| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Kim, Joon Tae, et al.
(författare)
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Dual antiplatelet Use for extended period taRgeted to AcuTe ischemic stroke with presumed atherosclerotic OrigiN (DURATION) trial : Rationale and design
- 2023
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 18:8, s. 1015-1020
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: The optimal duration of dual antiplatelet therapy (DAPT) with clopidogrel-aspirin for the large artery atherosclerotic (LAA) stroke subtype has been debated. Aims: To determine whether the 1-year risk of recurrent vascular events could be reduced by a longer duration of DAPT in patients with the LAA stroke subtype. Methods and study design: A total of 4806 participants will be recruited to detect a statistically significant relative risk reduction of 22% with 80% power and a two-sided alpha error of 0.05, including a 10% loss to follow-up. This is a registry-based, multicenter, prospective, randomized, open-label, blinded end point study designed to evaluate the efficacy and safety of a 12-month duration of DAPT compared with a 3-month duration of DAPT in the LAA stroke subtype. Patients will be randomized (1:1) to either DAPT for 12 months or DAPT for 3 months, followed by monotherapy (either aspirin or clopidogrel) for the remaining 9 months. Study outcomes: The primary efficacy outcome of the study is a composite of stroke (ischemic or hemorrhagic), myocardial infarction, and all-cause mortality for 1 year after the index stroke. The secondary efficacy outcomes are (1) stroke, (2) ischemic stroke or transient ischemic attack, (3) hemorrhagic stroke, and (4) all-cause mortality. The primary safety outcome is major bleeding. Discussion: This study will help stroke physicians determine the appropriate duration of dual therapy with clopidogrel-aspirin for patients with the LAA stroke subtype. Trial registration: URL: https://cris.nih.go.kr/cris. CRIS Registration Number: KCT0004407.
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| 4. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 5. |
- Jung, Se Yong, et al.
(författare)
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Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database
- 2022
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Ingår i: Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:2, s. 501-513
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Tidskriftsartikel (refereegranskat)abstract
- On October 2020, the US Food and Drug Administration (FDA) approved remdesivir as the first drug for the treatment of coronavirus disease 2019 (COVID-19), increasing remdesivir prescriptions worldwide. However, potential cardiovascular (CV) toxicities associated with remdesivir remain unknown. We aimed to characterize the CV adverse drug reactions (ADRs) associated with remdesivir using VigiBase, an individual case safety report database of the World Health Organization (WHO). Disproportionality analyses of CV-ADRs associated with remdesivir were performed using reported odds ratios and information components. We conducted in vitro experiments using cardiomyocytes derived from human pluripotent stem cell cardiomyocytes (hPSC-CMs) to confirm cardiotoxicity of remdesivir. To distinguish drug-induced CV-ADRs from COVID-19 effects, we restricted analyses to patients with COVID-19 and found that, after adjusting for multiple confounders, cardiac arrest (adjusted odds ratio [aOR]: 1.88, 95% confidence interval [CI]: 1.08-3.29), bradycardia (aOR: 2.09, 95% CI: 1.24-3.53), and hypotension (aOR: 1.67, 95% CI: 1.03-2.73) were associated with remdesivir. In vitro data demonstrated that remdesivir reduced the cell viability of hPSC-CMs in time- and dose-dependent manners. Physicians should be aware of potential CV consequences following remdesivir use and implement adequate CV monitoring to maintain a tolerable safety margin.
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| 6. |
- Lee, Hyun-Seob, et al.
