| 1. |
- Benedet, Andréa L., et al.
(författare)
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Plasma neurofilament light associates with Alzheimer's disease metabolic decline in amyloid-positive individuals
- 2019
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 11, s. 679-689
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurofilament light chain (NfL) is a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) and other brain disorders. However, there are limited reports of how longitudinal NfL relates to imaging biomarkers. We herein investigated the relationship between blood NfL and brain metabolism in AD. Methods: Voxelwise regression models tested the cross-sectional association between [18F]fluorodeoxyglucose ([18F]FDG) and both plasma and cerebrospinal fluid NfL in cognitively impaired and unimpaired subjects. Linear mixed models were also used to test the longitudinal association between NfL and [18F]FDG in amyloid positive (Aβ+) and negative (Aβ−) subjects. Results: Higher concentrations of plasma and cerebrospinal fluid NfL were associated with reduced [18F]FDG uptake in correspondent brain regions. In Aβ+ participants, NfL associates with hypometabolism in AD-vulnerable regions. Longitudinal changes in the association [18F]FDG-NfL were confined to cognitively impaired Aβ+ individuals. Discussion: These findings indicate that plasma NfL is a proxy for neurodegeneration in AD-related regions in Aβ+ subjects.
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| 2. |
- Davenne, Damien, et al.
(författare)
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Effectiveness of exercise
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Higher risk of accident is related to nocturnal activity when circadian clocks and sleep pressure increase sleepiness and decrease neurobehavioral performances. Performances assessed by simple reaction times remain stable for about 16 hr of wakefulness, and decrease thereafter to reach a dramatic impairment about 2-4 hr after the peak of melatonin. At that time the drowsiness that occurs has been identified as the reason behind fatal many individual and industrial accidents. Nocturnal neurobehavioral performance varies as a function of age. They are also widely dependant of individuals and only certain subjects seem significantly affected by sleep loss.Studies have demonstrated the efficiency of some countermeasures such as sleeping (or napping) and the use of alertness-increasing agents (i.e. caffeine) on driving. If alertness is improved immediately following exercise, during the day, this potential countermeasure has never been study during the night. Furthermore, Matsumoto et al. suggested that exercise during an extended period of wakefulness results in an increased risk in human error. The effect of physical exercise on cognitive and motor performance depends both on the intensity and the duration of the exercise. It is a physical exercise of moderate intensity and duration which appears to ameliorate brain function. Consequently, moderate physical exercise may minimize the declines of driving performances due to sleep deprivation. Furthermore, these effects may be dependent of the age of the participants.
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| 3. |
- Ding, Yuan C, et al.
(författare)
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A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers
- 2012
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 21:8, s. 1362-1370
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.
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| 4. |
- Field, Daniel J, et al.
(författare)
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Early Evolution of Modern Birds Structured by Global Forest Collapse at the End-Cretaceous Mass Extinction
- 2018
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Ingår i: Current Biology. - Amsterdam : Elsevier. - 0960-9822 .- 1879-0445. ; 28, s. 1825-1831
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Tidskriftsartikel (refereegranskat)abstract
- The fossil record and recent molecular phylogenies support an extraordinary early-Cenozoic radiation of crown birds (Neornithes) after the Cretaceous-Paleogene (K-Pg) mass extinction [1–3 ]. However, questions remain regarding the mechanisms underlying the survival of the deepest lineages within crown birds across the K-Pg boundary, particularly since this global catastrophe eliminated even the closest stem-group relatives of Neornithes [4 ]. Here, ancestral state reconstructions of neornithine ecology reveal a strong bias toward taxa exhibiting predominantly non-arboreal lifestyles across the K-Pg, with multiple convergent transitions toward predominantly arboreal ecologies later in the Paleocene and Eocene. By contrast, ecomorphological inferences indicate predominantly arboreal lifestyles among enantiornithines, the most diverse and widespread Mesozoic avialans [5–7 ]. Global paleobotanical and palynological data show that the K-Pg Chicxulub impact triggered widespread destruction of forests [8, 9 ]. We suggest that ecological filtering due to the temporary loss of significant plant cover across the K-Pg boundary selected against any flying dinosaurs (Avialae [10 ]) committed to arboreal ecologies, resulting in a predominantly non-arboreal postextinction neornithine avifauna composed of totalclade Palaeognathae, Galloanserae, and terrestrial total-clade Neoaves that rapidly diversified into the broad range of avian ecologies familiar today. The explanation proposed here provides a unifying hypothesis for the K-Pg-associated mass extinction of arboreal stem birds, as well as for the post-K-Pg radiation of arboreal crown birds. It also provides a baseline hypothesis to be further refined pending the discovery of additional neornithine fossils from the Latest Cretaceous and earliest Paleogene.
