1. |
- de Rojas, I., et al.
(author)
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Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).
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3. |
- Bellenguez, C, et al.
(author)
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New insights into the genetic etiology of Alzheimer's disease and related dementias
- 2022
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 54:4, s. 412-436
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Journal article (peer-reviewed)abstract
- Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
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7. |
- van der Lee, S. J., et al.
(author)
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A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity
- 2019
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 237-250
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Journal article (peer-reviewed)abstract
- The genetic variant rs72824905-G (minor allele) in the PLCG2 gene was previously associated with a reduced Alzheimer's disease risk (AD). The role of PLCG2 in immune system signaling suggests it may also protect against other neurodegenerative diseases and possibly associates with longevity. We studied the effect of the rs72824905-G on seven neurodegenerative diseases and longevity, using 53,627 patients, 3,516 long-lived individuals and 149,290 study-matched controls. We replicated the association of rs72824905-G with reduced AD risk and we found an association with reduced risk of dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). We did not find evidence for an effect on Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) risks, despite adequate sample sizes. Conversely, the rs72824905-G allele was associated with increased likelihood of longevity. By-proxy analyses in the UK Biobank supported the associations with both dementia and longevity. Concluding, rs72824905-G has a protective effect against multiple neurodegenerative diseases indicating shared aspects of disease etiology. Our findings merit studying the PLC gamma 2 pathway as drug-target.
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8. |
- Bujarrabal, V., et al.
(author)
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Herschel/HIFI observations of high-J CO transitions in the protoplanetary nebula CRL 618
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L3-
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Journal article (peer-reviewed)abstract
- Aims. We aim to study the physical conditions, particularly the excitation state, of the intermediate-temperature gas components in the protoplanetary nebula CRL 618. These components are particularly important for understanding the evolution of the nebula. Methods. We performed Herschel/HIFI observations of several CO lines in the far-infrared/sub-mm in the protoplanetary nebula CRL 618. The high spectral resolution provided by HIFI allows measurement of the line profiles. Since the dynamics and structure of the nebula is well known from mm-wave interferometric maps, it is possible to identify the contributions of the different nebular components (fast bipolar outflows, double shells, compact slow shell) to the line profiles. The observation of these relatively high-energy transitions allows an accurate study of the excitation conditions in these components, particularly in the warm ones, which cannot be properly studied from the low-energy lines. Results. The (CO)-C-12 J = 16-15, 10-9, and 6-5 lines are easily detected in this source. Both (CO)-C-13 J = 10-9 and 6-5 are also detected. Wide profiles showing spectacular line wings have been found, particularly in (CO)-C-12 J = 16-15. Other lines observed simultaneously with CO are also shown. Our analysis of the CO high-J transitions, when compared with the existing models, confirms the very low expansion velocity of the central, dense component, which probably indicates that the shells ejected during the last AGB phases were driven by radiation pressure under a regime of maximum transfer of momentum. No contribution of the diffuse halo found from mm-wave data is identified in our spectra, because of its low temperature. We find that the fast bipolar outflow is quite hot, much hotter than previously estimated; for instance, gas flowing at 100 km s(-1) must have a temperature higher than similar to 200 K. Probably, this very fast outflow, with a kinematic age
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9. |
- Decin, L., et al.
(author)
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Water content and wind acceleration in the envelope around the oxygen-rich AGB star IK Tauri as seen by Herschel/HIFI
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L4-
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Journal article (peer-reviewed)abstract
- During their asymptotic giant branch evolution, low-mass stars lose a significant fraction of their mass through an intense wind, enriching the interstellar medium with products of nucleosynthesis. We observed the nearby oxygen-rich asymptotic giant branch star IK Tau using the high-resolution HIFI spectrometer onboard Herschel. We report on the first detection of (H2O)-O-16 and the rarer isotopologues (H2O)-O-17 and (H2O)-O-18 in both the ortho and para states. We deduce a total water content (relative to molecular hydrogen) of 6.6 x 10(-5), and an ortho-to-para ratio of 3:1. These results are consistent with the formation of H2O in thermodynamical chemical equilibrium at photospheric temperatures, and does not require pulsationally induced non-equilibrium chemistry, vaporization of icy bodies or grain surface reactions. High-excitation lines of (CO)-C-12, (CO)-C-13, (SiO)-Si-28, (SiO)-Si-29, (SiO)-Si-30, HCN, and SO have also been detected. From the observed line widths, the acceleration region in the inner wind zone can be characterized, and we show that the wind acceleration is slower than hitherto anticipated.
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10. |
- Alcolea, J., et al.
