| 1. |
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| 2. |
- 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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| 3. |
- 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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| 7. |
- Carninci, P, et al.
(författare)
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The transcriptional landscape of the mammalian genome
- 2005
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5740, s. 1559-1563
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Tidskriftsartikel (refereegranskat)abstract
- This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5′ and 3′ boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.
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| 8. |
- Chen, Z. C., et al.
(författare)
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Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer's disease
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:3, s. 487-496
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The tau protein plays a central role in Alzheimer's disease (AD), and there is huge interest in measuring tau in blood and cerebrospinal fluid (CSF). Methods: We developed a set of immunoassays to measure tau in specimens from humans diagnosed based on current best clinical and CSF biomarker criteria. Results: In CSF, mid-region- and N-terminal-detected tau predominated and rose in disease. In plasma, an N-terminal assay (NT1) detected elevated levels of tau in AD and AD-mild cognitive impairment (MCI). Plasma NT1 measurements separated controls from AD-MCI (area under the curve [AUC] = 0.88) and AD (AUC = 0.96) in a discovery cohort and in a Validation Cohort (with AUCs = 0.79 and 0.75, respectively). Discussion: The forms of tau in CSF and plasma are distinct, but in each specimen type, the levels of certain fragments are increased in AD. Measurement of plasma NT1 tau should be aggressively pursued as a potential blood-based screening test for AD/AD-MCI. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 9. |
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| 11. |
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| 14. |
- Bethlehem, RAI, et al.
(författare)
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Brain charts for the human lifespan
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 604:79057906, s. 525-
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Tidskriftsartikel (refereegranskat)abstract
- Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.
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| 15. |
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| 16. |
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| 17. |
- Hill, M. S., et al.
(författare)
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Reconstruction of Family-Level Phylogenetic Relationships within Demospongiae (Porifera) Using Nuclear Encoded Housekeeping Genes
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:1, s. e50437-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Demosponges are challenging for phylogenetic systematics because of their plastic and relatively simple morphologies and many deep divergences between major clades. To improve understanding of the phylogenetic relationships within Demospongiae, we sequenced and analyzed seven nuclear housekeeping genes involved in a variety of cellular functions from a diverse group of sponges. Methodology/Principal Findings: We generated data from each of the four sponge classes (i.e., Calcarea, Demospongiae, Hexactinellida, and Homoscleromorpha), but focused on family-level relationships within demosponges. With data for 21 newly sampled families, our Maximum Likelihood and Bayesian-based approaches recovered previously phylogenetically defined taxa: Keratosap, Myxospongiaep, Spongillidap, Haploscleromorphap (the marine haplosclerids) and Democlaviap. We found conflicting results concerning the relationships of Keratosap and Myxospongiaep to the remaining demosponges, but our results strongly supported a clade of Haploscleromorphap+Spongillidap+Democlaviap. In contrast to hypotheses based on mitochondrial genome and ribosomal data, nuclear housekeeping gene data suggested that freshwater sponges (Spongillidap) are sister to Haploscleromorphap rather than part of Democlaviap. Within Keratosap, we found equivocal results as to the monophyly of Dictyoceratida. Within Myxospongiaep, Chondrosida and Verongida were monophyletic. A well-supported clade within Democlaviap, Tetractinellidap, composed of all sampled members of Astrophorina and Spirophorina (including the only lithistid in our analysis), was consistently revealed as the sister group to all other members of Democlaviap. Within Tetractinellidap, we did not recover monophyletic Astrophorina or Spirophorina. Our results also reaffirmed the monophyly of order Poecilosclerida (excluding Desmacellidae and Raspailiidae), and polyphyly of Hadromerida and Halichondrida. Conclusions/Significance: These results, using an independent nuclear gene set, confirmed many hypotheses based on ribosomal and/or mitochondrial genes, and they also identified clades with low statistical support or clades that conflicted with traditional morphological classification. Our results will serve as a basis for future exploration of these outstanding questions using more taxon- and gene-rich datasets.
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| 18. |
- Sexton, Claire E., et al.
(författare)
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Novel avenues of tau research
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260. ; 20:3, s. 2240-2261
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Forskningsöversikt (refereegranskat)abstract
- INTRODUCTION: The pace of innovation has accelerated in virtually every area of tau research in just the past few years. METHODS: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation. RESULTS: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research. DISCUSSION: The virtual meeting provided an opportunity to foster cross-sector collaboration and partnerships as well as a forum for updating colleagues on research-advancing tools and programs that are steadily moving the field forward.
