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| 2. |
- Wightman, D. P., et al.
(author)
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A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease
- 2021
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In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:9, s. 1276-1282
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Journal article (peer-reviewed)abstract
- Late-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50–70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer’s disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer’s disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants that contribute to Alzheimer’s pathology.
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| 3. |
- Jansen, I. E., et al.
(author)
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Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:3, s. 404-413
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.
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| 4. |
- Rijal, Dilli P., et al.
(author)
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Sedimentary ancient DNA shows terrestrial plant richness continuously increased over the Holocene in northern Fennoscandia
- 2021
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:31
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Journal article (peer-reviewed)abstract
- The effects of climate change on species richness are debated but can be informed by the past. Here, we generated a sedimentary ancient DNA dataset covering 10 lakes and applied novel methods for data harmonization. We assessed the impact of Holocene climate changes and nutrients on terrestrial plant richness in northern Fennoscandia. We find that richness increased steeply during the rapidly warming Early Holocene. In contrast to findings from most pollen studies, we show that richness continued to increase thereafter, although the climate was stable, with richness and the regional species pool only stabilizing during the past three millennia. Furthermore, overall increases in richness were greater in catchments with higher soil nutrient availability. We suggest that richness will increase with ongoing warming, especially at localities with high nutrient availability and assuming that human activity remains low in the region, although lags of millennia may be expected.
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| 5. |
- Willerslev, E, et al.
(author)
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Fifty thousand years of arctic vegetation change and megafauna diet
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 506:7486, s. 47-47
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Journal article (peer-reviewed)abstract
- Although it is generally agreed that the Arctic flora is among the youngest and least diverse on Earth, the processes that shaped it are poorly understood. Here we present 50 thousand years (kyr) of Arctic vegetation history, derived from the first large-scale ancient DNA metabarcoding study of circumpolar plant diversity. For this interval we also explore nematode diversity as a proxy for modelling vegetation cover and soil quality, and diets of herbivorous megafaunal mammals, many of which became extinct around 10 kyr bp (before present). For much of the period investigated, Arctic vegetation consisted of dry steppe-tundra dominated by forbs (non-graminoid herbaceous vascular plants). During the Last Glacial Maximum (25–15 kyr bp), diversity declined markedly, although forbs remained dominant. Much changed after 10 kyr bp, with the appearance of moist tundra dominated by woody plants and graminoids. Our analyses indicate that both graminoids and forbs would have featured in megafaunal diets. As such, our findings question the predominance of a Late Quaternary graminoid-dominated Arctic mammoth steppe.
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| 6. |
- Tedersoo, Leho, et al.
(author)
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Global patterns in endemicity and vulnerability of soil fungi.
- 2022
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In: Global change biology. - : Wiley. - 1365-2486 .- 1354-1013. ; 28:22, s. 6696-6710
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Journal article (peer-reviewed)abstract
- Fungi are highly diverse organisms, which provide multiple ecosystem services. However, compared with charismatic animals and plants, the distribution patterns and conservation needs of fungi have been little explored. Here, we examined endemicity patterns, global change vulnerability and conservation priority areas for functional groups of soil fungi based on six global surveys using a high-resolution, long-read metabarcoding approach. We found that the endemicity of all fungi and most functional groups peaks in tropical habitats, including Amazonia, Yucatan, West-Central Africa, Sri Lanka, and New Caledonia, with a negligible island effect compared with plants and animals. We also found that fungi are predominantly vulnerable to drought, heat and land-cover change, particularly in dry tropical regions with high human population density. Fungal conservation areas of highest priority include herbaceous wetlands, tropical forests, and woodlands. We stress that more attention should be focused on the conservation of fungi, especially root symbiotic arbuscular mycorrhizal and ectomycorrhizal fungi in tropical regions as well as unicellular early-diverging groups and macrofungi in general. Given the low overlap between the endemicity of fungi and macroorganisms, but high conservation needs in both groups, detailed analyses on distribution and conservation requirements are warranted for other microorganisms and soil organisms.
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| 7. |
- Barrio, Isabel C., et al.
(author)
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Background invertebrate herbivory on dwarf birch (Betula glandulosa-nana complex) increases with temperature and precipitation across the tundra biome
- 2017
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In: Polar Biology. - : Springer. - 0722-4060 .- 1432-2056. ; 40:11, s. 2265-2278
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Journal article (peer-reviewed)abstract
- Chronic, low intensity herbivory by invertebrates, termed background herbivory, has been understudied in tundra, yet its impacts are likely to increase in a warmer Arctic. The magnitude of these changes is however hard to predict as we know little about the drivers of current levels of invertebrate herbivory in tundra. We assessed the intensity of invertebrate herbivory on a common tundra plant, the dwarf birch (Betula glandulosa-nana complex), and investigated its relationship to latitude and climate across the tundra biome. Leaf damage by defoliating, mining and gall-forming invertebrates was measured in samples collected from 192 sites at 56 locations. Our results indicate that invertebrate herbivory is nearly ubiquitous across the tundra biome but occurs at low intensity. On average, invertebrates damaged 11.2% of the leaves and removed 1.4% of total leaf area. The damage was mainly caused by external leaf feeders, and most damaged leaves were only slightly affected (12% leaf area lost). Foliar damage was consistently positively correlated with mid-summer (July) temperature and, to a lesser extent, precipitation in the year of data collection, irrespective of latitude. Our models predict that, on average, foliar losses to invertebrates on dwarf birch are likely to increase by 6-7% over the current levels with a 1 degrees C increase in summer temperatures. Our results show that invertebrate herbivory on dwarf birch is small in magnitude but given its prevalence and dependence on climatic variables, background invertebrate herbivory should be included in predictions of climate change impacts on tundra ecosystems.