(author)
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HIFISTARS Herschel/HIFI observations of VY Canis Majoris. Molecular-line inventory of the envelope around the largest known star
- 2013
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 559, s. (article nr.) A93-
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Journal article (peer-reviewed)abstract
- Aims.The study of the molecular gas in the circumstellar envelopes of evolved stars is normally undertaken by observing lines ofCO (and other species) in the millimetre-wave domain. In general, the excitation requirements of the observed lines are low at thesewavelengths, and therefore these observations predominantly probe the cold outer envelope while studying the warm inner regions ofthe envelopes normally requires sub-millimetre (sub-mm) and far-infrared (FIR) observational data.Methods.To gain insight into the physical conditions and kinematics of the warm (100–1000 K) gas around the red hyper-giantVY CMa, we performed sensitive high spectral resolution observations of molecular lines in the sub-mm/FIR using the HIFI instru-ment of theHerschelSpace Observatory. We observed CO, H2O, and other molecular species, sampling excitation energies from afew tens to a few thousand K. These observations are part of theHerschelguaranteed time key program HIFISTARS.Results.We detected theJ=6–5,J=10–9, andJ=16–15 lines of12CO and13CO at∼100, 300, and 750 K above the groundstate (and the13COJ=9–8 line). These lines are crucial for improving the modelling of the internal layers of the envelope aroundVY CMa. We also detected 27 lines of H2O and its isotopomers, and 96 lines of species such as NH3,SiO,SO,SO2HCN, OH andothers, some of them originating from vibrationally excited levels. Three lines were not unambiguously assigned.Conclusions.Our observations confirm that VY CMa’s envelope must consist of two or more detached components. The molecularexcitation in the outer layers is significantly lower than in the inner ones, resulting in strong self-absorbed profiles in molecular linesthat are optically thick in this outer envelope, for instance, low-lying lines of H2O. Except for the most abundant species, CO and H2O,most of the molecular emission detected at these sub-mm/FIR wavelengths arise from the central parts of the envelope. The spectrumof VY CMa is very prominent in vibrationally excited lines, which are caused by the strong IR pumping present in the central regions.Compared with envelopes of other massive evolved stars, VY CMa’s emission is particularly strong in these vibrationally excitedlines, as well as in the emission from less abundant species such as H13CN, SO, and NH3.
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11. |
- Bujarrabal, V., et al.
(author)
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Herschel/HIFI observations of molecular emission in protoplanetary nebulae and young planetary nebulae
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 537, s. Article Number: A8-
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Journal article (peer-reviewed)abstract
- Aims. We aim to study the physical conditions, particularly the excitation state, of the intermediate-temperature gas in protoplanetary nebulae and young planetary nebulae (PPNe, PNe). The information that the observations of the different components deliver is of particular importance for understanding the evolution of these objects. Methods. We performed Herschel/HIFI observations of intermediate-excitation molecular lines in the far-infrared/submillimeter range in a sample of ten nebulae. The high spectral resolution provided by HIFI allows the accurate measurement of the line profiles. The dynamics and evolution of these nebulae are known to result from the presence of several gas components, notably fast bipolar outflows and slow shells (that often are the fossil AGB shells), and the interaction between them. Because of the diverse kinematic properties of the different components, their emissions can be identified in the line profiles. The observation of these high-energy transitions allows an accurate study of the excitation conditions, particularly in the warm gas, which cannot be properly studied from the low-energy lines. Results. We have detected FIR/sub-mm lines of several molecules, in particular of (CO)-C-12, (CO)-C-13, and H2O. Emission from other species, like NH3, OH, (H2O)-O-18, HCN, SiO, etc., has been also detected. Wide profiles showing sometimes spectacular line wings have been found. We have mainly studied the excitation properties of the high-velocity emission, which is known to come from fast bipolar outflows. From comparison with general theoretical predictions, we find that CRL 618 shows a particularly warm fast wind, with characteristic kinetic temperature T-k greater than or similar to 200 K. In contrast, the fast winds in OH 231.8+4.2 and NGC 6302 are cold, T-k similar to 30 K. Other nebulae, like CRL 2688, show intermediate temperatures, with characteristic values around 100 K. We also discuss how the complex structure of the nebulae can affect our estimates, considering two-component models. We argue that the differences in temperature in the different nebulae can be caused by cooling after the gas acceleration (that is probably caused by shocks); for instance, CRL 618 is a case of very recent acceleration, less than similar to 100 yr ago, while the fast gas in OH 231.8+4.2 was accelerated similar to 1000 yr ago. We also find indications that the densest gas tends to be cooler, which may be explained by the expected increase of the radiative cooling efficiency with the density.
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12. |
- Gonzalez, Maria Camila, et al.
(author)
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Cognitive and motor decline in dementia with lewy bodies and Parkinson's disease dementia
- 2023
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In: Movement Disorders Clinical Practice. - : John Wiley & Sons. - 2330-1619. ; 10:6, s. 980-986
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Journal article (peer-reviewed)abstract
- Background: There is a need to better understand the rate of cognitive and motor decline of Dementia with Lewy bodies (DLB) and Parkinson's disease Dementia (PDD).Objectives: To compare the rate of cognitive and motor decline in patients with DLB and PDD from the E-DLB Consortium and the Parkinson's Incidence Cohorts Collaboration (PICC) Cohorts.Methods: The annual change in MMSE and MDS-UPDRS part III was estimated using linear mixed regression models in patients with at least one follow-up (DLB n = 837 and PDD n = 157).Results: When adjusting for confounders, we found no difference in the annual change in MMSE between DLB and PDD (−1.8 [95% CI −2.3, −1.3] vs. −1.9 [95% CI −2.6, −1.2] [P = 0.74]). MDS-UPDRS part III showed nearly identical annual changes (DLB 4.8 [95% CI 2.1, 7.5]) (PDD 4.8 [95% CI 2.7, 6.9], [P = 0.98]).Conclusions: DLB and PDD showed similar rates of cognitive and motor decline. This is relevant for future clinical trial designs.