(författare)
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Foxa2 and Nurr1 Synergistically Yield A9 Nigral Dopamine Neurons Exhibiting Improved Differentiation, Function, and Cell Survival
- 2010
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 28:3, s. 501-512
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Tidskriftsartikel (refereegranskat)abstract
- Effective dopamine (DA) neuron differentiation from neural precursor cells (NPCs) is prerequisite for precursor/stem cell-based therapy of Parkinson's disease (PD). Nurr1, an orphan nuclear receptor, has been reported as a transcription factor that can drive DA neuron differentiation from non-dopaminergic NPCs in vitro. However, Nurr1 alone neither induces full neuronal maturation nor expression of proteins found specifically in midbrain DA neurons. In addition, Nurr1 expression is inefficient in inducing DA phenotype expression in NPCs derived from certain species such as mouse and human. We show here that Foxa2, a forkhead transcription factor whose role in midbrain DA neuron development was recently revealed, synergistically cooperates with Nurr1 to induce DA phenotype acquisition, midbrain-specific gene expression, and neuronal maturation. Thus, the combinatorial expression of Nurr1 and Foxa2 in NPCs efficiently yielded fully differentiated nigral (A9)-type midbrain neurons with clearly detectable DA neuronal activities. The effects of Foxa2 in DA neuron generation were observed regardless of the brain regions or species from which NPCs were derived. Furthermore, DA neurons generated by ectopic Foxa2 expression were more resistant to toxins. Importantly, Foxa2 expression resulted in a rapid cell cycle exit and reduced cell proliferation. Consistently, transplantation of NPCs transduced with Nurr1 and Foxa2 generated grafts enriched with midbrain-type DA neurons but reduced number of proliferating cells, and significantly reversed motor deficits in a rat PD model. Our findings can be applied to ongoing attempts to develop an efficient and safe precursor/stem cell-based therapy for PD. STEM CELLS 2010; 28: 501-512
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| 7. |
- Abbafati, Cristiana, et al.
(författare)
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- 2020
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Choi, Jae Won, et al.
(författare)
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Interface-driven seebeck effect in two-dimensional trilayer-stacked PtTe2/MoS2/MoS2 heterostructures via electron-electron interactions
- 2023
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Ingår i: Nano Energy. - : Elsevier. - 2211-2855 .- 2211-3282. ; 115
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Tidskriftsartikel (refereegranskat)abstract
- Two-dimensional (2D) platinum telluride (PtTe2), which is one of the promising metallic transition metal dichalcogenides, has been proven as an essential candidate for electronic devices, magnetic devices, type-II Dirac fermions, topological superconductors, and other optoelectronic applications. However, the formation and thermal transport as important thermoelectric (TE) device applications have not been realized in large-area 2D PtTe2 films due to their semi-metallic properties. Here, we report an innovative approach to enhance the in-plane TE power factors by piling the metallic PtTe2 films on high-resistance (> 10 MO) intrinsic MoS2 films to form bilayer-PtTe2/MoS2 (5 nm/7 nm)//sapphire and trilayer-PtTe2/MoS2/MoS2 (5 nm/7 nm/7 nm)//sapphire heterostructures via wet-transfer stacking method. Such approaches can be achieved by utilizing 2D/2D heterostructure to increase the electron effective mass due to the strong electron-electron interaction at interface under temperature gradient along the samples and ultimately increase Seebeck coefficients via interface-driven Seebeck effect along with a metallic high-conductivity top-PtTe2 films. The trilayer-stacked PtTe2/MoS2/MoS2 heterostructures exhibit an extremely high Seebeck coefficient of 21.6 mu V/K and power factor of similar to 0.2 mW/m.K-2, which are 231 % and similar to 727 %, higher than those of the metallic 5-nm-thick single PtTe2 film on the sapphire substrate, respectively. Our new physics and observation can pave the way toward an effective strategy for understating 2D/2D TMDC heterostructure materials for high Fig.-of-merit TE energy harvesting devices.
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| 9. |
- Choi, Jae Won, et al.
(författare)
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Observation of a Strong Decoupling Phenomenon in Pt/Si Hybrid Structures for In-Plane Thermoelectric Properties
- 2022
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Ingår i: The Journal of Physical Chemistry C. - : American Chemical Society (ACS). - 1932-7447 .- 1932-7455. ; 126:40, s. 17283-17290
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Tidskriftsartikel (refereegranskat)abstract
- The performance of thermoelectric (TE) materials is limited by the intrinsic coupling of the Seebeck coefficient and the electrical conductivity such that an increase in one leads to a decrease in the other with respect to the carrier concentration. This coupling makes it particularly difficult to enhance the TE power factor in TE materials. In this study, we added a Pt top layer over a silicon wafer, forming a hybridized Pt/Si structure to drive a strong decoupling of the Seebeck coefficient and electrical conductivity. The results show that the electrical resistance in the Pt/Si hybrid structure decreased by ∼94 times compared to that of a single-layer lightly doped Si substrate at 300 K, while the Seebeck coefficient in the hybrid structure decreased slightly compared to that of the single layer. The remarkably high TE performance of the Pt/Si hybrid structure is brought about by the hybridization of the intrinsic high-conductivity Pt layer and the high-Seebeck coefficient Si substrate. In addition, we demonstrate that this novel and effective decoupling method enables the assessment of the in-plane intrinsic Seebeck coefficient of a lightly doped Si wafer, which typically has an electrical resistance that is extremely high to measure the Seebeck coefficient even with a high-resolution voltmeter. These results represent a significant advancement in the understanding of electrical transport in TE materials, which will invigorate further research on Si-based devices for realizing large-area watt-scale TE generation at room temperature.
