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- Deming, Yuetiva, et al.
(författare)
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Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers
- 2017
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:5, s. 839-856
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Tidskriftsartikel (refereegranskat)abstract
- More than 20 genetic loci have been associated with risk for Alzheimer’s disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case–control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aβ42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aβ42 near GLIS1 on 1p32.3 (β = −0.059, P = 2.08 × 10−8) and within SERPINB1 on 6p25 (β = −0.025, P = 1.72 × 10−8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10−2), disease progression (GLIS1: β = 0.277, P = 1.92 × 10−2), and age at onset (SERPINB1: β = 0.043, P = 4.62 × 10−3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aβ-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aβ42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.
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- Dichgans, Martin, et al.
(författare)
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METACOHORTS for the study of vascular disease and its contribution to cognitive decline and neurodegeneration : An initiative of the Joint Programme for Neurodegenerative Disease Research
- 2016
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 12:12, s. 1235-1249
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Tidskriftsartikel (refereegranskat)abstract
- Dementia is a global problem and major target for health care providers. Although up to 45% of cases are primarily or partly due to cerebrovascular disease, little is known of these mechanisms or treatments because most dementia research still focuses on pure Alzheimer's disease. An improved understanding of the vascular contributions to neurodegeneration and dementia, particularly by small vessel disease, is hampered by imprecise data, including the incidence and prevalence of symptomatic and clinically “silent” cerebrovascular disease, long-term outcomes (cognitive, stroke, or functional), and risk factors. New large collaborative studies with long follow-up are expensive and time consuming, yet substantial data to advance the field are available. In an initiative funded by the Joint Programme for Neurodegenerative Disease Research, 55 international experts surveyed and assessed available data, starting with European cohorts, to promote data sharing to advance understanding of how vascular disease affects brain structure and function, optimize methods for cerebrovascular disease in neurodegeneration research, and focus future research on gaps in knowledge. Here, we summarize the results and recommendations from this initiative. We identified data from over 90 studies, including over 660,000 participants, many being additional to neurodegeneration data initiatives. The enthusiastic response means that cohorts from North America, Australasia, and the Asia Pacific Region are included, creating a truly global, collaborative, data sharing platform, linked to major national dementia initiatives. Furthermore, the revised World Health Organization International Classification of Diseases version 11 should facilitate recognition of vascular-related brain damage by creating one category for all cerebrovascular disease presentations and thus accelerate identification of targets for dementia prevention.
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| 3. |
- Mak, Elijah, et al.
(författare)
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In vivo coupling of tau pathology and cortical thinning in Alzheimer's disease
- 2018
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Ingår i: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 10, s. 678-687
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear.Methods: We estimated cortical thickness, tau ([18F]-AV-1451), and amyloid β (Aβ) status ([11C]-PiB) in 47 subjects who were stratified into Aβ- (14 healthy controls and six mild cognitive impairment-Aβ-) and Aβ+ (14 mild cognitive impairment-Aβ+ and 13 AD) groups.Results: Compared with the Aβ- group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Aβ group. Locally, regional tau was associated with temporoparietal atrophy.Discussion: These findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD.
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| 4. |
- Stewart, Christopher J., et al.
(författare)
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Temporal development of the gut microbiome in early childhood from the TEDDY study
- 2018
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 562:7728, s. 583-588
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Tidskriftsartikel (refereegranskat)abstract
- The development of the microbiome from infancy to childhood is dependent on a range of factors, with microbial–immune crosstalk during this time thought to be involved in the pathobiology of later life diseases1–9 such as persistent islet autoimmunity and type 1 diabetes10–12. However, to our knowledge, no studies have performed extensive characterization of the microbiome in early life in a large, multi-centre population. Here we analyse longitudinal stool samples from 903 children between 3 and 46 months of age by 16S rRNA gene sequencing (n = 12,005) and metagenomic sequencing (n = 10,867), as part of the The Environmental Determinants of Diabetes in the Young (TEDDY) study. We show that the developing gut microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3–14), a transitional phase (months 15–30), and a stable phase (months 31–46). Receipt of breast milk, either exclusive or partial, was the most significant factor associated with the microbiome structure. Breastfeeding was associated with higher levels of Bifidobacterium species (B. breve and B. bifidum), and the cessation of breast milk resulted in faster maturation of the gut microbiome, as marked by the phylum Firmicutes. Birth mode was also significantly associated with the microbiome during the developmental phase, driven by higher levels of Bacteroides species (particularly B. fragilis) in infants delivered vaginally. Bacteroides was also associated with increased gut diversity and faster maturation, regardless of the birth mode. Environmental factors including geographical location and household exposures (such as siblings and furry pets) also represented important covariates. A nested case–control analysis revealed subtle associations between microbial taxonomy and the development of islet autoimmunity or type 1 diabetes. These data determine the structural and functional assembly of the microbiome in early life and provide a foundation for targeted mechanistic investigation into the consequences of microbial–immune crosstalk for long-term health.
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- Chapuis, Julien, et al.
(författare)
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Genome-wide, high-content siRNA screening identifies the Alzheimer’s genetic risk factor FERMT2 as a major modulator of APP metabolism
- 2017
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 133:6, s. 955-966
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer’s disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the “post-GWAS” era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
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| 41. |
- De Guio, François, et al.