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| 19. |
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| 20. |
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| 21. |
- Villa, Luisa L., et al.
(författare)
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Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions
- 2007
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 356:19, s. 1915-1927
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papillomavirus types 16 (HPV-16) and 18 (HPV-18) cause approximately 70% of cervical cancers worldwide. A phase 3 trial was conducted to evaluate a quadrivalent vaccine against HPV types 6, 11, 16, and 18 (HPV-6/11/16/18) for the prevention of high-grade cervical lesions associated with HPV-16 and HPV-18. METHODS: In this randomized, double-blind trial, we assigned 12,167 women between the ages of 15 and 26 years to receive three doses of either HPV-6/11/16/18 vaccine or placebo, administered at day 1, month 2, and month 6. The primary analysis was performed for a per-protocol susceptible population that included 5305 women in the vaccine group and 5260 in the placebo group who had no virologic evidence of infection with HPV-16 or HPV-18 through 1 month after the third dose (month 7). The primary composite end point was cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18. RESULTS: Subjects were followed for an average of 3 years after receiving the first dose of vaccine or placebo. Vaccine efficacy for the prevention of the primary composite end point was 98% (95.89% confidence interval [CI], 86 to 100) in the per-protocol susceptible population and 44% (95% CI, 26 to 58) in an intention-to-treat population of all women who had undergone randomization (those with or without previous infection). The estimated vaccine efficacy against all high-grade cervical lesions, regardless of causal HPV type, in this intention-to-treat population was 17% (95% CI, 1 to 31). CONCLUSIONS: In young women who had not been previously infected with HPV-16 or HPV-18, those in the vaccine group had a significantly lower occurrence of high-grade cervical intraepithelial neoplasia related to HPV-16 or HPV-18 than did those in the placebo group.
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| 22. |
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| 23. |
- Jack, Jr., et al.
(författare)
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NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease
- 2018
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:4, s. 535-562
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Forskningsöversikt (refereegranskat)abstract
- In 2011, the National Institute on Aging and Alzheimer's Association created separate diagnostic recommendations for the preclinical, mild cognitive impairment, and dementia stages of Alzheimer's disease. Scientific progress in the interim led to an initiative by the National Institute on Aging and Alzheimer's Association to update and unify the 2011 guidelines. This unifying update is labeled a “research framework” because its intended use is for observational and interventional research, not routine clinical care. In the National Institute on Aging and Alzheimer's Association Research Framework, Alzheimer's disease (AD) is defined by its underlying pathologic processes that can be documented by postmortem examination or in vivo by biomarkers. The diagnosis is not based on the clinical consequences of the disease (i.e., symptoms/signs) in this research framework, which shifts the definition of AD in living people from a syndromal to a biological construct. The research framework focuses on the diagnosis of AD with biomarkers in living persons. Biomarkers are grouped into those of β amyloid deposition, pathologic tau, and neurodegeneration [AT(N)]. This ATN classification system groups different biomarkers (imaging and biofluids) by the pathologic process each measures. The AT(N) system is flexible in that new biomarkers can be added to the three existing AT(N) groups, and new biomarker groups beyond AT(N) can be added when they become available. We focus on AD as a continuum, and cognitive staging may be accomplished using continuous measures. However, we also outline two different categorical cognitive schemes for staging the severity of cognitive impairment: a scheme using three traditional syndromal categories and a six-stage numeric scheme. It is important to stress that this framework seeks to create a common language with which investigators can generate and test hypotheses about the interactions among different pathologic processes (denoted by biomarkers) and cognitive symptoms. We appreciate the concern that this biomarker-based research framework has the potential to be misused. Therefore, we emphasize, first, it is premature and inappropriate to use this research framework in general medical practice. Second, this research framework should not be used to restrict alternative approaches to hypothesis testing that do not use biomarkers. There will be situations where biomarkers are not available or requiring them would be counterproductive to the specific research goals (discussed in more detail later in the document). Thus, biomarker-based research should not be considered a template for all research into age-related cognitive impairment and dementia; rather, it should be applied when it is fit for the purpose of the specific research goals of a study. Importantly, this framework should be examined in diverse populations. Although it is possible that β-amyloid plaques and neurofibrillary tau deposits are not causal in AD pathogenesis, it is these abnormal protein deposits that define AD as a unique neurodegenerative disease among different disorders that can lead to dementia. We envision that defining AD as a biological construct will enable a more accurate characterization and understanding of the sequence of events that lead to cognitive impairment that is associated with AD, as well as the multifactorial etiology of dementia. This approach also will enable a more precise approach to interventional trials where specific pathways can be targeted in the disease process and in the appropriate people.