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13. |
- Harwit, M., et al.
(author)
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Polarisation observations of VY Canis Majoris H2O 5(32)-4(41) 620.701 GHz maser emission with HIFI
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521, s. L51-
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Journal article (peer-reviewed)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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14. |
- Hong, S. J., et al.
(author)
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TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels
- 2021
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:10, s. 1628-1640
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Journal article (peer-reviewed)abstract
- Introduction Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. Methods We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. Results We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. Discussion Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
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15. |
- Jansen, Willemijn J, et al.
(author)
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Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia.
- 2018
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 75:1, s. 84-95
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.To investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.This cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Global cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.Among 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P=.16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P<.001) and low MMSE (mean difference, 14% [95% CI, 12%-17%], P<.001) scores, and this association decreased with age. Low cognitive scores had limited utility for screening of amyloid positivity in persons with normal cognition and those with MCI. In persons with normal cognition, the age-related increase in low memory score paralleled the age-related increase in amyloid positivity with an intervening period of 10 to 15 years.Although low memory scores are an early marker of amyloid positivity, their value as a screening measure for early AD among persons without dementia is limited.
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16. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
- 2022
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In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
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Journal article (peer-reviewed)abstract
- One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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17. |
- Jansen, Willemijn J, et al.
(author)
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Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.
- 2015
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In: JAMA. - : American Medical Association (AMA). - 1538-3598 .- 0098-7484. ; 313:19, s. 1924-38
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Journal article (peer-reviewed)abstract
- Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.
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18. |
- Justtanont, Kay, 1965, et al.
(author)
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A HIFI preview of warm molecular gas around chi Cygni: first detection of H2O emission toward an S-type AGB star
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L6-
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Journal article (peer-reviewed)abstract
- Aims. A set of new, sensitive, and spectrally resolved, sub-millimeter line observations are used to probe the warm circumstellar gas around the S-type AGB star chi Cyg. The observed lines involve high rotational quantum numbers, which, combined with previously obtained lower-frequency data, make it posible to study in detail the chemical and physical properties of, essentially, the entire circumstellar envelope of chi Cyg. Methods. The data were obtained using the HIFI instrument aboard Herschel, whose high spectral resolution provides valuable information about the line profiles. Detailed, non-LTE, radiative transfer modelling, including dust radiative transfer coupled with a dynamical model, has been performed to derive the temperature, density, and velocity structure of the circumstellar envelope. Results. We report the first detection of circumstellar H2O rotational emission lines in an S-star. Using the high-J CO lines to derive the parameters for the circumstellar envelope, we modelled both the ortho-and para-H2O lines. Our modelling results are consistent with the velocity structure expected for a dust-driven wind. The derived total H2O abundance (relative to H-2) is (1.1 +/- 0.2) x 10(-5), much lower than that in O-rich stars. The derived ortho-to-para ratio of 2.1 +/- 0.6 is close to the high-temperature equilibrium limit, consistent with H2O being formed in the photosphere.
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19. |
- Justtanont, Kay, 1965, et al.
(author)
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Herschel/HIFI observations of O-rich AGB stars: molecular inventory
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 537, s. Article Number: A144 -
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Journal article (peer-reviewed)abstract
- Aims. Spectra, taken with the heterodyne instrument, HIFI, aboard the Herschel Space Observatory, of O-rich asymptotic giant branch (AGB) stars which form part of the guaranteed time key program HIFISTARS are presented. The aim of this program is to study the dynamical structure, mass-loss driving mechanism, and chemistry of the outflows from AGB stars as a function of chemical composition and initial mass. Methods. We used the HIFI instrument to observe nine AGB stars, mainly in the H2O and high rotational CO lines. We investigate the correlation between line luminosity, line ratio and mass-loss rate, line width and excitation energy. Results. A total of nine different molecules, along with some of their isotopologues have been identified, covering a wide range of excitation temperature. Maser emission is detected in both the ortho-and para-H2O molecules. The line luminosities of ground state lines of ortho- and para-H2O, the high-J CO and NH3 lines show a clear correlation with mass-loss rate. The line ratios of H2O and NH3 relative to CO J = 6-5 correlate with the mass-loss rate while ratios of higher CO lines to the 6-5 is independent of it. In most cases, the expansion velocity derived from the observed line width of highly excited transitions formed relatively close to the stellar photosphere is lower than that of lower excitation transitions, formed farther out, pointing to an accelerated outflow. In some objects, the vibrationally excited H2O and SiO which probe the acceleration zone suggests the wind reaches its terminal velocity already in the innermost part of the envelope, i.e., the acceleration is rapid. Interestingly, for R Dor we find indications of a deceleration of the outflow in the region where the material has already escaped from the star.
