| 26. |
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| 27. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
-
Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 28. |
- Di Angelantonio, Emanuele, et al.
(författare)
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Association of Cardiometabolic Multimorbidity With Mortality : The Emerging Risk Factors Collaboration
- 2015
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
-
Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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| 29. |
- Manzoni, Claudia, et al.
(författare)
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Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia
- 2024
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Ingår i: American Journal of Human Genetics. - 0002-9297. ; 111:7, s. 1316-1329
-
Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10−12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10−12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10−8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.
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| 30. |
- Loranty, Michael M., et al.
(författare)
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Reviews and syntheses : Changing ecosystem influences on soil thermal regimes in northern high-latitude permafrost regions
- 2018
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Ingår i: Biogeosciences. - : Copernicus GmbH. - 1726-4170 .- 1726-4189. ; 15:17, s. 5287-5313
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Forskningsöversikt (refereegranskat)abstract
- Soils in Arctic and boreal ecosystems store twice as much carbon as the atmosphere, a portion of which may be released as high-latitude soils warm. Some of the uncertainty in the timing and magnitude of the permafrost-climate feedback stems from complex interactions between ecosystem properties and soil thermal dynamics. Terrestrial ecosystems fundamentally regulate the response of permafrost to climate change by influencing surface energy partitioning and the thermal properties of soil itself. Here we review how Arctic and boreal ecosystem processes influence thermal dynamics in permafrost soil and how these linkages may evolve in response to climate change. While many of the ecosystem characteristics and processes affecting soil thermal dynamics have been examined individually (e.g., vegetation, soil moisture, and soil structure), interactions among these processes are less understood. Changes in ecosystem type and vegetation characteristics will alter spatial patterns of interactions between climate and permafrost. In addition to shrub expansion, other vegetation responses to changes in climate and rapidly changing disturbance regimes will affect ecosystem surface energy partitioning in ways that are important for permafrost. Lastly, changes in vegetation and ecosystem distribution will lead to regional and global biophysical and biogeochemical climate feedbacks that may compound or offset local impacts on permafrost soils. Consequently, accurate prediction of the permafrost carbon climate feedback will require detailed understanding of changes in terrestrial ecosystem distribution and function, which depend on the net effects of multiple feedback processes operating across scales in space and time.
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| 31. |
- Roth, Gregory A, et al.
(författare)
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Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019 : Update From the GBD 2019 Study
- 2020
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 76:25, s. 2982-3021
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Tidskriftsartikel (refereegranskat)abstract
- Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.
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| 32. |
- Smith, Gustav, et al.
(författare)
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Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure
- 2016
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 12:5
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Tidskriftsartikel (refereegranskat)abstract
- Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinants of mortality in patients with new-onset heart failure, we performed a meta-analysis of genome-wide association studies and follow-up genotyping in independent populations. We identified and replicated an association for a genetic variant on chromosome 5q22 with 36% increased risk of death in subjects with heart failure (rs9885413, P = 2.7x10-9). We provide evidence from reporter gene assays, computational predictions and epigenomic marks that this polymorphism increases activity of an enhancer region active in multiple human tissues. The polymorphism was further reproducibly associated with a DNA methylation signature in whole blood (P = 4.5x10-40) that also associated with allergic sensitization and expression in blood of the cytokine TSLP (P = 1.1x10-4). Knockdown of the transcription factor predicted to bind the enhancer region (NHLH1) in a human cell line (HEK293) expressing NHLH1 resulted in lower TSLP expression. In addition, we observed evidence of recent positive selection acting on the risk allele in populations of African descent. Our findings provide novel genetic leads to factors that influence mortality in patients with heart failure.
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| 33. |
- Allison, Samantha L, et al.
(författare)
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Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age.
- 2021
-
Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 102, s. 151-160
-
Tidskriftsartikel (refereegranskat)abstract
- This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age=58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median=5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aβ42×global atrophy×age interaction; individuals with less global atrophy and lower ptau181/Aβ42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aβ42. The hippocampal volume×age×ptau181/Aβ42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.
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| 34. |
- Illán-Gala, Ignacio, et al.
(författare)
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Plasma tau and neurofilament light in frontotemporal lobar degeneration and Alzheimer's disease.