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| 24. |
- Jansen, Willemijn J, et al.
(författare)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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Ingår i: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Tidskriftsartikel (refereegranskat)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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| 25. |
- Jehi, L., et al.
(författare)
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Timing of referral to evaluate for epilepsy surgery: Expert Consensus Recommendations from the Surgical Therapies Commission of the International League Against Epilepsy
- 2022
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 63:10, s. 2491-2506
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Tidskriftsartikel (refereegranskat)abstract
- Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.
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| 26. |
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| 27. |
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| 28. |
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| 29. |
- Hansson, Oskar, et al.
(författare)
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The Alzheimer's Association appropriate use recommendations for blood biomarkers in Alzheimer's disease
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:12, s. 2669-2686
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Tidskriftsartikel (refereegranskat)abstract
- Blood-based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work-up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre-)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease-modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work-up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand-alone diagnostic AD markers, or before considering use in primary care.
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| 30. |
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| 31. |
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| 32. |
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| 33. |
- Naylor, Mary D, et al.
(författare)
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Advancing Alzheimer's disease diagnosis, treatment, and care: recommendations from the Ware Invitational Summit.
- 2012
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 8:5, s. 445-52
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Tidskriftsartikel (refereegranskat)abstract
- To address the pending public health crisis due to Alzheimer's disease (AD) and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania held a meeting entitled "State of the Science Conference on the Advancement of Alzheimer's Diagnosis, Treatment and Care," on June 21-22, 2012. The meeting comprised four workgroups focusing on Biomarkers; Clinical Care and Health Services Research; Drug Development; and Health Economics, Policy, and Ethics. The workgroups shared, discussed, and compiled an integrated set of priorities, recommendations, and action plans, which are presented in this article.
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| 34. |
- Rabe, Benjamin, et al.
(författare)
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The MOSAiC Distributed Network: Observing the coupled Arctic system with multidisciplinary, coordinated platforms
- 2024
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Ingår i: Elementa. - 2325-1026. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Central Arctic properties and processes are important to the regional and global coupled climate system. The Multidisciplinary drifting Observatory for the Study of Arctic Climate (MOSAiC) Distributed Network (DN) of autonomous ice-tethered systems aimed to bridge gaps in our understanding of temporal and spatial scales, in particular with respect to the resolution of Earth system models. By characterizing variability around local measurements made at a Central Observatory, the DN covers both the coupled system interactions involving the ocean-ice-atmosphere interfaces as well as three-dimensional processes in the ocean, sea ice, and atmosphere. The more than 200 autonomous instruments (“buoys”) were of varying complexity and set up at different sites mostly within 50 km of the Central Observatory. During an exemplary midwinter month, the DN observations captured the spatial variability of atmospheric processes on sub-monthly time scales, but less so for monthly means. They show significant variability in snow depth and ice thickness, and provide a temporally and spatially resolved characterization of ice motion and deformation, showing coherency at the DN scale but less at smaller spatial scales. Ocean data show the background gradient across the DN as well as spatially dependent time variability due to local mixed layer sub-mesoscale and mesoscale processes, influenced by a variable ice cover. The second case (May–June 2020) illustrates the utility of the DN during the absence of manually obtained data by providing continuity of physical and biological observations during this key transitional period. We show examples of synergies between the extensive MOSAiC remote sensing observations and numerical modeling, such as estimating the skill of ice drift forecasts and evaluating coupled system modeling. The MOSAiC DN has been proven to enable analysis of local to mesoscale processes in the coupled atmosphere-ice-ocean system and has the potential to improve model parameterizations of important, unresolved processes in the future.
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| 35. |
- Salloway, S, et al.
(författare)
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A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease.
- 2009
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Ingår i: Neurology. - 1526-632X. ; 73:24, s. 2061-70
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Bapineuzumab, a humanized anti-amyloid-beta (Abeta) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD. METHODS: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale-Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline. RESULTS: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study "completers" and APOE epsilon4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE epsilon4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms. CONCLUSIONS: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE epsilon4 carrier status. Classification of evidence: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
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| 36. |
- Smith, P., et al.
(författare)
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How much land-based greenhouse gas mitigation can be achieved without compromising food security and environmental goals?