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20. |
- Kruse, N., et al.
(author)
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Validation of a quantitative cerebrospinal fluid alpha-synuclein assay in a European-wide interlaboratory study
- 2015
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In: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 36:9, s. 2587-2596
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Journal article (peer-reviewed)abstract
- Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program -Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given. (C) 2015 Elsevier Inc. All rights reserved.
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21. |
- Lleo, A., et al.
(author)
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Phosphorylated tau181 in plasma as a potential biomarker for Alzheimer's disease in adults with Down syndrome
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology with high accuracy in the general population. In this study, we investigated plasma p-tau181 as a biomarker of AD in individuals with Down syndrome (DS). We included 366 adults with DS (240 asymptomatic, 43 prodromal AD, 83 AD dementia) and 44 euploid cognitively normal controls. We measured plasma p-tau181 with a Single molecule array (Simoa) assay. We examined the diagnostic performance of p-tau181 for the detection of AD and the relationship with other fluid and imaging biomarkers. Plasma p-tau181 concentration showed an area under the curve of 0.80 [95% CI 0.73-0.87] and 0.92 [95% CI 0.89-0.95] for the discrimination between asymptomatic individuals versus those in the prodromal and dementia groups, respectively. Plasma p-tau181 correlated with atrophy and hypometabolism in temporoparietal regions. Our findings indicate that plasma p-tau181 concentration can be useful to detect AD in DS. Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer's disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
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22. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimers disease
- 2018
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In: Alzheimer's & Dementia. - : ELSEVIER SCIENCE INC. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
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Journal article (peer-reviewed)abstract
- Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimers disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P amp;lt;.05) but not in A beta+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE E4 prevalence in AD was higher than that in previous studies, which did not require presence of A beta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. (C) 2018 the Alzheimers Association. Published by Elsevier Inc. All rights reserved.
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23. |
- Mattsson, Niklas, et al.
(author)
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Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease
- 2018
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 14:7, s. 913-924
-
Journal article (peer-reviewed)abstract
- Introduction: Apolipoprotein E (APOE) ε4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid β (Aβ) pathology. Methods: We included 3451 Aβ+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE ε4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE ε4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in Aβ+ cognitively normal and Aβ+ mild cognitive impairment (P <.05) but not in Aβ+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE ε4 prevalence in AD was higher than that in previous studies, which did not require presence of Aβ pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location.
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24. |
- Menten, K. M., et al.
(author)
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Herschel/HIFI deepens the circumstellar NH3 enigma
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L7-
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Journal article (peer-reviewed)abstract
- Context. Circumstellar envelopes (CSEs) of a variety of evolved stars have been found to contain ammonia (NH3) in amounts that exceed predictions from conventional chemical models by many orders of magnitude. Aims. The observations reported here were performed in order to better constrain the NH3 abundance in the CSEs of four, quite diverse, oxygen-rich stars using the NH3 ortho J(K) = 1(0)-0(0) ground-state line. Methods. We used the Heterodyne Instrument for the Far Infrared aboard Herschel to observe the NH3 J(K) = 1(0)-0(0) transition near 572.5 GHz, simultaneously with the ortho-H2O J(Ka,Kc) = 1(1,0)-1(0,1) transition, toward VY CMa, OH 26.5+0.6, IRC+10420, and IK Tau. We conducted non-LTE radiative transfer modeling with the goal to derive the NH3 abundance in these objects' CSEs. For the last two stars, Very Large Array imaging of NH3 radio-wavelength inversion lines were used to provide further constraints, particularly on the spatial extent of the NH3-emitting regions. Results. We find remarkably strong NH3 emission in all of our objects with the NH3 line intensities rivaling those of the ground state H2O line. The NH3 abundances relative to H-2 are very high and range from 2 x 10(-7) to 3 x 10(-6) for the objects we have studied. Conclusions. Our observations confirm and even deepen the circumstellar NH3 enigma. While our radiative transfer modeling does not yield satisfactory fits to the observed line profiles, it does lead to abundance estimates that confirm the very high values found in earlier studies. New ways to tackle this mystery will include further Herschel observations of more NH3 lines and imaging with the Expanded Very Large Array.
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25. |
- Neufeld, D. A., et al.
