The Sant Pau Initiative on Neurodegeneration (SPIN) cohort : A data set for biomarker discovery and validation in neurodegenerative disorders

Altres ajuts: The SPIN cohort has received funding from CIBERNED; Instituto de Salud Carlos III; jointly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, "Una manera de hacer Europa"; Generalitat de Catalunya; Fundació "La Marató TV3" Fundació Bancària Obra Social La Caixa; Fundación BBVA; Fundación Española para el Fomento de la Investigación de la Esclerosis Lateral Amiotrófica (FUNDELA); Global Brain Health Institute; Fundació Catalana Síndrome de Down; and Fundació Víctor Grífols i Lucas. These funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.The SPIN (Sant Pau Initiative on Neurodegeneration) cohort is a multimodal biomarker platform designed for neurodegenerative disease research following an integrative approach. Participants of the SPIN cohort provide informed consent to donate blood and cerebrospinal fluid samples, receive detailed neurological and neuropsychological evaluations, and undergo a structural 3T brain MRI scan. A subset also undergoes other functional or imaging studies (video-polysomnogram, 18 F-fluorodeoxyglucose PET, amyloid PET, Tau PET). Participants are followed annually for a minimum of 4 years, with repeated cerebrospinal fluid collection and imaging studies performed every other year, and brain donation is encouraged. The integration of clinical, neuropsychological, genetic, biochemical, imaging, and neuropathological information and the harmonization of protocols under the same umbrella allows the discovery and validation of key biomarkers across several neurodegenerative diseases. We describe our particular 10-year experience and how different research projects were unified under an umbrella biomarker program, which might be of help to other research teams pursuing similar approaches

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series

Ultraviolet variability of the narrow-line Seyfert 1 IRAS 13224-3809

We present an analysis of the IUE observations of the Narrow-line Seyfert 1 galaxy IRAS13224-3809. This galaxy is a radio-quiet object, very luminous in the IRAS bands and with a very steep (soft) and rapidly variable spectrum in the soft X-ray domain. More remarkably, it has recently revealed giant soft X-ray variations, becoming up to date the most X-ray variable Seyfert known (Boller et al. 1997). We have performed a detailed analysis of the variability behaviour of the whole IUE data set. Only the Lyαλ1216 core and the continuum flux at wavelengths longer than 1750 Å are found to vary significantly. The largest 1800-Å continuum change (maximum to minimum flux) is close to a factor two but only at the 2.9σ level. During the giant amplitude soft X-ray fluctuations mentioned above, and despite of the extreme X-ray behaviour, the available ultraviolet data only suggest a quiescent phase. We have detected Lyα and C IV λ1549 emission, with complex profiles, showing absorption features and broad wings (not detected in the optical permitted lines of Hydrogen). The continuum spectral energy distribution is similar to that of normal Seyfert Is from the radio to the IR domain and in the hard X-rays. However, it is peculiar in that the UV flux is underluminous compared to the IR or to the X-ray fluxes and in that the soft X-ray spectrum is very steep. It is suggested that the ionizing continuum is extremely hard and intense in IRAS 13224-3809 giving rise to a highly ionized broad-line region where only the UV lines are emitted.Sin financiaciónNo data (1998)UE

Detection of a possible multiphase ultra-fast outflow in IRAS 13349+2438 with NuSTAR and XMM-Newton

We present joint NuSTAR and XMM-Newton observations of the bright, variable quasar IRAS 13349+2438. This combined data set shows two clear iron absorption lines at 8 and 9 keV, which are most likely associated with two layers of mildly relativistic blueshifted absorption, with velocities of 0.14c and 0.27c. We also find strong evidence for a series of Ly absorption lines at intermediate energies in a stacked XMM-Newton EPIC-pn spectrum, at the same blueshift as the lower velocity iron feature. This is consistent with a scenario where an outflowing wind is radially stratified, so faster, higher ionization material is observed closer to the black hole, and cooler, slower material is seen from streamlines at larger radii.With funding from the Spanish government through the "María de Maeztu Unit of Excellence" accreditation (MDM-2017-0737

Correction : Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer's disease (AD) and their clinical utility in predicting disease progression. pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile. Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005). pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD. The online version contains supplementary material available at 10.1186/s40035-021-00275-w

