| 1. |
- 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. |
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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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| 4. |
- Feng, Shaohong, et al.
(författare)
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Dense sampling of bird diversity increases power of comparative genomics
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 587:7833
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing projects are increasingly populating the tree of life and characterizing biodiversity(1-4). Sparse taxon sampling has previously been proposed to confound phylogenetic inference(5), and captures only a fraction of the genomic diversity. Here we report a substantial step towards the dense representation of avian phylogenetic and molecular diversity, by analysing 363 genomes from 92.4% of bird families-including 267 newly sequenced genomes produced for phase II of the Bird 10,000 Genomes (B10K) Project. We use this comparative genome dataset in combination with a pipeline that leverages a reference-free whole-genome alignment to identify orthologous regions in greater numbers than has previously been possible and to recognize genomic novelties in particular bird lineages. The densely sampled alignment provides a single-base-pair map of selection, has more than doubled the fraction of bases that are confidently predicted to be under conservation and reveals extensive patterns of weak selection in predominantly non-coding DNA. Our results demonstrate that increasing the diversity of genomes used in comparative studies can reveal more shared and lineage-specific variation, and improve the investigation of genomic characteristics. We anticipate that this genomic resource will offer new perspectives on evolutionary processes in cross-species comparative analyses and assist in efforts to conserve species. A dataset of the genomes of 363 species from the Bird 10,000 Genomes Project shows increased power to detect shared and lineage-specific variation, demonstrating the importance of phylogenetically diverse taxon sampling in whole-genome sequencing.
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| 5. |
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| 6. |
- Preece, Paul, et al.
(författare)
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Amyloid precursor protein mRNA levels in Alzheimer's disease brain
- 2004
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Ingår i: Brain Research. Molecular Brain Research. - : Elsevier BV. - 0169-328X .- 1872-6941. ; 122:1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Insoluble beta-amyloid deposits in Alzheimer's disease (AD) brain are proteolytically derived from the membrane bound amyloid precursor protein (APP). The APP gene is differentially spliced to produce isoforms that can be classified into those containing a Kunitz-type serine protease inhibitor domain (K(+), APP(751), APP(770), APRP(365) and APRP(563)), and those without (K(-), APP(695) and APP(714)). Given the hypothesis that Abeta is a result of aberrant catabolism of APP, differential expression of mRNA isoforms containing protease inhibitors might play an active role in the pathology of AD. We took 513 cerebral cortex samples from 90 AD and 81 control brains and quantified the mRNA isoforms of APP with TaqMan real-time RT-PCR. After adjustment for age at death, brain pH and gender we found a change in the ratio of KPI(+) to KPI(-) mRNA isoforms of APP. Three separate probes, designed to recognise only KPI(+) mRNA species, gave increases of between 28% and 50% in AD brains relative to controls (p=0.002). There was no change in the mRNA levels of KPI-(APP 695) (p=0.898). Therefore, whilst KPI-mRNA levels remained stable the KPI(+) species increased specifically in the AD brains.
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| 7. |
- Preece, Paul, et al.
(författare)
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An optimistic view for quantifying mRNA in post-mortem human brain
- 2003
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Ingår i: Brain Research. Molecular Brain Research. - 0169-328X .- 1872-6941. ; 116:1-2, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Quantitative human mRNA data are derived from post-mortem or biopsied tissue. RNA degradation, poor replication, a large mRNA variance and confounding factors such as brain pH and age of death are often cited, however, as objections to the data's reliability. A central question is whether post-mortem human mRNA can be treated as a statistically ordered system. TaqMan real-time RT-PCR was used to measure seven mRNAs in 513 cortical samples taken from 90 Alzheimer's disease and 81 control brains. Despite a high mRNA variance strong correlations were found between the mRNA transcripts in a single brain. Where a brain has a high/low level of one mRNA, the same brain invariably has a high/low level of other mRNAs; correlated order is present and allows removal of that source of variation common to all genes. Although levels of mRNA are highly variable between subjects (>1000-fold), quantitative order is present in post-mortem human mRNA, allowing effects due to pathology or gender to be isolated and tested for significance.
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| 8. |
- Preece, Paul, et al.
(författare)
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Beta-secretase (BACE) and GSK-3 mRNA levels in Alzheimer's disease
- 2003
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Ingår i: Brain Research. Molecular Brain Research. - 0169-328X .- 1872-6941. ; 116:1-2, s. 155-158
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Tidskriftsartikel (refereegranskat)abstract
- Beta-secretase (BACE) and glycogen synthase kinase (GSK 3) are two enzymes thought to play a role in Alzheimer's disease. We extracted mRNA from 90 Alzheimer and 81 control brains. Levels of mRNA were quantified for BACE and GSK 3 with TaqMan real-time RT-PCR. We found no change in the Alzheimer's disease brains relative to controls for either the BACE or the GSK 3alpha mRNA levels.
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| 9. |
- Duong, Vicky, et al.
(författare)
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Exploring translational gaps between basic scientists, clinical researchers, clinicians, and consumers : Proceedings and recommendations arising from the 2020 mine the gap online workshop
- 2021
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Ingår i: Osteoarthritis and Cartilage Open. - : Elsevier BV. - 2665-9131. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To provide a summary of the translational gaps in musculoskeletal research as identified in the Mine the Gap workshop and propose possible solutions. Methods: The Mine the Gap online workshop was hosted on October 14th and 15th, 2020. Five international panels, each comprised of a clinician, clinical researcher and basic scientist, presented gaps and proposed solutions for the themes of biomechanics, pain, biological measurements, phenotypes and imaging. This was followed by an interactive panel discussion with consumer insights. Results: A number of translational gaps and proposed solutions across each of the five themes were identified. A consumer panel provided constructive feedback highlighting the need for improved resources, communication and shared decision making, and treatment individualisation. Conclusion: This brief report provides a greater understanding of the diverse work and gaps relevant to fundamental/discovery scientists, clinical researchers and clinicians working across the musculoskeletal field. The numerous translational gaps highlight the need to improve communication and collaboration across the musculoskeletal field.
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| 10. |
- Morris, J. H., et al.
(författare)
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Implementation in rehabilitation: a roadmap for practitioners and researchers
- 2020
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Ingår i: Disability and Rehabilitation. - : Informa UK Limited. - 0963-8288 .- 1464-5165. ; 42:22, s. 3265-74
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Despite growth in rehabilitation research, implementing research findings into rehabilitation practice has been slow. This creates inequities for patients and is an ethical issue. However, methods to investigate and facilitate evidence implementation are being developed. This paper aims to make these methods relevant and accessible for rehabilitation researchers and practitioners. Methods: Rehabilitation practice is varied and complex and occurs within multilevel healthcare systems. Using a "road map" analogy, we describe how implementation concepts and theories can inform implementation strategies in rehabilitation. The roadmap involves a staged journey that considers: the nature of evidence; context for implementation; navigation tools for implementation; strategies to facilitate implementation; evaluation of implementation outcomes; and sustainability of implementation. We have developed a model to illustrate the journey, and four case studies exemplify implementation stages in rehabilitation settings. Results and Conclusions: Effective implementation strategies for the complex world of rehabilitation are urgently required. The journey we describe unpacks that complexity to provide a template for effective implementation, to facilitate translation of the growing evidence base in rehabilitation into improved patient outcomes. It emphasizes the importance of understanding context and application of relevant theory, and highlights areas which should be targeted in new implementation research in rehabilitation.
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