(author)
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Discovery of water vapour in the carbon star V Cygni from observations with Herschel/HIFI
- 2010
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L5-
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Journal article (peer-reviewed)abstract
- We report the discovery of water vapour toward the carbon star V Cygni. We have used Herschel's HIFI instrument, in dual beam switch mode, to observe the 1(11)-0(00) para-water transition at 1113.3430 GHz in the upper sideband of the Band 4b receiver. The observed spectral line profile is nearly parabolic, but with a slight asymmetry associated with blueshifted absorption, and the integrated antenna temperature is 1.69 +/- 0.17 K km s(-1). This detection of thermal water vapour emission, carried out as part of a small survey of water in carbon-rich stars, is only the second such detection toward a carbon-rich AGB star, the first having been obtained by the Submillimeter Wave Astronomy Satellite toward IRC+ 10216. For an assumed ortho-to-para ratio of 3 for water, the observed line intensity implies a water outflow rate similar to 3-6 x 10(-5) Earth masses per year and a water abundance relative to H-2 of similar to 2-5 x 10(-6). This value is a factor of at least 10(4) larger than the expected photospheric abundance in a carbon-rich environment, and - as in IRC+ 10216 - raises the intriguing possibility that the observed water is produced by the vapourisation of orbiting comets or dwarf planets. However, observations of the single line observed to date do not permit us to place strong constraints upon the spatial distribution or origin of the observed water, but future observations of additional transitions will allow us to determine the inner radius of the H2O-emitting zone, and the H2O ortho-to-para ratio, and thereby to place important constraints upon the origin of the observed water emission.
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26. |
- Neufeld, D. A., et al.
(author)
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The Widespread Occurrence of Water Vapor in the Circumstellar Envelopes of Carbon-Rich Asymptotic Giant Branch Stars: First Results From a Survey With Herschel/HIFI
- 2011
-
In: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 727:2
-
Journal article (peer-reviewed)abstract
- We report the preliminary results of a survey for water vapor in a sample of eight C stars with large mid-IR continuum fluxes: V384 Per, CIT 6, V Hya, Y CVn, IRAS 15194-5115, V Cyg, S Cep, and IRC+40540. This survey, performed using the HIFI instrument on board the Herschel Space Observatory, entailed observations of the lowest transitions of both ortho-and para-water: the 556.936 GHz 1(10)-1(01) and 1113.343 GHz 1(11)-0(00) transitions, respectively. Water vapor was unequivocally detected in all eight of the target stars. Prior to this survey, IRC+10216 was the only carbon-rich asymptotic giant branch (AGB) star from which thermal water emissions had been discovered, in that case with the use of the Submillimeter Wave Astronomy Satellite (SWAS). Our results indicate that IRC+10216 is not unusual, except insofar as its proximity to Earth leads to a large line flux that was detectable with SWAS. The water spectral line widths are typically similar to those of CO rotational lines, arguing against the vaporization of a Kuiper Belt analog being the general explanation for water vapor in carbon-rich AGB stars. There is no apparent correlation between the ratio of the integrated water line fluxes to the 6.3 mu m continuum flux-a ratio which measures the water outflow rate-and the total mass-loss rate for the stars in our sample.
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27. |
- Schmidt, M. R., et al.
(author)
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Herschel/HIFI observations of the circumstellar ammonia lines in IRC+10216
- 2016
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 592
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Journal article (peer-reviewed)abstract
- Context. A discrepancy exists between the abundance of ammonia (NH3) derived previously for the circumstellar envelope (CSE) of IRC+10216 from far-IR submillimeter rotational lines and that inferred from radio inversion or mid-infrared (MIR) absorption transitions. Aims. To address the discrepancy described above, new high-resolution far-infrared (FIR) observations of both ortho-and para-NH3 transitions toward IRC+10216 were obtained with Herschel, with the goal of determining the ammonia abundance and constraining the distribution of NH3 in the envelope of IRC+10216. Methods. We used the Heterodyne Instrument for the Far Infrared (HIFI) on board Herschel to observe all rotational transitions up to the J = 3 level (three ortho-and six para-NH3 lines). We conducted non-LTE multilevel radiative transfer modelling, including the effects of near-infrared (NIR) radiative pumping through vibrational transitions. The computed emission line profiles are compared with the new HIFI data, the radio inversion transitions, and the MIR absorption lines in the nu(2) band taken from the literature. Results. We found that NIR pumping is of key importance for understanding the excitation of rotational levels of NH3. The derived NH3 abundances relative to molecular hydrogen were (2.8 +/- 0.5) x 10(-8) for ortho-NH3 and (3.2(-0.6)(+0.7)) x 10(-8) for para-NH3, consistent with an ortho/para ratio of 1. These values are in a rough agreement with abundances derived from the inversion transitions, as well as with the total abundance of NH3 inferred from the MIR absorption lines. To explain the observed rotational transitions, ammonia must be formed near to the central star at a radius close to the end of the wind acceleration region, but no larger than about 20 stellar radii (1 sigma confidence level).
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28. |
- Teyssier, D., et al.