- 2021
-
Ingår i: Neurology. - 1526-632X. ; 96:5
-
Tidskriftsartikel (refereegranskat)abstract
- To test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically-diagnosed Alzheimer's disease (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses.We measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-Tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression and survival and cortical thickness.Plasma NfL, but not plasma t-tau discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-Tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone.Plasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.This study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance than plasma t-tau in FTLD and AD.
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| 35. |
- Motovylyak, Alice, et al.
(författare)
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Age-related differences in white matter microstructure measured by advanced diffusion MRI in healthy older adults at risk for Alzheimer’s disease
- 2022
-
Ingår i: Aging Brain. - : Elsevier. - 2589-9589. ; 2
-
Tidskriftsartikel (refereegranskat)abstract
- Neurite orientation dispersion and density imaging (NODDI) is an advanced diffusion imaging technique, which can detect more distinct microstructural features compared to conventional Diffusion Tensor Imaging (DTI). NODDI allows the signal to be divided into multiple water compartments and derive measures for orientation dispersion index (ODI), neurite density index (NDI) and volume fraction of isotropic diffusion compartment (FISO). This study aimed to investigate which diffusion metric—fractional anisotropy (FA), mean diffusivity (MD), NDI, ODI, or FISO—is most influenced by aging and reflects cognitive function in a population of healthy older adults at risk for Alzheimer’s disease (AD). Age was significantly associated with all but one diffusion parameters and regions of interest. NDI and MD in the cingulate region adjacent to the cingulate cortex showed a significant association with a composite measure of Executive Function and was proven to partially mediate the relationship between aging and Executive Function decline. These results suggest that both DTI and NODDI parameters are sensitive to age-related differences in white matter regions vulnerable to aging, particularly among older adults at risk for AD.
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| 36. |
- Myers-Smith, Isla H., et al.
(författare)
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Complexity revealed in the greening of the Arctic
- 2020
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Ingår i: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 10:2, s. 106-117
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Tidskriftsartikel (refereegranskat)abstract
- As the Arctic warms, vegetation is responding, and satellite measures indicate widespread greening at high latitudes. This ‘greening of the Arctic’ is among the world’s most important large-scale ecological responses to global climate change. However, a consensus is emerging that the underlying causes and future dynamics of so-called Arctic greening and browning trends are more complex, variable and inherently scale-dependent than previously thought. Here we summarize the complexities of observing and interpreting high-latitude greening to identify priorities for future research. Incorporating satellite and proximal remote sensing with in-situ data, while accounting for uncertainties and scale issues, will advance the study of past, present and future Arctic vegetation change.
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| 37. |
- Warren, Wesley C, et al.
(författare)
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The genome of a songbird
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 757-762
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Tidskriftsartikel (refereegranskat)abstract
- The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.
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| 38. |
- Austin, Thomas R., et al.
(författare)
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A plasma protein-based risk score to predict hip fractures
- 2024
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Ingår i: NATURE AGING. - 2662-8465.
-
Tidskriftsartikel (refereegranskat)abstract
- As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Tr & oslash;ndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53-1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined. The authors developed a proteomic risk score that improved the prediction of hip fractures in three validation cohorts analyzed by two different proteomic platforms. This risk score constitutes a new tool to stratify patients by hip fracture risk.
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| 39. |
- Austin, Thomas R, et al.
(författare)
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Large-scale circulating proteome association study (CPAS) meta-analysis identifies circulating proteins and pathways predicting incident hip fractures.