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| 10. |
- Kang, Min-Sung, et al.
(författare)
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Enhanced Transverse Seebeck Coefficients in 2D/2D PtSe2/MoS2 Heterostructures Using Wet-Transfer Stacking
- 2022
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Ingår i: ACS Applied Materials and Interfaces. - : American Chemical Society (ACS). - 1944-8244 .- 1944-8252. ; 14:46, s. 51881-51888
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Tidskriftsartikel (refereegranskat)abstract
- It is very challenging to estimate thermoelectric (TE) properties when applying millimeter-scale two-dimensional (2D) transition metal dichalcogenide (TMDC) materials to TE device applications, particularly their Seebeck coefficient due to their high intrinsic electrical resistance. This paper proposes an innovative approach to measure large transverse (i.e., in-plane) Seebeck coefficients for 2D TMDC materials by placing a low resistance (LR) semimetallic PtSe2 film on high-resistance (HR) semiconducting MoS2 (>10 M omega), whose internal resistance is too high to measure the Seebeck coefficient, forming a heterojunction structure using wet-transfer stacking. The vertically stacked LRPtSe2 (3 nm)/HR-MoS2 (12 nm) heterostructure film exhibits a high Seebeck coefficient > 190 mu V/K up to 5 K temperature difference. This unusual behavior can be explained by an additional Seebeck effect induced at the interface between the LR-2D/HR2D heterostructure. The proposed stacked LR-PtSe2/HR-MoS2 heterostructure film offers promising phenomena 2D/2D materials that enable innovative TE device applications.
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| 11. |
- Kim, Min-Jeong, et al.
(författare)
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Intrinsic Seebeck coefficients of 2D polycrystalline PtSe2 semiconducting films through two-step annealing
- 2023
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Ingår i: Journal of Materials Chemistry A. - : Royal Society of Chemistry. - 2050-7488 .- 2050-7496. ; 11:11, s. 5714-5724
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Tidskriftsartikel (refereegranskat)abstract
- Because of the high contact resistance between a metal and a film, evaluating the intrinsic Seebeck coefficient of large-area two-dimensional (2D) semiconducting films with high-resistance is challenging. Here, we report a simple scheme to measure the large-area Seebeck coefficients of 2D polycrystalline platinum diselenide (PtSe2) thin films, whose electrical resistance (>2 M omega) is too high to measure the thermoelectric (TE) properties, by thermal annealing. As-prepared PtSe2 thin films deposited on sapphire substrates and treated by a two-step thermal annealing process at 574 K exhibited an intrinsic Seebeck coefficient > similar to 160 mu V K-1, which is 400% higher than that of the single-crystalline PtSe2 bulk, under a temperature gradient of up to 5 K along the samples. In addition, we confirm that the in-plane Seebeck coefficient of the two-step annealed samples was independent of the metal electrode. In addition, the role of thermal annealing in intrinsically-high-resistance 2D PtSe2 semiconducting films based on the atomic-scale crystallographic characteristics of these films and the measured contact resistance between the metal and PtSe2 layer is further discussed. Our finding represents an important achievement in understanding and measuring the Seebeck effect of high-TE-performance 2D layered transition metal dichalcogenide materials.
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| 12. |
- Kim, Yun-Ho, et al.