(author)
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Herschel/HIFI observations of red supergiants and yellow hypergiants I. Molecular inventory
- 2012
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 545, s. A99 (article no.)-
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Journal article (peer-reviewed)abstract
- Context. Red supergiant stars (RSGs) and yellow hypergiant stars (YHGs) are believed to be the high-mass counterparts of stars in the asymptotic giant branch (AGB) and early post-AGB phases. As such, they are scarcer and the properties and evolution of their envelopes are still poorly understood. Aims. We study the mass-loss in the post main-sequence evolution of massive stars, through the properties of their envelopes in the intermediate and warm gas layers. These are the regions where the acceleration of the gas takes place and the most recent mass-loss episodes can be seen. Methods. We used the HIFI instrument on-board the Herschel Space Observatory to observe sub-millimetre and far-infrared (FIR) transitions of CO, water, and their isotopologues in a sample of two RSGs (NML Cyg and Betelgeuse) and two YHGs (IRC + 10420 and AFGL 2343) stars. We present an inventory of the detected lines and analyse the information revealed by their spectral profiles. A comparison of the line intensity and shape in various transitions is used to qualitatively derive a picture of the envelope physical structure. On the basis of the results presented in an earlier study, we model the CO and (CO)-C-13 emission in IRC + 10420 and compare it to a set of lines ranging from the millimetre to the FIR. Results. Red supergiants have stronger high-excitation lines than the YHGs, indicating that they harbour dense and hot inner shells contributing to these transitions. Consequently, these high-J lines in RSGs originate from acceleration layers that have not yet reached the circumstellar terminal velocity and have narrower profiles than their flat-topped lower-J counterparts. The YHGs tend to lack this inner component, in line with the picture of detached, hollow envelopes derived from studies at longer wavelengths. NH3 is only detected in two sources (NML Cyg and IRC + 10420), which are also observed to be the strongest water-line emitters of the studied sample. In contrast, OH is detected in all sources and does not seem to correlate with the water line intensities. We show that the IRC + 10420 model derived solely from millimetre low-J CO transitions is capable of reproducing the high-J transitions when the temperature in the inner shell is simply lowered by about 30%.
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29. |
- Varga, A. W., et al.
(author)
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Reduced Slow-Wave Sleep Is Associated with High Cerebrospinal Fluid A beta 42 Levels in Cognitively Normal Elderly
- 2016
-
In: Sleep. - : Oxford University Press (OUP). - 0161-8105 .- 1550-9109. ; 39:11, s. 2041-2048
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Journal article (peer-reviewed)abstract
- Study Objectives: Emerging evidence suggests a role for sleep in contributing to the progression of Alzheimer disease (AD). Slow wave sleep (SWS) is the stage during which synaptic activity is minimal and clearance of neuronal metabolites is high, making it an ideal state to regulate levels of amyloid beta (A beta). We thus aimed to examine relationships between concentrations of A beta 42 in the cerebrospinal fluid (CSF) and measures of SWS in cognitively normal elderly subjects. Methods: Thirty-six subjects underwent a clinical and cognitive assessment, a structural MRI, a morning to early afternoon lumbar puncture, and nocturnal polysomnography. Correlations and linear regression analyses were used to assess for associations between CSF A beta 42 levels and measures of SWS controlling for potential confounders. Resulting models were compared to each other using ordinary least squared linear regression analysis. Additionally, the participant sample was dichotomized into "high" and "low" A beta 42 groups to compare SWS bout length using survival analyses. Results: A significant inverse correlation was found between CSF A beta 42 levels, SWS duration and other SWS characteristics. Collectively, total SWA in the frontal lead was the best predictor of reduced CSF A beta 42 levels when controlling for age and ApoE status. Total sleep time, time spent in NREM1, NREM2, or REM sleep were not correlated with CSF A beta 42. Conclusions: In cognitively normal elderly, reduced and fragmented SWS is associated with increases in CSF A beta 42, suggesting that disturbed sleep might drive an increase in soluble brain A beta levels prior to amyloid deposition.
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30. |
- Alcolea, D., et al.
(author)
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Use of plasma biomarkers for AT(N) classification of neurodegenerative dementias
- 2021
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In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 92:11, s. 1206-1214
-
Journal article (peer-reviewed)abstract
- Objectives: All categories included in the AT(N) classification can now be measured in plasma. However, their agreement with cerebrospinal fluid (CSF) markers is not fully established. A blood signature to generate the AT(N) classification would facilitate early diagnosis of patients with Alzheimer's disease (AD) through an easy and minimally invasive approach. Methods: We measured Aβ, pTau181 and neurofilament light (NfL) in 150 plasma samples of the Sant Pau Initiative on Neurodegeneration cohort including patients with mild cognitive impairment, AD dementia, frontotemporal dementia, dementia with Lewy bodies and cognitively normal participants. We classified participants in the AT(N) categories according to CSF biomarkers and studied the diagnostic value of plasma biomarkers within each category individually and in combination. Results: The plasma Aβ composite, pTau181 and NfL yielded areas under the curve (AUC) of 0.75, 0.78 and 0.88 to discriminate positive and negative participants in their respective A, T and N categories. The combination of all three markers did not outperform pTau181 alone (AUC=0.81) to discriminate A+T+ from A-T- participants. There was a moderate correlation between plasma Aβ composite and CSF Aβ1-42/Aβ1-40 (Rho=-0.5, p<0.001) and between plasma pTau181 and CSF pTau181 in the entire cohort (Rho=0.51, p<0.001). NfL levels in plasma showed high correlation with those in CSF (Rho=0.78, p<0.001). Conclusions: Plasma biomarkers are useful to detect the AT(N) categories, and their use can differentiate patients with pathophysiological evidence of AD. A blood AT(N) signature may facilitate early diagnosis and follow-up of patients with AD through an easy and minimally invasive approach. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.