- 2024
-
Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 1523-4681. ; 39:2, s. 139-149
-
Tidskriftsartikel (refereegranskat)abstract
- Hip fractures are associated with significant disability, high cost, and mortality. However, the exact biological mechanisms underlying susceptibility to hip fractures remain incompletely understood. In an exploratory search of the underlying biology as reflected through the circulating proteome, we performed a comprehensive Circulating Proteome Association Study (CPAS) meta-analysis for incident hip fractures. Analyses included 6430 subjects from two prospective cohort studies (Cardiovascular Health Study and Trøndelag Health Study) with circulating proteomics data (aptamer-based 5K SomaScan version 4.0 assay; 4979 aptamers). Associations between circulating protein levels and incident hip fractures were estimated for each cohort using age and sex-adjusted Cox regression models. Participants experienced 643 incident hip fractures. Compared with the individual studies, inverse-variance weighted meta-analyses yielded more statistically significant associations, identifying 23 aptamers associated with incident hip fractures (conservative Bonferroni correction 0.05/4979, P<1.0×10-5). The aptamers most strongly associated with hip fracture risk corresponded to two proteins of the growth hormone/insulin growth factor system (GHR and IGFBP2), as well as GDF15 and EGFR. High levels of several inflammation-related proteins (CD14, CXCL12, MMP12, ITIH3) were also associated with increased hip fracture risk. Ingenuity pathway analysis identified reduced LXR/RXR activation and increased acute phase response signaling to be overrepresented among those proteins associated with increased hip fracture risk. These analyses identified several circulating proteins and pathways consistently associated with incident hip fractures. These findings underscore the usefulness of the meta-analytic approach for comprehensive CPAS in a similar manner as has previously been observed for large-scale human genetic studies. Future studies should investigate the underlying biology of these potential novel drug targets.
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| 40. |
- Dilday, Benjamin, et al.
(författare)
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Measurements of the Rate of Type Ia Supernovae at Redshift lsim0.3 from the Sloan Digital Sky Survey II Supernova Survey
- 2010
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 713, s. 1026-1036
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Tidskriftsartikel (refereegranskat)abstract
- We present a measurement of the volumetric Type Ia supernova (SN Ia) rate based on data from the Sloan Digital Sky Survey II (SDSS-II) Supernova Survey. The adopted sample of supernovae (SNe) includes 516 SNe Ia at redshift z <~ 0.3, of which 270(52%) are spectroscopically identified as SNe Ia. The remaining 246 SNe Ia were identified through their light curves; 113 of these objects have spectroscopic redshifts from spectra of their host galaxy, and 133 have photometric redshifts estimated from the SN light curves. Based on consideration of 87 spectroscopically confirmed non-Ia SNe discovered by the SDSS-II SN Survey, we estimate that 2.04+1.61 -0.95% of the photometric SNe Ia may be misidentified. The sample of SNe Ia used in this measurement represents an order of magnitude increase in the statistics for SN Ia rate measurements in the redshift range covered by the SDSS-II Supernova Survey. If we assume an SN Ia rate that is constant at low redshift (z < 0.15), then the SN observations can be used to infer a value of the SN rate of rV = (2.69+0.34+0.21 -0.30-0.01)×10-5 SNe yr-1 Mpc-3 (H 0/(70 km s-1 Mpc-1))3 at a mean redshift of ~0.12, based on 79 SNe Ia of which 72 are spectroscopically confirmed. However, the large sample of SNe Ia included in this study allows us to place constraints on the redshift dependence of the SN Ia rate based on the SDSS-II Supernova Survey data alone. Fitting a power-law model of the SN rate evolution, rV (z) = Ap × ((1 + z)/(1 + z 0))ν, over the redshift range 0.0 < z < 0.3 with z 0 = 0.21, results in Ap = (3.43+0.15 -0.15) × 10-5 SNe yr-1 Mpc-3 (H 0/(70 km s-1 Mpc-1))3 and ν = 2.04+0.90 -0.89.
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| 41. |
- Du, Lianlian, et al.
(författare)
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Harnessing cognitive trajectory clusterings to examine subclinical decline risk factors
- 2023
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Ingår i: Brain Communications. - 2632-1297. ; 5:6
-
Tidskriftsartikel (refereegranskat)abstract
- Cognitive decline in Alzheimer's disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally based random slope and change point parameter estimates from a Preclinical Alzheimer's disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer's disease and vascular disease varied across these cognitive clusters. Data were drawn from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer's disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with ≥3 cognitive visits were included in trajectory modelling (n = 1068). The following biomarker data were available for subsets: positron emission tomography amyloid (amyloid: n = 367; [11C]Pittsburgh compound B (PiB): global PiB distribution volume ratio); positron emission tomography tau (tau: n = 321; [18F]MK-6240: primary regions of interest meta-temporal composite); MRI neurodegeneration (neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2 fluid-attenuated inversion recovery MRI white matter ischaemic lesion volumes (vascular: white matter hyperintensities; n = 419); and plasma pTau217 (n = 165). Posterior median estimate person-level change points, slopes' pre- and post-change point and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modelling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify amyloid/tau/neurodegeneration/vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and amyloid/tau/neurodegeneration/vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, χ2, and Fisher's exact tests. Mean (standard deviation) baseline and last cognitive assessment ages were 58.4 (6.4) and 66.6 (6.6) years, respectively. Cluster analysis identified three cognitive trajectory groups representing steep, n = 77 (7.2%); intermediate, n = 446 (41.8%); and minimal, n = 545 (51.0%) cognitive decline. The steep decline group was older, had more females, APOE e4 carriers and mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher amyloid, tau, neurodegeneration and white matter hyperintensity positive proportions at last visit. Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on aetiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and amyloid/tau/neurodegeneration/vascular biomarker differences in late middle-aged adults. The result explains some of the heterogeneity in cognitive performance within cognitively unimpaired late middle-aged adults.