(författare)
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Barrier-free semimetallic PtSe2 contact formation in two-dimensional PtSe2/PtSe2 homostructure for high-performance field-effect transistors
- 2023
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Ingår i: Applied Surface Science. - : ELSEVIER. - 0169-4332 .- 1873-5584. ; 638
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Tidskriftsartikel (refereegranskat)abstract
- The search for low-resistance metal contacts on two-dimensional (2D) layered transition metal dichalcogenide (TMDC) materials for high-performance electronic devices remains challenging owing to the lack of interfacial bonding on the surface and a strong Fermi-level pinning effect. In this study, we demonstrate a high-performance 2D large-area homostructured PtSe2/PtSe2 field-effect transistor (FET) by introducing a Schottky-barrier-free and semimetallic PtSe2 film (top layer) as an ohmic contact to semiconducting 2D PtSe2 films (bottom layer) via the wet-transfer method. We successfully improved the current on/off ratio of homostructured 2D/2D PtSe2/PtSe2 FET by more than approximately twofold increase compared to the PtSe2 FET with Pt contacts owing to the barrier-free homojunction PtSe2 layer. Our finding represents a significant achievement in obtaining highperformance electronic devices with barrier-free contacts on homostructured PtSe2 FETs and paves the way toward a promising strategy for wafer-scale 2D TMDC electronic devices.
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| 13. |
- Kwon, Hyuk Sung, et al.
(författare)
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Early increment of soluble triggering receptor expressed on myeloid cells 2 in plasma might be a predictor of poor outcome after ischemic stroke
- 2020
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Ingår i: Journal of clinical neuroscience. - : ELSEVIER SCI LTD. - 0967-5868 .- 1532-2653. ; 73, s. 215-218
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Tidskriftsartikel (refereegranskat)abstract
- Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) is derived from cleavage of TREM2, which is expressed on the cell surface of microlgia and other tissue-specific macrophages. In the present study, the changes in the sTREM2 levels after ischemic stroke (IS) and their association with clinical outcomes were evaluated. A total of 43 patients diagnosed with non-cardioembolic IS between June 2011 and May 2014 were consecutively included in this study. Patients treated with intravenous thrombolysis or intra-arterial thrombectomy were excluded. Plasma samples were collected three times (days 1, 7, and 90) after ictus. The sTREM2 level was measured in the samples using the highly sensitive solid-phase proximity ligation assay (SP-PLA). Among the 43 subjects, higher initial NIH stroke scale (NIHSS) score (P = 0.005), early increment of sTREM2 (P < 0.001), and late decrement of sTREM2 (P = 0.002), were more common in patients with poor outcome. Based on multivariate analysis, initial NIHSS score (P = 0.015) and early increment of sTREM2 (P = 0.032) were independently associated with poor outcome. The results from the present study indicate that increment of sTREM2 level at the early phase was a predictor of poor outcome. Serial follow-up of sTREM2 may aid prognosis after stroke.
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| 14. |
- Lee, Won-Yong, et al.
(författare)
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Abnormal Seebeck Effect in Vertically Stacked 2D/2D PtSe2/PtSe2 Homostructure
- 2022
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Ingår i: Advanced Science. - : Wiley-VCH Verlagsgesellschaft. - 2198-3844. ; 9:36
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Tidskriftsartikel (refereegranskat)abstract
- When a thermoelectric (TE) material is deposited with a secondary TE material, the total Seebeck coefficient of the stacked layer is generally represented by a parallel conductor model. Accordingly, when TE material layers of the same thickness are stacked vertically, the total Seebeck coefficient in the transverse direction may change in a single layer. Here, an abnormal Seebeck effect in a stacked two-dimensional (2D) PtSe2/PtSe2 homostructure film, i.e., an extra in-plane Seebeck voltage is produced by wet-transfer stacking at the interface between the PtSe2 layers under a transverse temperature gradient is reported. This abnormal Seebeck effect is referred to as the interfacial Seebeck effect in stacked PtSe2/PtSe2 homostructures. This effect is attributed to the carrier-interface interaction, and has independent characteristics in relation to carrier concentration. It is confirmed that the in-plane Seebeck coefficient increases as the number of stacked PtSe2 layers increase and observed a high Seebeck coefficient exceeding ≈188 µV K−1 at 300 K in a four-layer-stacked PtSe2/PtSe2 homostructure.
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| 15. |
- Lee, Won-Yong, et al.