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31. |
- Aranha, M. R., et al.
(author)
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Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome
- 2023
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In: Alzheimers & Dementia. - 1552-5260. ; 19:11, s. 4817-4827
-
Journal article (peer-reviewed)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.
(author)
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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
-
In: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149. ; 78:8, s. 937-947
-
Journal article (peer-reviewed)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.
(author)
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New observations and models of circumstellar CO line emission of AGB stars in the Herschel SUCCESS programme
- 2015
-
In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 581
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Journal article (peer-reviewed)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.
(author)
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The messy death of a multiple star system and the resulting planetary nebula as observed by JWST
- 2022
-
In: Nature Astronomy. - : Springer Science and Business Media LLC. - 2397-3366. ; 6:12, s. 1421-1432
-
Journal article (peer-reviewed)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.
(author)
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Blood amyloid and tau biomarkers as predictors of cerebrospinal fluid profiles
- 2022
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In: Journal of Neural Transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 129, s. 231-237
-
Journal article (peer-reviewed)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.
(author)
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Clinical reporting following the quantification of cerebrospinal fluid biomarkers in Alzheimer's disease: An international overview.
- 2022
-
In: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 18:10, s. 1868-1879
-
Journal article (peer-reviewed)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.
(author)
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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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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
-
Journal article (peer-reviewed)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.
(author)
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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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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 521:1, s. Article Number: L51-
-
Journal article (peer-reviewed)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.
(author)
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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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In: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 5:2
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Journal article (peer-reviewed)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.
(author)
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Characteristics of subjective cognitive decline associated with amyloid positivity
- 2022
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:10, s. 1832-1845
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Journal article (peer-reviewed)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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41. |
- Khouri, T., et al.
(author)
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The wind of W Hydrae as seen by Herschel II. The molecular envelope of W Hydrae
- 2014
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In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 570, s. Art. no. A67-
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Journal article (peer-reviewed)abstract
- Context. The evolution of low- and intermediate-mass stars on the asymptotic giant branch (AGB) is mainly controlled by the rate at which these stars lose mass in a stellar wind. Understanding the driving mechanism and strength of the stellar winds of AGB stars and the processes enriching their surfaces with products of nucleosynthesis are paramount to constraining AGB evolution and predicting the chemical evolution of galaxies. Aims. In a previous paper we have constrained the structure of the outflowing envelope of W Hya using spectral lines of the (CO)-C-12 molecule. Here we broaden this study by including an extensive set of H2O and (SiO)-Si-28 lines. It is the first time such a comprehensive study is performed for this source. The oxygen isotopic ratios and the (SiO)-Si-28 abundance profile can be connected to the initial stellar mass and to crucial aspects of dust formation at the base of the stellar wind, respectively. Methods. We model the molecular emission observed by the three instruments on board Herschel Space Observatory using a state-of-the-art molecular excitation and radiative transfer code. We also account for the dust radiation field in our calculations. Results. We find an H2O ortho-to-para ratio of 2.5(-1.0)(+2.5), consistent with what is expected for an AGB wind. The O-16/O-17 ratio indicates that W Hya has an initial mass of about 1.5 M-circle dot. Although the ortho-and para-H2O lines observed by HIFI appear to trace gas of slightly different physical properties, we find that a turbulence velocity of 0.7 +/- 0.1 km s(-1) fits the HIFI lines of both spin isomers and those of (SiO)-Si-28 well. Conclusions. The modelling of H2O and (SiO)-Si-28 confirms the properties of the envelope model of W Hya, as derived from (CO)-C-12 lines, and allows us to constrain the turbulence velocity. The ortho-and para-(H2O)-O-16 and (SiO)-Si-28 abundances relative to H-2 are (6(2)(+3)) x 10(-4), (3(-1)(+2)) x 10(-4), and (3.3 +/- 0.8) x 10(-5), respectively, in agreement with expectations for oxygen-rich AGB outflows. Assuming a solar silicon-to-carbon ratio, the (SiO)-Si-28 line emission model is consistent with about one-third of the silicon atoms being locked up in dust particles.
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42. |
- Kleinberger, G., et al.
