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- Vermunt, L., et al.
(författare)
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Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:7, s. 888-898
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We estimated the age-specific duration of the preclinical, prodromal, and dementia stages of Alzheimer's disease (AD) and the influence of sex, setting, apolipoprotein E (APOE) genotype, and cerebrospinal fluid tau on disease duration. Methods: We performed multistate modeling in a combined sample of 6 cohorts (n = 3268) with death as the end stage and estimated the preclinical, prodromal, and dementia stage duration. Results: The overall AD duration varied between 24 years (age 60) and 15 years (age 80). For individuals presenting with preclinical AD, age 70, the estimated preclinical AD duration was 10 years, prodromal AD 4 years, and dementia 6 years. Male sex, clinical setting, APOE epsilon 4 allele carriership, and abnormal cerebrospinal fluid tau were associated with a shorter duration, and these effects depended on disease stage. Discussion: Estimates of AD disease duration become more accurate if age, sex, setting, APOE, and cerebrospinal fluid tau are taken into account. This will be relevant for clinical practice and trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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- Neumann, A., et al.
(författare)
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Rare variants in IFFO1, DTNB, NLRC3 and SLC22A10 associate with Alzheimer's disease CSF profile of neuronal injury and inflammation
- 2022
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 27, s. 1990-1999
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer's disease (AD) biomarkers represent several neurodegenerative processes, such as synaptic dysfunction, neuronal inflammation and injury, as well as amyloid pathology. We performed an exome-wide rare variant analysis of six AD biomarkers (beta-amyloid, total/phosphorylated tau, NfL, YKL-40, and Neurogranin) to discover genes associated with these markers. Genetic and biomarker information was available for 480 participants from two studies: EMIF-AD and ADNI. We applied a principal component (PC) analysis to derive biomarkers combinations, which represent statistically independent biological processes. We then tested whether rare variants in 9576 protein-coding genes associate with these PCs using a Meta-SKAT test. We also tested whether the PCs are intermediary to gene effects on AD symptoms with a SMUT test. One PC loaded on NfL and YKL-40, indicators of neuronal injury and inflammation. Four genes were associated with this PC: IFFO1, DTNB, NLRC3, and SLC22A10. Mediation tests suggest, that these genes also affect dementia symptoms via inflammation/injury. We also observed an association between a PC loading on Neurogranin, a marker for synaptic functioning, with GABBR2 and CASZ1, but no mediation effects. The results suggest that rare variants in IFFO1, DTNB, NLRC3, and SLC22A10 heighten susceptibility to neuronal injury and inflammation, potentially by altering cytoskeleton structure and immune activity disinhibition, resulting in an elevated dementia risk. GABBR2 and CASZ1 were associated with synaptic functioning, but mediation analyses suggest that the effect of these two genes on synaptic functioning is not consequential for AD development.
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- Aas, W., et al.
(författare)
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Lessons learnt from the first EMEP intensive measurement periods
- 2012
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Ingår i: Atmospheric Chemistry and Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 12:17, s. 8073-8094
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Tidskriftsartikel (refereegranskat)abstract
- The first EMEP intensive measurement periods were held in June 2006 and January 2007. The measurements aimed to characterize the aerosol chemical compositions, including the gas/aerosol partitioning of inorganic compounds. The measurement program during these periods included daily or hourly measurements of the secondary inorganic components, with additional measurements of elemental- and organic carbon (EC and OC) and mineral dust in PM1, PM2.5 and PM10. These measurements have provided extended knowledge regarding the composition of particulate matter and the temporal and spatial variability of PM, as well as an extended database for the assessment of chemical transport models. This paper summarise the first experiences of making use of measurements from the first EMEP intensive measurement periods along with EMEP model results from the updated model version to characterise aerosol composition. We investigated how the PM chemical composition varies between the summer and the winter month and geographically. The observation and model data are in general agreement regarding the main features of PM10 and PM2.5 composition and the relative contribution of different components, though the EMEP model tends to give slightly lower estimates of PM10 and PM2.5 compared to measurements. The intensive measurement data has identified areas where improvements are needed. Hourly concurrent measurements of gaseous and particulate components for the first time facilitated testing of modelled diurnal variability of the gas/aerosol partitioning of nitrogen species. In general, the modelled diurnal cycles of nitrate and ammonium aerosols are in fair agreement with the measurements, but the diurnal variability of ammonia is not well captured. The largest differences between model and observations of aerosol mass are seen in Italy during winter, which to a large extent may be explained by an underestimation of residential wood burning sources. It should be noted that both primary and secondary OC has been included in the calculations for the first time, showing promising results. Mineral dust is important, especially in southern Europe, and the model seems to capture the dust episodes well. The lack of measurements of mineral dust hampers the possibility for model evaluation for this highly uncertain PM component. There are also lessons learnt regarding improved measurements for future intensive periods. There is a need for increased comparability between the measurements at different sites. For the nitrogen compounds it is clear that more measurements using artefact free methods based on continuous measurement methods and/or denuders are needed. For EC/OC, a reference methodology (both in field and laboratory) was lacking during these periods giving problems with comparability, though measurement protocols have recently been established and these should be followed by the Parties to the EMEP Protocol. For measurements with no defined protocols, it might be a good solution to use centralised laboratories to ensure comparability across the network. To cope with the introduction of these new measurements, new reporting guidelines have been developed to ensure that all proper information about the methodologies and data quality is given.
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- Bos, I., et al.
(författare)
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Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum
- 2019
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:5, s. 644-654
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: We investigated relations between amyloid-beta (A beta) status, apolipoprotein E (APOE) e4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). Methods: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with A beta status (Ab beta- vs. A beta+), clinical diagnosis APOE epsilon 4 carriership, baseline cognition, and change in cognition. Results: Ng and T-tau distinguished between A beta+ from A beta- individuals in each clinical group, whereas NFL and YKL-40 were associated with A beta+ in nondemented individuals only. APOE epsilon 4 carriership did not influence NFL, Ng, and YKL-40 in A beta+ individuals. NFL was the best predictor of cognitive decline in A beta+ individuals across the cognitive spectrum. Discussion: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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