(författare)
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Reproducibility and variability of quantitative magnetic resonance imaging markers in cerebral small vessel disease
- 2016
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X. ; 36:8, s. 1319-1337
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Forskningsöversikt (refereegranskat)abstract
- Brain imaging is essential for the diagnosis and characterization of cerebral small vessel disease. Several magnetic resonance imaging markers have therefore emerged, providing new information on the diagnosis, progression, and mechanisms of small vessel disease. Yet, the reproducibility of these small vessel disease markers has received little attention despite being widely used in cross-sectional and longitudinal studies. This review focuses on the main small vessel disease-related markers on magnetic resonance imaging including: white matter hyperintensities, lacunes, dilated perivascular spaces, microbleeds, and brain volume. The aim is to summarize, for each marker, what is currently known about: (1) its reproducibility in studies with a scan-rescan procedure either in single or multicenter settings; (2) the acquisition-related sources of variability; and, (3) the techniques used to minimize this variability. Based on the results, we discuss technical and other challenges that need to be overcome in order for these markers to be reliably used as outcome measures in future clinical trials. We also highlight the key points that need to be considered when designing multicenter magnetic resonance imaging studies of small vessel disease.
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| 42. |
- Maxwell, Paul S., et al.
(författare)
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The fundamental role of ecological feedback mechanisms for the adaptive management of seagrass ecosystems - a review
- 2017
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Ingår i: Biological Reviews. - : Wiley. - 1464-7931 .- 1469-185X. ; 92:3, s. 1521-1538
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Forskningsöversikt (refereegranskat)abstract
- Seagrass meadows are vital ecosystems in coastal zones worldwide, but are also under global threat. One of the major hurdles restricting the success of seagrass conservation and restoration is our limited understanding of ecological feedback mechanisms. In these ecosystems, multiple, self-reinforcing feedbacks can undermine conservation efforts by masking environmental impacts until the decline is precipitous, or alternatively they can inhibit seagrass recovery in spite of restoration efforts. However, no clear framework yet exists for identifying or dealing with feedbacks to improve the management of seagrass ecosystems. Here we review the causes and consequences of multiple feedbacks between seagrass and biotic and/or abiotic processes. We demonstrate how feedbacks have the potential to impose or reinforce regimes of either seagrass dominance or unvegetated substrate, and how the strength and importance of these feedbacks vary across environmental gradients. Although a myriad of feedbacks have now been identified, the co-occurrence and likely interaction among feedbacks has largely been overlooked to date due to difficulties in analysis and detection. Here we take a fundamental step forward by modelling the interactions among two distinct above-and belowground feedbacks to demonstrate that interacting feedbacks are likely to be important for ecosystem resilience. On this basis, we propose a five-step adaptive management plan to address feedback dynamics for effective conservation and restoration strategies. The management plan provides guidance to aid in the identification and prioritisation of likely feedbacks in different seagrass ecosystems.
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- Vrooman, Lynda M., et al.
(författare)
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Survival and Late Effects after Allogeneic Hematopoietic Cell Transplantation for Hematologic Malignancy at Less than Three Years of Age
- 2017
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 23:8, s. 1327-1334
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Tidskriftsartikel (refereegranskat)abstract
- Very young children undergoing hematopoietic cell transplantation (HCT) are a unique and vulnerable population. We analyzed outcomes of 717 patients from 117 centers who survived relapse free for year after allogeneic myeloablative HCT for hematologic malignancy at <3 years of age, between 1987 and 2012. The median follow-up was 8.3 years (range, 1.0 to 26.4 years); median age at follow-up was 9 years (range, 2 to 29 years). Ten-year overall and relapse-free survival were 87% (95% confidence interval [CI], 85% to 90%) and 84% (95% CI, 81% to 87%). Ten-year cumulative incidence of relapse was 11% (95% CI, 9% to 13%). Of 84 deaths, relapse was the leading cause (43%). Chronic graft-versus-host-disease 1 year after HCT was associated with increased risk of mortality (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.3; P=.0018). Thirty percent of patients experienced >= 1 organ toxicity/late effect >1 year after HCT. The most frequent late effects included growth hormone deficiency/growth disturbance (10-year cumulative incidence, 23%; 95% CI, 19% to 28%), cataracts (18%; 95% CI, 15% to 22%), hypothyroidism (13%; 95% CI, 10% to 16%), gonadal dysfunction/infertility requiring hormone replacement (3%; 95% CI, 2% to 5%), and stroke/seizure (3%; 95% CI, 2% to 5%). Subsequent malignancy was reported in 3.6%. In multivariable analysis, total body irradiation (TBI) was predictive of increased risk of cataracts (HR, 17.2; 95% CI, 7.4 to 39.8; P <.001), growth deficiency (HR, 3.5; 95% CI, 2.2 to 5.5; P <.001), and hypothyroidism (HR, 5.3; 95% CI, 3.0 to 9.4; P <.001). In summary, those who survived relapse free year after HCT for hematologic malignancy at <3 years of age had favorable overall survival. Chronic graft-versus host-disease and TBI were associated with adverse outcomes. Future efforts should focus on reducing the risk of relapse and late effects after HCT at early age.
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| 49. |
- Aad, G., et al.
(författare)
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- 2015
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Tidskriftsartikel (refereegranskat)
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| 50. |
- Aad, G., et al.
(författare)
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- 2015
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813 .- 1089-490X. ; 92:3
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Tidskriftsartikel (refereegranskat)
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