| 31. |
- Aranha, M. R., et al.
(författare)
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Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome
- 2023
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Ingår i: Alzheimers & Dementia. - 1552-5260. ; 19:11, s. 4817-4827
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundBasal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. MethodsWe included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. ResultsIn DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. DiscussionBF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS.
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| 32. |
- Bejanin, A., et al.
(författare)
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Association of Apolipoprotein e ϵ4 Allele with Clinical and Multimodal Biomarker Changes of Alzheimer Disease in Adults with down Syndrome
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 937-947
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Alzheimer disease (AD) is the leading cause of death in individuals with Down syndrome (DS). Previous studies have suggested that the APOE ϵ4 allele plays a role in the risk and age at onset of dementia in DS; however, data on in vivo biomarkers remain scarce. Objective: To investigate the association of the APOE ϵ4 allele with clinical and multimodal biomarkers of AD in adults with DS. Design, Setting, and Participants: This dual-center cohort study recruited adults with DS in Barcelona, Spain, and in Cambridge, UK, between June 1, 2009, and February 28, 2020. Included individuals had been genotyped for APOE and had at least 1 clinical or AD biomarker measurement; 2 individuals were excluded because of the absence of trisomy 21. Participants were either APOE ϵ4 allele carriers or noncarriers. Main Outcomes and Measures: Participants underwent a neurological and neuropsychological assessment. A subset of participants had biomarker measurements: Aβ1-42, Aβ1-40, phosphorylated tau 181 (pTau181) and neurofilament light chain (NfL) in cerebrospinal fluid (CSF), pTau181, and NfL in plasma; amyloid positron emission tomography (PET); fluorine 18-labeled-fluorodeoxyglucose PET; and/or magnetic resonance imaging. Age at symptom onset was compared between APOE ϵ4 allele carriers and noncarriers, and within-group local regression models were used to compare the association of biomarkers with age. Voxelwise analyses were performed to assess topographical differences in gray matter metabolism and volume. Results: Of the 464 adults with DS included in the study, 97 (20.9%) were APOE ϵ4 allele carriers and 367 (79.1%) were noncarriers. No differences between the 2 groups were found by age (median [interquartile range], 45.9 [36.4-50.2] years vs 43.7 [34.9-50.2] years; P =.56) or sex (51 male carriers [52.6%] vs 199 male noncarriers [54.2%]). APOE ϵ4 allele carriers compared with noncarriers presented with AD symptoms at a younger age (mean [SD] age, 50.7 [4.4] years vs 52.7 [5.8] years; P =.02) and showed earlier cognitive decline. Locally estimated scatterplot smoothing curves further showed between-group differences in biomarker trajectories with age as reflected by nonoverlapping CIs. Specifically, carriers showed lower levels of the CSF Aβ1-42 to Aβ1-40 ratio until age 40 years, earlier increases in amyloid PET and plasma pTau181, and earlier loss of cortical metabolism and hippocampal volume. No differences were found in NfL biomarkers or CSF total tau and pTau181. Voxelwise analyses showed lower metabolism in subcortical and parieto-occipital structures and lower medial temporal volume in APOE ϵ4 allele carriers. Conclusions and Relevance: In this study, the APOE ϵ4 allele was associated with earlier clinical and biomarker changes of AD in DS. These results provide insights into the mechanisms by which APOE increases the risk of AD, emphasizing the importance of APOE genotype for future clinical trials in DS. © 2021 American Medical Association. All rights reserved.
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| 33. |
- Danilovich, Taissa, 1987, et al.
