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- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 2. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 8. |
- Link, Verena M, et al.
(författare)
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Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.
- 2018
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Ingår i: Cell. - Cambridge, United States : Cell Press. - 0092-8674 .- 1097-4172. ; 173:7, s. 1796-1809.e17
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Tidskriftsartikel (refereegranskat)abstract
- Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.
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| 9. |
- Sitar, R J, et al.
(författare)
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Multi-instrument analysis of the ionospheric signatures of a hot flow anomaly occurring on July 24, 1996
- 1998
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Ingår i: JOURNAL OF GEOPHYSICAL RESEARCH-SPACE PHYSICS. ; 103, s. 23357-23372
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Tidskriftsartikel (refereegranskat)abstract
- We present the analysis of a coordinated set of observations from the POLAR ultraviolet imager (UVI), ground magnetometers, incoherent scatter radar, solar wind monitors, and the DMSP satellite, focused on a traveling convection vortex (TCV) event on July 24, 1996. Starting at approximately 1036 UT, ground magnetometers in Greenland and eastern Canada observe pulsations consistent with the passing overhead of a series of TCV field-aligned current pairs. Azimuthal scans by the Sondrestrom incoherent scatter radar located near Kangerlussuaq (formerly Sondrestrom), Greenland, at this time show strong modulation in the strength and direction of ionospheric plasma flow. The magnetometer pulsations grow in magnitude over the next hour, peaking in intensity at 1137 UT. Images from the UVI instrument show a localized intensification of auroral emissions over central and western Greenland at 1139 UT. Subsequent images show the intensification grow in strength and propagate westward (tailward) until approximately 1158 UT, at which time the intensification fades, These observations are consistent with the westward passage of four pairs of TCVs over central Greenland. The intensification of auroral emissions at 1139 UT is associated with the leading vortex of the fourth TCV pair, thought to be the result of an upward field-aligned current. The modulated flow observed by the radar is the result of the strong electric fields associated with the field-aligned current systems responsible for the impulsive TCV as they pass through the field of view of the radar. Measurements taken in the solar wind by the Wind spacecraft suggest that a pressure change triggers the onset of TCV activity. A subsequent sudden change in the orientation of the interplanetary magnetic field produces a hot flow anomaly which forms at the bow shock. We believe that the interaction of the hot flow anomaly with the magnetopause intensified the fourth TCV pair and. produced the associated auroral brightening. DMSP particle data indicate that the TCVs occur on field lines which map to the boundary plasma sheet-low latitude boundary layer interface. The ground observations associated with the hot flow anomaly are the first of their kind and provide a mechanism to tie an interplanetary magnetic field orientation change into the existing theory that TCVs result from a deformation of the magnetopause.
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