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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. |
- Brownstein, Catherine A., et al.
(författare)
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An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R53-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. Results: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. Conclusions: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups.
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| 5. |
- 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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| 9. |
- Semenas, E, et al.
(författare)
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Surgical Outcome Risk Tool (SORT) to predict 30-day postoperative mortality in a mixed surgical population in Swedish tertiary hospitals
- 2023
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 110:5, s. 584-590
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe Surgical Outcome Risk Tool (SORT) was derived and validated in the UK to improve preoperative prediction of postoperative risk. The aim of this study was to validate the SORT in a European mixed-case surgical population outside of the UK.MethodsThe study included patients aged at least 18 years with ASA Physical Status (ASA-PS) grades I–V who underwent non-cardiac surgery at four tertiary hospitals in Sweden between November 2015 and February 2016. Exclusion criteria were surgery under local anaesthesia and missing data on the SORT predictors (ASA-PS, surgical urgency, high-risk surgery, surgical severity, malignancy, age over 65 years). The outcome was 30-day mortality. Discrimination and calibration of the SORT were assessed using area under the receiver operating curve (AUROC) statistics and calibration plots. A sensitivity analysis was done in a high-risk subgroup (ASA-PS III or higher; surgical complexity major to Xmajor according to the SORT; gastrointestinal, orthopaedic, urogenital/obstetric surgery; and age at least 18 years).ResultsThe validation cohort included 17 965 patients; median age was 58 (i.q.r. 40–70) years, 43.2 per cent were men, and the mortality rate at 30 days was 1.6 per cent. The SORT had excellent discrimination, with an AUROC of 0.91 (95 per cent c.i. 0.89 to 0.92), and good calibration. The high-risk subgroup (1807 patients) had a 30-day mortality rate of 5.6 per cent; in the sensitivity analysis, the SORT had good discrimination, with an AUROC of 0.79 (0.74 to 0.83), and calibration remained good.ConclusionThe estimates of the original the SORT for prediction of 30-day mortality were valid and reliable in a mixed-case surgical population in a non-UK European setting.
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| 10. |
- Bartha, Erzsebet, et al.
(författare)
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A 1-year perspective on goal-directed therapy in elderly with hip fracture: Secondary outcomes
- 2019
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Ingår i: Acta Anaesthesiologica Scandinavica. - : WILEY. - 0001-5172 .- 1399-6576. ; 63:5, s. 610-614
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Tidskriftsartikel (refereegranskat)abstract
- Background We have previously reported inconclusive results from a randomized controlled trial in elderly with hip-fracture comparing intra-operative goal-directed therapy with routine fluid treatment. Now we aimed to describe and compare secondary outcomes at 4 months and 1 year follow-up and to analyze the cost-effectiveness. Methods Patients with hip fracture (age amp;gt;= 70) were randomized for GDT or routine fluid treatment (RFT). The secondary outcomes were long-term survival, complications, number of hospital readmissions, and quality of life (EQ-5D) changes. Additionally, cost effectiveness was analyzed by an analytic tool which combines the clinical effectiveness, quality of life changes and costs. Results Patient data (GDT n = 74; RFT n = 75) were analyzed on an intention to treat basis. Statistically significant differences (GDT vs RFT) were not found considering survival (RR 0.76, 95%CI 0.45-1.28) and complications (RR 0.68, 95% CI 0.4-1.10) at 12 months. No statistically significant difference was found between hospital readmissions and quality of life changes. Conclusion The statistical uncertainty of risk reduction of negative outcomes and the large variability of the collected data indicate the need of further research in large sample sizes. To enable future health economic evaluation for decision support surrounding implementation of GDT, we suggest adding patient-oriented outcomes in future trials.
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