached that of tau-PET (0.44 ≤ R 2 ≤ 0.52). MTBR-tau243 levels longitudinally increased with insoluble tau aggregates, unlike CSF p-tau species. CSF MTBR-tau243 is a specific biomarker of tau aggregate pathology, which may be utilized in interventional trials and in the diagnosis of patients. Based on these findings, we propose to revise the A/T/(N) criteria to include MTBR-tau243 as representing insoluble tau aggregates (‘T’).
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| 18. |
- Janelidze, Shorena, et al.
(författare)
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Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment
- 2024
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Ingår i: JAMA NEUROLOGY. - 2168-6149 .- 2168-6157.
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain beta-amyloid (A beta) levels who are at high risk of accumulating A beta. OBJECTIVE To investigate if combining plasma biomarkers could be useful in predicting subsequent development of A beta pathology in CU individuals with subthreshold brain A beta levels (defined as A beta levels <40 Centiloids) at baseline. DESIGN, SETTING, AND PARTICIPANTS This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and A beta 42/40 assessments and A beta assessments with positron emission tomography (A beta-PET) or cerebrospinal fluid (CSF) A beta 42/40. Data were analyzed between April 2023 and May 2024. EXPOSURES Baseline plasma levels of A beta 42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). MAIN OUTCOMES AND MEASURES Cross-sectional and longitudinal PET and CSF measures of brain A beta pathology. RESULTS This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF A beta-status, a combination of plasma %p-tau217 and A beta 42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline A beta-PET, baseline plasma %p-tau217 and A beta 42/40 levels were significantly associated with baseline A beta-PET (n = 384) and increases in A beta-PET over time (n = 224). Associations of plasma %p-tau217 and A beta 42/40 and their interaction with baseline A beta-PET (%p-tau217: beta = 2.77; 95% CI, 1.84-3.70; A beta 42/40: beta = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 x A beta 42/40: beta = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal A beta-PET (%p-tau217: beta = 0.67; 95% CI, 0.48-0.87; A beta 42/40: beta = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 x A beta 42/40: beta = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and A beta 42/40 were independently associated with longitudinal A beta-PET in Knight ADRC (%p-tau217: beta = 0.71; 95% CI, 0.26-1.16; P = .002; A beta 42/40: beta = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF A beta 42/40 in BioFINDER-1 (p-tau217: beta = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; A beta 42/40: beta = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold A beta levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. CONCLUSIONS AND RELEVANCE Results of this cohort study suggest that combining plasma p-tau217and A beta 42/40 levels could be useful for predicting development of A beta pathology in people with early stages of subthreshold A beta accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.
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| 19. |
- Kraft, Andrew W, et al.
(författare)
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Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.
- 2013
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Ingår i: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. - : Wiley. - 1530-6860. ; 27:1, s. 187-98
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Tidskriftsartikel (refereegranskat)abstract
- The accumulation of aggregated amyloid-β (Aβ) in amyloid plaques is a neuropathological hallmark of Alzheimer's disease (AD). Reactive astrocytes are intimately associated with amyloid plaques; however, their role in AD pathogenesis is unclear. We deleted the genes encoding two intermediate filament proteins required for astrocyte activation-glial fibrillary acid protein (Gfap) and vimentin (Vim)-in transgenic mice expressing mutant human amyloid precursor protein and presenilin-1 (APP/PS1). The gene deletions increased amyloid plaque load: APP/PS1 Gfap(-/-)Vim(-/-) mice had twice the plaque load of APP/PS1 Gfap(+/+)Vim(+/+) mice at 8 and 12 mo of age. APP expression and soluble and interstitial fluid Aβ levels were unchanged, suggesting that the deletions had no effect on APP processing or Aβ generation. Astrocyte morphology was markedly altered by the deletions: wild-type astrocytes had hypertrophied processes that surrounded and infiltrated plaques, whereas Gfap(-/-)Vim(-/-) astrocytes had little process hypertrophy and lacked contact with adjacent plaques. Moreover, Gfap and Vim gene deletion resulted in a marked increase in dystrophic neurites (2- to 3-fold higher than APP/PS1 Gfap(+/+)Vim(+/+) mice), even after normalization for amyloid load. These results suggest that astrocyte activation limits plaque growth and attenuates plaque-related dystrophic neurites. These activities may require intimate contact between astrocyte and plaque.-Kraft, A. W., Hu, X., Yoon, H., Yan, P., Xiao, Q., Wang, Y., Gil, S. C., Brown, J., Wilhelmsson, U., Restivo, J. L., Cirrito, J. R., Holtzman, D. M., Kim, J., Pekny, M., Lee, J.-M. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice.
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| 20. |
- Nidever, David L., et al.
(författare)
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The Lazy Giants : APOGEE Abundances Reveal Low Star Formation Efficiencies in the Magellanic Clouds
- 2020
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Ingår i: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 895:2
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Tidskriftsartikel (refereegranskat)abstract
- We report the first APOGEE metallicities and alpha-element abundances measured for 3600 red giant stars spanning a large radial range of both the Large (LMC) and Small Magellanic Clouds, the largest Milky Way (MW) dwarf galaxies. Our sample is an order of magnitude larger than that of previous studies and extends to much larger radial distances. These are the first results presented that make use of the newly installed southern APOGEE instrument on the du Pont telescope at Las Campanas Observatory. Our unbiased sample of the LMC spans a large range in metallicity, from [Fe/H] = -0.2 to very metal-poor stars with [Fe/H] -2.5, the most metal-poor Magellanic Cloud (MC) stars detected to date. The LMC [alpha/Fe]-[Fe/H] distribution is very flat over a large metallicity range but rises by similar to 0.1 dex at -1.0 < [Fe/H] less than or similar to -0.5. We interpret this as a sign of the known recent increase in MC star formation activity and are able to reproduce the pattern with a chemical evolution model that includes a recent "starburst." At the metal-poor end, we capture the increase of [alpha/Fe] with decreasing [Fe/H] and constrain the "alpha-knee" to [Fe/H] less than or similar to -2.2 in both MCs, implying a low star formation efficiency of similar to 0.01 Gyr(-1). The MC knees are more metal-poor than those of less massive MW dwarf galaxies such as Fornax, Sculptor, or Sagittarius. One possible interpretation is that the MCs formed in a lower-density environment than the MW, a hypothesis that is consistent with the paradigm that the MCs fell into the MW's gravitational potential only recently.
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