(författare)
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New observations and models of circumstellar CO line emission of AGB stars in the Herschel SUCCESS programme
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 581
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Tidskriftsartikel (refereegranskat)abstract
- Asymptotic giant branch (AGB) stars are in one of the latest evolutionary stages of low to intermediate-mass stars. Their vigorous mass loss has a significant effect on the stellar evolution, and is a significant source of heavy elements and dust grains for the interstellar medium. The mass-loss rate can be well traced by carbon monoxide (CO) line emission. Aims. We present new Herschel/HIFI and IRAM 30 m telescope CO line data for a sample of 53 galactic AGB stars. The lines cover a fairly large range of excitation energy from the J = 1 → 0 line to the J = 9 → 8 line, and even the J = 14 → 13 line in a few cases. We perform radiative transfer modelling for 38 of these sources to estimate their mass-loss rates. Methods. We used a radiative transfer code based on the Monte Carlo method to model the CO line emission. We assume spherically symmetric circumstellar envelopes that are formed by a constant mass-loss rate through a smoothly accelerating wind. Results. We find models that are consistent across a broad range of CO lines for most of the stars in our sample, i.e., a large number of the circumstellar envelopes can be described with a constant mass-loss rate. We also find that an accelerating wind is required to fit, in particular, the higher-J lines and that a velocity law will have a significant effect on the model line intensities. The results cover a wide range of mass-loss rates (~10-8 to 2 × 10-5 M⊙ yr-1) and gas expansion velocities (2 to 21.5 km s-1), and include M-, S-, and C-type AGB stars. Our results generally agree with those of earlier studies, although we tend to find slightly lower mass-loss rates by about 40%, on average. We also present "bonus" lines detected during our CO observations.
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| 34. |
- De Marco, O., et al.
(författare)
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The messy death of a multiple star system and the resulting planetary nebula as observed by JWST
- 2022
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Ingår i: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 6:12, s. 1421-1432
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Tidskriftsartikel (refereegranskat)abstract
- Planetary nebulae—the ejected envelopes of red giant stars—provide us with a history of the last, mass-losing phases of 90% of stars initially more massive than the Sun. Here we analyse images of the planetary nebula NGC 3132 from the James Webb Space Telescope (JWST) Early Release Observations. A structured, extended hydrogen halo surrounding an ionized central bubble is imprinted with spiral structures, probably shaped by a low-mass companion orbiting the central star at about 40–60 au. The images also reveal a mid-infrared excess at the central star, interpreted as a dusty disk, which is indicative of an interaction with another closer companion. Including the previously known A-type visual companion, the progenitor of the NGC 3132 planetary nebula must have been at least a stellar quartet. The JWST images allow us to generate a model of the illumination, ionization and hydrodynamics of the molecular halo, demonstrating the power of JWST to investigate complex stellar outflows. Furthermore, new measurements of the A-type visual companion allow us to derive the value for the mass of the progenitor of a central star with excellent precision: 2.86 ± 0.06 M⊙. These results serve as pathfinders for future JWST observations of planetary nebulae, providing unique insight into fundamental astrophysical processes including colliding winds and binary star interactions, with implications for supernovae and gravitational-wave systems.
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| 35. |
- Delaby, C., et al.
(författare)
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Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles
- 2022
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Ingår i: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 129
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Blood biomarkers represent a major advance for improving the management, diagnosis, and monitoring of Alzheimer's disease (AD). However, their context of use in relation to routine cerebrospinal fluid (CSF) analysis for the quantification of amyloid peptides and tau proteins remains to be determined. Methods We studied in two independent cohorts, the performance of blood biomarkers in detecting "nonpathological" (A-/T-/N-), amyloid (A+) or neurodegenerative (T+ /N+) CSF profiles. Results Plasma A beta(1-42)/A beta(1-40) ratio and phosphorylated tau (p-tau(181)) were independent and complementary predictors of the different CSF profile and in particular of the nonpathological (A-/T-/N-) profile with a sensitivity and specificity close to 85%. These performances and the corresponding biomarker thresholds were significantly different from those related to AD detection. Conclusion The use of blood biomarkers to identify patients who may benefit from secondary CSF testing represents an attractive stratification strategy in the clinical management of patients visiting memory clinics. This could reduce the need for lumbar puncture and foreshadow the use of blood testing on larger populations.
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| 36. |
- Delaby, Constance, et al.
(författare)
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Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.