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| 9. |
- Eliassen, I. V., et al.
(author)
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Predictive and diagnostic utility of brief neuropsychological assessment in detecting Alzheimer's pathology and progression to dementia
- 2020
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In: Neuropsychology. - : American Psychological Association (APA). - 1931-1559 .- 0894-4105. ; 34:8, s. 851-861
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Journal article (peer-reviewed)abstract
- Objective: To assess the role of brief neuropsychological assessments in prediction and identification of Alzheimer's disease (AD) pathology and progression to AD dementia. Method: Adults (N = 255; range = 40-81 years) with self-reported cognitive decline underwent baseline and 2-year follow-up clinical assessment, including a brief neuropsychological screening and lumbar puncture. Five different mild cognitive impairment (MCI) algorithms were applied on baseline cognitive test results: one conventional, three amnestic (lenient, stringent, multidomain), and one comprehensive criterion. We compared predictive and diagnostic accuracy of these MCI criteria by performing logistic regression analyses and calculating diagnostic accuracy measures for 2-year outcomes of (1) clinical diagnosis of AD dementia and (2) cerebrospinal fluid biomarkers in the Alzheimer's continuum. Results: The lenient amnestic MCI criterion showed the largest effect size for predicting progression to AD dementia (OR = 13.762, 99% CI = 1.969-96.194, p = .001) and AD biomarkers (OR = 4.855, 99% CI = 1.974-11.924, p < .001) after 2 years. This criterion was sensitive for progression to dementia (sensitivity = 92.0%, specificity = 54.8%, positive likelihood ratio [LR+] = 2.03, LR- = 0.15) and showed the highest overall diagnostic accuracy for AD biomarkers (sensitivity = 72.7%, specificity = 59.1%, LR+ = 1.78, negative likelihood ratio [LR-] = 0.46). The multidomain amnestic MCI criterion produced the highest specificity for dementia (sensitivity = 76.0%, specificity = 73.0%, LR+ = 2.82, LR- = 0.33) and AD biomarkers (sensitivity = 46.8% specificity = 70.9% LR+ = 1.61, LR- = 0.75). Conclusions: Defining MCI using a brief neuropsychological battery provided limited accuracy for progression to AD dementia and cerebrospinal fluid Aβ. The lenient amnestic MCI criterion identified the highest number of individuals who progressed to clinical AD or showed biomarker pathology, but this approach included a substantial number of false positives. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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| 11. |
- Kliest, Tessa, et al.
(author)
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Clinical trials in pediatric ALS: a TRICALS feasibility study
- 2022
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In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. - : Taylor & Francis Group. - 2167-8421 .- 2167-9223. ; 23:7-8, s. 481-488
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Journal article (peer-reviewed)abstract
- Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA).Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe.Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS.Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS.Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information.
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| 12. |
- Nordengen, Kaja, et al.
(author)
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Longitudinal cerebrospinal fluid measurements show glial hypo- and hyperactivation in predementia Alzheimer's disease.
- 2023
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In: Journal of neuroinflammation. - 1742-2094. ; 20:1
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Journal article (peer-reviewed)abstract
- Brain innate immune activation is associated with Alzheimer's disease (AD), but degrees of activation may vary between disease stages. Thus, brain innate immune activation must be assessed in longitudinal clinical studies that include biomarker negative healthy controls and cases with established AD pathology. Here, we employ longitudinally sampled cerebrospinal fluid (CSF) core AD, immune activation and glial biomarkers to investigate early (predementia stage) innate immune activation levels and biomarker profiles.We included non-demented cases from a longitudinal observational cohort study, with CSF samples available at baseline (n=535) and follow-up (n=213), between 1 and 6years from baseline (mean 2.8years). We measured Aβ42/40 ratio, p-tau181, and total-tau to determine Ab (A+), tau-tangle pathology (T+), and neurodegeneration (N+), respectively. We classified individuals into these groups: A-/T-/N-, A+/T-/N-, A+/T+ or N+, or A-/T+ or N+. Using linear and mixed linear regression, we compared levels of CSF sTREM2, YKL-40, clusterin, fractalkine, MCP-1, IL-6, IL-1, IL-18, and IFN-γ both cross-sectionally and longitudinally between groups. A post hoc analysis was also performed to assess biomarker differences between cognitively healthy and impaired individuals in the A+/T+ or N+ group.Cross-sectionally, CSF sTREM2, YKL-40, clusterin and fractalkine were higher only in groups with tau pathology, independent of amyloidosis (p<0.001, A+/T+ or N+ and A-/T+ or N+, compared to A-/T-/N-). No significant group differences were observed for the cytokines CSF MCP-1, IL-6, IL-10, IL18 or IFN-γ. Longitudinally, CSF YKL-40, fractalkine and IFN-γ were all significantly lower in stable A+/T-/N- cases (all p<0.05). CSF sTREM2, YKL-40, clusterin, fractalkine (p<0.001) and MCP-1 (p<0.05) were all higher in T or N+, with or without amyloidosis at baseline, but remained stable over time. High CSF sTREM2 was associated with preserved cognitive function within the A+/T+ or N+ group, relative to the cognitively impaired with the same A/T/N biomarker profile (p<0.01).Immune hypoactivation and reduced neuron-microglia communication are observed in isolated amyloidosis while activation and increased fractalkine accompanies tau pathology in predementia AD. Glial hypo- and hyperactivation through the predementia AD continuum suggests altered glial interaction with Ab and tau pathology, and may necessitate differential treatments, depending on the stage and patient-specific activation patterns.
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