(författare)
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Alternatingly Stacked Low- and High-Resistance PtSe2/PtSe2 Homostructures Boost Thermoelectric Power Factors
- 2023
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Ingår i: Advanced Electronic Materials. - : John Wiley & Sons. - 2199-160X. ; 9:8
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Tidskriftsartikel (refereegranskat)abstract
- 2D transition-metal dichalcogenide (TMDC) materials are promising candidates with excellent thermoelectric (TE) properties owing to their low dimensionality in electronic and phonon transport. However, the considerable coupling of the Seebeck coefficient and electrical conductivity in such TE materials eventually results in the limit of the TE power factor increase, which severely hinders potential TE device applications. Herein, an alternative approach is demonstrated for breaking the strong coupling between the Seebeck coefficient and electrical conductivity in single TE materials by adopting a novel stacked PtSe2/PtSe2 homostructure. By alternately piling low-resistance (LR) PtSe2 (3 nm) onto high-resistance (HR) PtSe2 (2 nm) as one unit, the Seebeck coefficient and electrical conductivity of such stacked homostructures can be greatly enhanced with slightly improved electrical conductivity, ultimately resulting in a TE power factor in three-unit-stacked homostructures that is approximate to 1,648% higher than that of a single PtSe2 (15 nm) layer with the same thickness. This enhancement is attributed to an independent increase in the Seebeck coefficient, which depends on the interface among the LR and HR PtSe2 layers. The findings pave the way for a method that, unlike power factor optimization in conventional thermoelectric materials, can only utilize the Seebeck coefficient and electrical conductivity of each layer in a stacked homostructure.
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| 16. |
- Ossenkoppele, Rik, et al.
(författare)
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Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease : A Head-to-Head Comparison against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 961-971
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear. Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers. Design, Setting, and Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ). Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation. Main Outcomes and Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations. Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P <.001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P <.001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P <.001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P =.71). Age (t = -2.28; P =.02), but not sex (t = 0.92; P =.36) or APOE genotype (t = 1.06; P =.29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels. Conclusions and Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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| 17. |
- Ossenkoppele, Rik, et al.
(författare)
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Assessment of Demographic, Genetic, and Imaging Variables Associated with Brain Resilience and Cognitive Resilience to Pathological Tau in Patients with Alzheimer Disease
- 2020
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 77:5, s. 632-642
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Better understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience). Objective: To examine the demographic (age, sex, and educational level), genetic (APOE-ϵ4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time. Design, Setting, an Participants: In this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019. Exposures: Standard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET. Main Outcomes and Measures: Separate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ϵ4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable. Results: A total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β =-0.15, P =.02) and young patients (standardized β =-0.20, P =.006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P <.001) and global cortical thickness (standardized β = 0.23, P <.001) were associated with greater cognitive resilience to pathological tau. Linear mixed models indicated a significant interaction of brain resilience × cognitive resilience × time on MMSE (β [SE] =-0.235 [0.111], P =.03), with steepest slopes for individuals with both low brain and cognitive resilience. Conclusions and Relevance: Results of this study suggest that women and young patients with AD have relative preservation of brain structure when exposed to neocortical pathological tau. Interindividual differences in resilience to pathological tau may be important to disease progression because participants with both low brain and cognitive resilience had the most rapid cognitive decline over time.
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| 18. |
- Ossenkoppele, Rik, et al.
(författare)
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Distinct tau PET patterns in atrophy-defined subtypes of Alzheimer's disease
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:2, s. 335-344
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) “typical”, (2) “limbic-predominant”, (3) “hippocampal-sparing”, and (4) “mild atrophy”. We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes. Methods: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β–positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results: Voxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline. Discussion: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.
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| 19. |
- Ossenkoppele, Rik, et al.
(författare)
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The impact of demographic, clinical, genetic, and imaging variables on tau PET status
- 2021
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 48:7, s. 2245-2258
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: A substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer’s disease (AD) dementia and mild cognitive impairment (MCI) are tau PET–negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET–positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status. Methods: We included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model. Results: Tau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan. Conclusion: We identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.
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| 20. |
- Wang, Haidong, et al.
(författare)
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Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015 : the Global Burden of Disease Study 2015.
- 2016
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Ingår i: The lancet. HIV. - : Elsevier. - 2352-3018. ; 3:8, s. e361-e387
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.METHODS: For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.FINDINGS: Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.INTERPRETATION: Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.
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| 21. |
- Wen, Wanqing, et al.
(författare)
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Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in Europeanancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3, CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.
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