- 2022
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:10, s. 1868-1879
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Tidskriftsartikel (refereegranskat)abstract
- The current practice of quantifying cerebrospinal fluid (CSF) biomarkers as an aid in the diagnosis of Alzheimer's disease (AD) varies from center to center. For a same biochemical profile, interpretation and reporting of results may differ, which can lead to misunderstandings and raises questions about the commutability of tests.We obtained a description of (pre-)analytical protocols and sample reports from 40 centers worldwide. A consensus approach allowed us to propose harmonized comments corresponding to the different CSF biomarker profiles observed in patients.The (pre-)analytical procedures were similar between centers. There was considerable heterogeneity in cutoff definitions and report comments. We therefore identified and selected by consensus the most accurate and informative comments regarding the interpretation of CSF biomarkers in the context of AD diagnosis.This is the first time that harmonized reports are proposed across worldwide specialized laboratories involved in the biochemical diagnosis of AD.
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| 37. |
- Deming, Y., et al.
(författare)
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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
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Tidskriftsartikel (refereegranskat)abstract
- Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
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| 38. |
- Harwit, M., et al.
(författare)
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Polarisation observations of VY Canis Majoris H2O 532-441 620.701 GHz maser emission with HIFI
- 2010
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L51-
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Tidskriftsartikel (refereegranskat)abstract
- Context. Water vapour maser emission from evolved oxygen-rich stars remains poorly understood. Additional observations, including polarisation studies and simultaneous observation of different maser transitions may ultimately lead to greater insight. Aims. We have aimed to elucidate the nature and structure of the VY CMa water vapour masers in part by observationally testing a theoretical prediction of the relative strengths of the 620.701 GHz and the 22.235 GHz maser components of ortho H2O. Methods. In its high-resolution mode (HRS) the Herschel Heterodyne Instrument for the Far Infrared (HIFI) offers a frequency resolution of 0.125 MHz, corresponding to a line-of-sight velocity of 0.06 km s(-1), which we employed to obtain the strength and linear polarisation of maser spikes in the spectrum of VY CMa at 620.701 GHz. Simultaneous ground based observations of the 22.235 GHz maser with the Max-Planck-Institut fur Radioastronomie 100-m telescope at Effelsberg, provided a ratio of 620.701 GHz to 22.235 GHz emission. Results. We report the first astronomical detection to date of H2O maser emission at 620.701 GHz. In VY CMa both the 620.701 and the 22.235 GHz polarisation are weak. At 620.701 GHz the maser peaks are superposed on what appears to be a broad emission component, jointly ejected from the star. We observed the 620.701 GHz emission at two epochs 21 days apart, both to measure the potential direction of linearly polarised maser components and to obtain a measure of the longevity of these components. Although we do not detect significant polarisation levels in the core of the line, they rise up to approximately 6% in its wings.
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| 39. |
- Iulita, M. F., et al.
(författare)
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Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome
- 2023
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-beta 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein.4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein.4, female.4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein.4 and biomarkers showed that female.4 carriers tended to exhibit lower CSF amyloid-beta 42/amyloid-beta 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein.4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.
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| 40. |
- Janssen, O., et al.
(författare)
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Characteristics of subjective cognitive decline associated with amyloid positivity
- 2022
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:10, s. 1832-1845
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The evidence for characteristics of persons with subjective cognitive decline (SCD) associated with amyloid positivity is limited. Methods In 1640 persons with SCD from 20 Amyloid Biomarker Study cohort, we investigated the associations of SCD-specific characteristics (informant confirmation, domain-specific complaints, concerns, feelings of worse performance) demographics, setting, apolipoprotein E gene (APOE) epsilon 4 carriership, and neuropsychiatric symptoms with amyloid positivity. Results Between cohorts, amyloid positivity in 70-year-olds varied from 10% to 76%. Only older age, clinical setting, and APOE epsilon 4 carriership showed univariate associations with increased amyloid positivity. After adjusting for these, lower education was also associated with increased amyloid positivity. Only within a research setting, informant-confirmed complaints, memory complaints, attention/concentration complaints, and no depressive symptoms were associated with increased amyloid positivity. Feelings of worse performance were associated with less amyloid positivity at younger ages and more at older ages. Discussion Next to age, setting, and APOE epsilon 4 carriership, SCD-specific characteristics may facilitate the identification of amyloid-positive individuals.
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