- 2013
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Ingår i: Global Change Biology. - : Wiley. - 1365-2486 .- 1354-1013. ; 19:8, s. 2285-2302
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Forskningsöversikt (refereegranskat)abstract
- Feeding 9-10billion people by 2050 and preventing dangerous climate change are two of the greatest challenges facing humanity. Both challenges must be met while reducing the impact of land management on ecosystem services that deliver vital goods and services, and support human health and well-being. Few studies to date have considered the interactions between these challenges. In this study we briefly outline the challenges, review the supply- and demand-side climate mitigation potential available in the Agriculture, Forestry and Other Land Use AFOLU sector and options for delivering food security. We briefly outline some of the synergies and trade-offs afforded by mitigation practices, before presenting an assessment of the mitigation potential possible in the AFOLU sector under possible future scenarios in which demand-side measures codeliver to aid food security. We conclude that while supply-side mitigation measures, such as changes in land management, might either enhance or negatively impact food security, demand-side mitigation measures, such as reduced waste or demand for livestock products, should benefit both food security and greenhouse gas (GHG) mitigation. Demand-side measures offer a greater potential (1.5-15.6Gt CO2-eq. yr(-1)) in meeting both challenges than do supply-side measures (1.5-4.3Gt CO2-eq. yr(-1) at carbon prices between 20 and 100US$ tCO(2)-eq. yr(-1)), but given the enormity of challenges, all options need to be considered. Supply-side measures should be implemented immediately, focussing on those that allow the production of more agricultural product per unit of input. For demand-side measures, given the difficulties in their implementation and lag in their effectiveness, policy should be introduced quickly, and should aim to codeliver to other policy agenda, such as improving environmental quality or improving dietary health. These problems facing humanity in the 21st Century are extremely challenging, and policy that addresses multiple objectives is required now more than ever.
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| 37. |
- Sperling, L, et al.
(författare)
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How to identify twins at low risk of spontaneous preterm delivery
- 2005
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Ingår i: Ultrasound in Obstetrics & Gynecology. - : Wiley. - 1469-0705 .- 0960-7692. ; 26:2, s. 138-144
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Tidskriftsartikel (refereegranskat)abstract
- Objective The aim of this study was to evaluate transvaginal sonograpbic assessment of cervical length at 23 weeks as a screening test for spontaneous preterm delivery in order to define a cut-off value that could be used to select twin pregnancies at low risk of spontaneous preterm delivery. Methods In a prospective multicenter study of 383 twin pregnancies included before 14 + 6 weeks a cervical scan with measurement of the cervical length was performed at 23 weeks' gestation. The results were blinded for the clinicians if the cervical length was >= 15 mm. The rates of spontaneous delivery at different cut-off levels of cervical length were determined. Results Eighty-nine percent of the twins had dichorionic placentation and 58% were conceived after assisted reproduction. The rate of spontaneous preterm delivery was 2.3% (1.5% for dichorionic (DC) and 9.1% for (MC) monochorionic twins) before 28 weeks and 18.5% (17.1% for DC and 29.5% for MC twins) before 35 weeks. The screen-positive rate was 5% for a cervical length <= 20, 7-8% at <= 25, 16-17% at <= 30 and 34-48% at <= 35mm depending on chorionicity. The false-negative rate (1 - negative predictive value) ranged from 1.2% at 28 weeks to 18.6% at 35 weeks for all twins. Receiver-operating characteristics curves showed that the sensitivity increased with declining gestation I age with cut-off levels of highest accuracy at 21 mm for 28 weeks and 29 mm for 33 weeks. Conclusions Cervical length measurement at 23 weeks of gestation is a good screening test for predicting twins at low risk of preterm and very preterm delivery, especially in DC twins. The present results suggest that a cut-off of 25 mm should be recommended.
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| 38. |
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| 39. |
- Therriault, Joseph, et al.
(författare)
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Biomarker-based staging of Alzheimer disease: rationale and clinical applications.
- 2024
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Ingår i: Nature reviews. Neurology. - 1759-4766. ; 20:4, s. 232-244
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Tidskriftsartikel (refereegranskat)abstract
- Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity ofAlzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications.
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| 40. |
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| 41. |
- Van Egroo, M., et al.