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| 42. |
- Dussex, Nicolas, et al.
(författare)
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Population genomics of the critically endangered kākāpō
- 2021
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Ingår i: Cell Genomics. - : Elsevier BV. - 2666-979X. ; 1:1
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Tidskriftsartikel (refereegranskat)abstract
- Summary The kākāpō is a flightless parrot endemic to New Zealand. Once common in the archipelago, only 201 individuals remain today, most of them descending from an isolated island population. We report the first genome-wide analyses of the species, including a high-quality genome assembly for kākāpō, one of the first chromosome-level reference genomes sequenced by the Vertebrate Genomes Project (VGP). We also sequenced and analyzed 35 modern genomes from the sole surviving island population and 14 genomes from the extinct mainland population. While theory suggests that such a small population is likely to have accumulated deleterious mutations through genetic drift, our analyses on the impact of the long-term small population size in kākāpō indicate that present-day island kākāpō have a reduced number of harmful mutations compared to mainland individuals. We hypothesize that this reduced mutational load is due to the island population having been subjected to a combination of genetic drift and purging of deleterious mutations, through increased inbreeding and purifying selection, since its isolation from the mainland ∼10,000 years ago. Our results provide evidence that small populations can survive even when isolated for hundreds of generations. This work provides key insights into kākāpō breeding and recovery and more generally into the application of genetic tools in conservation efforts for endangered species.
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| 43. |
- Groot, Colin, et al.
(författare)
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Latent atrophy factors related to phenotypical variants of posterior cortical atrophy
- 2020
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Ingår i: Neurology. - 1526-632X. ; 95:12, s. 1672-1685
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To determine whether atrophy relates to phenotypical variants of posterior cortical atrophy (PCA) recently proposed in clinical criteria (i.e., dorsal, ventral, dominant-parietal, and caudal) we assessed associations between latent atrophy factors and cognition. METHODS: We employed a data-driven Bayesian modeling framework based on latent Dirichlet allocation to identify latent atrophy factors in a multicenter cohort of 119 individuals with PCA (age 64 ± 7 years, 38% male, Mini-Mental State Examination 21 ± 5, 71% β-amyloid positive, 29% β-amyloid status unknown). The model uses standardized gray matter density images as input (adjusted for age, sex, intracranial volume, MRI scanner field strength, and whole-brain gray matter volume) and provides voxelwise probabilistic maps for a predetermined number of atrophy factors, allowing every individual to express each factor to a degree without a priori classification. Individual factor expressions were correlated to 4 PCA-specific cognitive domains (object perception, space perception, nonvisual/parietal functions, and primary visual processing) using general linear models. RESULTS: The model revealed 4 distinct yet partially overlapping atrophy factors: right-dorsal, right-ventral, left-ventral, and limbic. We found that object perception and primary visual processing were associated with atrophy that predominantly reflects the right-ventral factor. Furthermore, space perception was associated with atrophy that predominantly represents the right-dorsal and right-ventral factors. However, individual participant profiles revealed that the large majority expressed multiple atrophy factors and had mixed clinical profiles with impairments across multiple domains, rather than displaying a discrete clinical-radiologic phenotype. CONCLUSION: Our results indicate that specific brain behavior networks are vulnerable in PCA, but most individuals display a constellation of affected brain regions and symptoms, indicating that classification into 4 mutually exclusive variants is unlikely to be clinically useful.