(author)
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TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis
- 2014
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In: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 6:243
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Journal article (peer-reviewed)abstract
- Genetic variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to Nasu-Hakola disease, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and FTD-like syndrome without bone involvement. TREM2 is an innate immune receptor preferentially expressed by microglia and is involved in inflammation and phagocytosis. Whether and how TREM2 missense mutations affect TREM2 function is unclear. We report that missense mutations associated with FTD and FTD-like syndrome reduce TREM2 maturation, abolish shedding by ADAM proteases, and impair the phagocytic activity of TREM2-expressing cells. As a consequence of reduced shedding, TREM2 is virtually absent in the cerebrospinal fluid (CSF) and plasma of a patient with FTD-like syndrome. A decrease in soluble TREM2 was also observed in the CSF of patients with AD and FTD, further suggesting that reduced TREM2 function may contribute to increased risk for two neurodegenerative disorders.
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43. |
- Kluska, J., et al.
(author)
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VLTI images of circumbinary disks around evolved stars
- 2020
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In: Proceedings of SPIE - The International Society for Optical Engineering. - : SPIE. - 0277-786X .- 1996-756X. ; 11446
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Conference paper (peer-reviewed)abstract
- The new generation of VLTI instruments (GRAVITY, MATISSE) aims to produce routinely interferometric images to uncover the morphological complexity of different objects at high angular resolution. Image reconstruction is, however, not a fully automated process. Here we focus on a specific science case, namely the complex circumbinary environments of a subset of evolved binaries, for which interferometric imaging provides the spatial resolution required to resolve the immediate circumbinary environment. Indeed, many binaries where the main star is in the post-asymptotic giant branch (post-AGB) phase are surrounded by circumbinary disks. Those disks were first inferred from the infrared excess produced by dust. Snapshot interferometric observations in the infrared confirmed disk-like morphology and revealed high spatial complexity of the emission that the use of geometrical models could not recover without being strongly biased. Arguably, the most convincing proof of the disk-like shape of the circumbinary environment came from the first interferometric image of such a system (IRAS08544-4431) using the PIONIER instrument at the VLTI. This image was obtained using the SPARCO image reconstruction approach that enables to subtract a model of a component of the image and reconstruct an image of its environment only. In the case of IRAS08544-4431, the model involved a binary and the image of the remaining signal revealed several unexpected features. Then, a second image revealed a different but also complex circumstellar morphology around HD101584 that was well studied by ALMA. To exploit the VLTI imaging capability to understand these targets, we started a large programme at the VLTI to image post-AGB binary systems using both PIONIER and GRAVITY instruments.
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44. |
- Lennol, M. P., et al.
(author)
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Apolipoprotein E imbalance in the cerebrospinal fluid of Alzheimer's disease patients
- 2022
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In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
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Journal article (peer-reviewed)abstract
- Objective: The purpose of this study was to examine the levels of cerebrospinal fluid (CSF) apolipoprotein E (apoE) species in Alzheimer's disease (AD) patients. Methods: We analyzed two CSF cohorts of AD and control individuals expressing different APOE genotypes. Moreover, CSF samples from the TgF344-AD rat model were included. Samples were run in native- and SDS-PAGE under reducing or non-reducing conditions (with or without beta-mercaptoethanol). Immunoprecipitation combined with mass spectrometry or western blotting analyses served to assess the identity of apoE complexes. Results: In TgF344-AD rats expressing a unique apoE variant resembling human apoE4, a similar to 35-kDa apoE monomer was identified, increasing at 16.5 months compared with wild-types. In humans, apoE isoforms form disulfide-linked dimers in CSF, except apoE4, which lacks a cysteine residue. Thus, controls showed a decrease in the apoE dimer/monomer quotient in the APOE epsilon 3/epsilon 4 group compared with epsilon 3/epsilon 3 by native electrophoresis. A major contribution of dimers was found in APOE epsilon 3/epsilon 4 AD cases, and, unexpectedly, dimers were also found in epsilon 4/epsilon 4 AD cases. Under reducing conditions, two apoE monomeric glycoforms at 36 kDa and at 34 kDa were found in all human samples. In AD patients, the amount of the 34-kDa species increased, while the 36-kDa/34-kDa quotient was lower compared with controls. Interestingly, under reducing conditions, a similar to 100-kDa apoE complex, the identity of which was confirmed by mass spectrometry, also appeared in human AD individuals across all APOE genotypes, suggesting the occurrence of aberrantly resistant apoE aggregates. A second independent cohort of CSF samples validated these results. Conclusion: These results indicate that despite the increase in total apoE content the apoE protein is altered in AD CSF, suggesting that function may be compromised.
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45. |
- Montoliu-Gaya, Laia, et al.
(author)
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Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study
- 2023
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In: eBioMedicine. - : Elsevier BV. - 2352-3964. ; 90
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Journal article (peer-reviewed)abstract
- Background The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) isa marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. Methods We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universitat, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. Findings This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymp-tomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF A beta changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9-0.95) and its con-centrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Interpretation Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials.
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46. |
- Swift, Imogen J, et al.
(author)
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A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.
- 2024
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In: Alzheimer's Research & Therapy. - 1758-9193. ; 16:1
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Journal article (peer-reviewed)abstract
- Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations.Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data.We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p=0.007) with a trend in non-carriers (p=0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers.These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.
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