(författare)
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Ultra-high field imaging, plasma markers and autopsy data uncover a specific rostral locus coeruleus vulnerability to hyperphosphorylated tau
- 2023
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Ingår i: Molecular Psychiatry. - 1359-4184. ; 28:6, s. 2412-2422
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Tidskriftsartikel (refereegranskat)abstract
- Autopsy data indicate that the locus coeruleus (LC) is one of the first sites in the brain to accumulate hyperphosphorylated tau pathology, with the rostral part possibly being more vulnerable in the earlier stages of the disease. Taking advantage of recent developments in ultra-high field (7 T) imaging, we investigated whether imaging measures of the LC also reveal a specific anatomic correlation with tau using novel plasma biomarkers of different species of hyperphosphorylated tau, how early in adulthood these associations can be detected and if are associated with worse cognitive performance. To validate the anatomic correlations, we tested if a rostro-caudal gradient in tau pathology is also detected at autopsy in data from the Rush Memory and Aging Project (MAP). We found that higher plasma measures of phosphorylated tau, in particular ptau(231), correlated negatively with dorso-rostral LC integrity, whereas correlations for neurodegenerative plasma markers (neurofilament light, total tau) were scattered throughout the LC including middle to caudal sections. In contrast, the plasma A beta(42/40) ratio, associated with brain amyloidosis, did not correlate with LC integrity. These findings were specific to the rostral LC and not observed when using the entire LC or the hippocampus. Furthermore, in the MAP data, we observed higher rostral than caudal tangle density in the LC, independent of the disease stage. The in vivo LC-phosphorylated tau correlations became significant from midlife, with the earliest effect for ptau(231), starting at about age 55. Finally, interactions between lower rostral LC integrity and higher ptau(231) concentrations predicted lower cognitive performance. Together, these findings demonstrate a specific rostral vulnerability to early phosphorylated tau species that can be detected with dedicated magnetic resonance imaging measures, highlighting the promise of LC imaging as an early marker of AD-related processes.
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| 42. |
- Yeh, Sonia, 1973, et al.
(författare)
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A review of low carbon fuel policies: Principles, program status and future directions
- 2016
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Ingår i: Energy Policy. - : Elsevier BV. - 0301-4215. ; 97, s. 220-234
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Forskningsöversikt (refereegranskat)abstract
- A low carbon fuel standard (LCFS) is a market-based policy that specifies declining standards for the average lifecycle fuel carbon intensity (AFCI) of transportation fuels sold in a region. This paper: (i) compares transportation fuel carbon policies in terms of their economic efficiency, fuel price impacts, greenhouse gas emission reductions, and incentives for innovation; (ii) discusses key regulatory design features of LCFS policies; and (iii) provides an update on the implementation status of LCFS policies in California, the European Union, British Columbia, and Oregon. The economics literature finds that an intensity standard implicitly taxes emissions and subsidizes output. The output subsidy results in an intensity standard being inferior to a carbon tax in a first-best world, although the inefficiency can be corrected with a properly designed consumption tax (or mitigated by a properly designed carbon tax or cap-and-trade program). In California, from 2011 to 2015 the share of alternative fuels in the regulated transportation fuels pool increased by 30%, and the reported AFCI of all alternative fuels declined 21%. LCFS credit prices have varied considerably, rising to above $100/credit in the first half of 2016. LCFS programs in other jurisdictions share many features with California's, but have distinct provisions as well. (C) 2016 Elsevier Ltd. All rights reserved.
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| 43. |
- Zumberge, J. Alex, et al.
(författare)
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Demosponge steroid biomarker 26-methylstigmastane provides evidence for Neoproterozoic animals
- 2018
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Ingår i: Nature Ecology & Evolution. - : NATURE PUBLISHING GROUP. - 2397-334X. ; 2:11, s. 1709-1714
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Tidskriftsartikel (refereegranskat)abstract
- Sterane biomarkers preserved in ancient sedimentary rocks hold promise for tracking the diversification and ecological expansion of eukaryotes. The earliest proposed animal biomarkers from demosponges (Demospongiae) are recorded in a sequence around 100 Myr long of Neoproterozoic-Cambrian marine sedimentary strata from the Huqf Supergroup, South Oman Salt Basin. This C-30 sterane biomarker, informally known as 24-isopropylcholestane (24-ipc), possesses the same carbon skeleton as sterols found in some modern-day demosponges. However, this evidence is controversial because 24-ipc is not exclusive to demosponges since 24-ipc sterols are found in trace amounts in some pelagophyte algae. Here, we report a new fossil sterane biomarker that co-occurs with 24-ipc in a suite of late Neoproterozoic-Cambrian sedimentary rocks and oils, which possesses a rare hydrocarbon skeleton that is uniquely found within extant demosponge taxa. This sterane is informally designated as 26-methylstigmastane (26-mes), reflecting the very unusual methylation at the terminus of the steroid side chain. It is the first animal-specific sterane marker detected in the geological record that can be unambiguously linked to precursor sterols only reported from extant demosponges. These new findings strongly suggest that demosponges, and hence multicellular animals, were prominent in some late Neoproterozoic marine environments at least extending back to the Cryogenian period.
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