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| 5. |
- Hof, Tineke, et al.
(författare)
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Multilevel Intervention Mapping with sleepiness in focus
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Driver fatigue is an important risk factor in traffic safety and an issue for both private and professional drivers. This report provides an analysis of risk factors related to fatigue-related road accidents, and describes intervention goals at multiple levels in order to reduce sleepy driving among drivers. Private drivers who are on their way to or from their holiday were assigned as the specific target group.
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| 6. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 7. |
- Lessa Benedet, Andréa, et al.
(författare)
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Stage-specific links between plasma neurofilament light and imaging biomarkers of Alzheimer's disease
- 2020
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 143:12, s. 3793-3804
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Tidskriftsartikel (refereegranskat)abstract
- Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ϵ4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials.
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| 8. |
- Leuzy, Antoine, et al.
(författare)
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Use of amyloid PET across the spectrum of Alzheimer's disease : clinical utility and associated ethical issues
- 2014
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 21:3, s. 143-148
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Forskningsöversikt (refereegranskat)abstract
- Recent advances have made possible the in vivo detection of beta-amyloid (Ab) pathology using positron emission tomography. While the gold standard for amyloid imaging, carbon-11 labeled Pittsburgh compound B is increasingly being replaced by fluorine-18 labeled radiopharmaceuticals, with three already approved for clinical use by US and European regulatory bodies. Appropriate use criteria proposed by an amyloid imaging taskforce convened by the Alzheimer's Association and the Society of Nuclear Medicine and Molecular Imaging recommend restricting use of this technology to the evaluation of patients with mild cognitive impairment or atypical dementia syndromes. While use among asymptomatic individuals is currently viewed as inappropriate due prognostic uncertainty, elevated levels of brain Ab among asymptomatic individuals may represent preclinical Alzheimer's disease. Amyloid imaging is likewise expected to play a role in the design of clinical trials. Though preliminary results suggest amyloid imaging to possess clinical utility and cost-effectiveness, both domains have yet to be assessed systematically. As the field moves toward adoption of a pro-disclosure stance for amyloid imaging findings, it is imperative that a broad range of stakeholders be involved to ensure the appropriateness of emerging policies and protocols.
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| 9. |
- Pascoal, Tharick A., et al.
(författare)
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Discriminative accuracy of the A/T/N scheme to identify cognitive impairment due to Alzheimer's disease
- 2023
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Ingår i: Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring. - : Wiley. - 2352-8729. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The optimal combination of amyloid-β/tau/neurodegeneration (A/T/N) biomarker profiles for the diagnosis of Alzheimer's disease (AD) dementia is unclear. Methods: We examined the discriminative accuracy of A/T/N combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non-AD neurodegenerative diseases in the TRIAD, BioFINDER-1 and BioFINDER-2 cohorts (total n = 832) using area under the receiver operating characteristic curves (AUC). Results: For the diagnosis of AD dementia (vs. CU elderly), T biomarkers performed as well as the complete A/T/N system (AUC range: 0.90–0.99). A and T biomarkers in isolation performed as well as the complete A/T/N system in differentiating AD dementia from non-AD neurodegenerative diseases (AUC range; A biomarker: 0.84–1; T biomarker: 0.83–1). Discussion: In diagnostic settings, the use of A or T neuroimaging biomarkers alone can reduce patient burden and medical costs compared with using their combination, without significantly compromising accuracy.
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| 10. |
- Vigorito, Elena, et al.
(författare)
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Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95% CI: 0.68 to 0.79, p-value 2x 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95% CI: 0.59 to 0.80, p-value 1.0 x 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.
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