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| 45. |
- Rojas, Julio C, et al.
(författare)
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Plasma neurofilament light chain predicts progression in progressive supranuclear palsy.
- 2016
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Ingår i: Annals of clinical and translational neurology. - : Wiley. - 2328-9503. ; 3:3, s. 216-25
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based biomarkers for neurodegenerative conditions could improve diagnosis and treatment development. Neurofilament light chain (NfL), a marker of axonal injury, is elevated in cerebrospinal fluid (CSF) of patients with progressive supranuclear palsy (PSP). The goal of this study was to determine the diagnostic and prognostic value of plasma NfL in patients with PSP.
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| 46. |
- Singer, Andrew C, et al.
(författare)
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Meeting Report : Risk Assessment of Tamiflu Use Under Pandemic Conditions
- 2008
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Ingår i: Environmental Health Perspectives. ; 116:11, s. 1563-7
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Tidskriftsartikel (refereegranskat)abstract
- On 3 October 2007, 40 participants with diverse expertise attended the workshop Tamiflu and the Environment: Implications of Use under Pandemic Conditions to assess the potential human health impact and environmental hazards associated with use of Tamiflu during an influenza pandemic. Based on the identification and risk-ranking of knowledge gaps, the consensus was that oseltamivir ethylester-phosphate (OE-P) and oseltamivir carboxylate (OC) were unlikely to pose an ecotoxicologic hazard to freshwater organisms. OC in river water might hasten the generation of OC-resistance in wildfowl, but this possibility seems less likely than the potential disruption that could be posed by OC and other pharmaceuticals to the operation of sewage treatment plants. The workgroup members agreed on the following research priorities: a) available data on the ecotoxicology of OE-P and OC should be published ; b) risk should be assessed for OC-contaminated river water generating OC-resistant viruses in wildfowl ; c) sewage treatment plant functioning due to microbial inhibition by neuraminidase inhibitors and other antimicrobials used during a pandemic should be investigated ; and d) realistic worst-case exposure scenarios should be developed. Additional modeling would be useful to identify localized areas within river catchments that might be prone to high pharmaceutical concentrations in sewage treatment plant effluent. Ongoing seasonal use of Tamiflu in Japan offers opportunities for researchers to assess how much OC enters and persists in the aquatic environment.
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| 47. |
- Singleton, Ellen H., et al.
(författare)
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Investigating the clinico-anatomical dissociation in the behavioral variant of Alzheimer disease
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: We previously found temporoparietal-predominant atrophy patterns in the behavioral variant of Alzheimer’s disease (bvAD), with relative sparing of frontal regions. Here, we aimed to understand the clinico-anatomical dissociation in bvAD based on alternative neuroimaging markers. Methods: We retrospectively included 150 participants, including 29 bvAD, 28 “typical” amnestic-predominant AD (tAD), 28 behavioral variant of frontotemporal dementia (bvFTD), and 65 cognitively normal participants. Patients with bvAD were compared with other diagnostic groups on glucose metabolism and metabolic connectivity measured by [18F]FDG-PET, and on subcortical gray matter and white matter hyperintensity (WMH) volumes measured by MRI. A receiver-operating-characteristic-analysis was performed to determine the neuroimaging measures with highest diagnostic accuracy. Results: bvAD and tAD showed predominant temporoparietal hypometabolism compared to controls, and did not differ in direct contrasts. However, overlaying statistical maps from contrasts between patients and controls revealed broader frontoinsular hypometabolism in bvAD than tAD, partially overlapping with bvFTD. bvAD showed greater anterior default mode network (DMN) involvement than tAD, mimicking bvFTD, and reduced connectivity of the posterior cingulate cortex with prefrontal regions. Analyses of WMH and subcortical volume showed closer resemblance of bvAD to tAD than to bvFTD, and larger amygdalar volumes in bvAD than tAD respectively. The top-3 discriminators for bvAD vs. bvFTD were FDG posterior-DMN-ratios (bvADbvFTD, area under the curve [AUC] range 0.85–0.91, all p < 0.001). The top-3 for bvAD vs. tAD were amygdalar volume (bvAD>tAD), MRI anterior-DMN-ratios (bvAD
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