The first broad-band X-ray view of the narrow-line Seyfert 1 Ton S180

We present joint XMM-Newton and NuSTAR observations of the 'bare' narrow-line Seyfert 1 Ton S180 (z = 0.062), carried out in 2016 and providing the first hard X-ray view of this luminous galaxy. We find that the 0.4-30 keV band cannot be self-consistently reproduced by relativistic reflection models, which fail to account simultaneously for the soft and hard X-ray emission. The smooth soft excess prefers extreme blurring parameters, confirmed by the nearly featureless nature of the Reflection Grating Spectrometer (RGS) spectrum, while the moderately broad FeK line and the modest hard excess above 10 keV appear to arise in a milder gravity regime. By allowing a different origin of the soft excess, the broad-band X-ray spectrum and overall spectral energy distribution (SED) are well explained by a combination of (a) direct thermal emission from the accretion disc, dominating from the optical to the far/extreme UV; (b) Comptonization of seed disc photons by a warm (kTe ~ 0.3 keV) and optically thick (t ~ 10) corona, mostly contributing to the soft X-rays; (c) Comptonization by a standard hot (kTe > 100 keV) and optically thin (t < 0.5) corona, responsible for the primary X-ray continuum; and (d) reflection from the mid/outer part of the disc. The two coronae are suggested to be rather compact, with R hot < Rwarm < 10 rg. Our SED analysis implies that Ton S180 accretes at super-Eddington rates. This is a key condition for the launch of a wind, marginal (i.e. 3.1s significance) evidence of which is indeed found in the RGS spectrum

The Aβ1-42/Aβ1-40 ratio in CSF is more strongly associated to tau markers and clinical progression than Aβ1-42 alone

Altres ajuts: Fundació La Marató: 20141210, 044412, 20142610Cerebrospinal fluid (CSF) Aβ1-42 levels and the Aβ1-42/Aβ1-40 ratio are markers of amyloid pathology, but previous studies suggest that their levels might be influenced by additional pathophysiological processes. To compare Aβ1-42 and the Aβ1-42/Aβ1-40 ratio in CSF in different neurodegenerative disorders and study their association with other biomarkers (tTau, pTau181, and NfL) and with cognitive and functional progression. We included all participants from the Sant Pau Initiative on Neurodegeneration (SPIN) with CSF Aβ1-42 and Aβ1-42/Aβ1-40. Participants had diagnoses of Alzheimer's disease (AD), dementia with Lewy bodies, frontotemporal lobar degeneration-related syndromes, non-neurodegenerative conditions, or were cognitively normal. We classified participants as "positive" or "negative" according to each marker. We compared CSF levels of tTau, pTau181, and NfL between concordant and discordant groups through ANCOVA and assessed differences in cognitive (MMSE, FCSRT) and functional (GDS, CDR-SOB) progression using Cox regression and linear-mixed models. In the 1791 participants, the agreement between Aβ1-42 and Aβ1-42/Aβ1-40 was 78.3%. The Aβ1-42/Aβ1-40 ratio showed a stronger correlation with tTau and pTau181 than Aβ1-42 and an agreement with tTau and pTau181 of 73.1% and 77.1%, respectively. Participants with a low Aβ1-42/Aβ1-40 ratio showed higher tTau and pTau181 and worse cognitive and functional prognosis, regardless of whether they were positive or negative for Aβ1-42. The results were consistent across stages, diagnostic categories, and use of different cutoffs. Although Aβ1-42 and Aβ1-42/Aβ1-40 are considered markers of the same pathophysiological pathway, our findings provide evidence favoring the use of the Aβ1-42/Aβ1-40 ratio in clinical laboratories in the context of AD. The online version contains supplementary material available at 10.1186/s13195-022-00967-z

Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia

Altres ajuts: Marató TV3" foundation grants 20141210 to JF, 044412 to RB and 20142610 to AL.Background: Astrocytes play an essential role in neuroinflammation and are involved in the pathogenesis of neurodenegerative diseases. Studies of glial fibrillary acidic protein (GFAP), an astrocytic damage marker, may help advance our understanding of different neurodegenerative diseases. In this study, we investigated the diagnostic performance of plasma GFAP (pGFAP), plasma neurofilament light chain (pNfL) and their combination for frontotemporal dementia (FTD) and Alzheimer's disease (AD) and their clinical utility in predicting disease progression. Methods: pGFAP and pNfL concentrations were measured in 72 FTD, 56 AD and 83 cognitively normal (CN) participants using the Single Molecule Array technology. Of the 211 participants, 199 underwent cerebrospinal (CSF) analysis and 122 had magnetic resonance imaging. We compared cross-sectional biomarker levels between groups, studied their diagnostic performance and assessed correlation between CSF biomarkers, cognitive performance and cortical thickness. The prognostic performance was investigated, analyzing cognitive decline through group comparisons by tertile. Results: Unlike pNfL, which was increased similarly in both clinical groups, pGFAP was increased in FTD but lower than in AD (all P < 0.01). Combination of both plasma markers improved the diagnostic performance to discriminate FTD from AD (area under the curve [AUC]: combination 0.78; pGFAP 0.7; pNfL 0.61, all P < 0.05). In FTD, pGFAP correlated with cognition, CSF and plasma NfL, and cortical thickness (all P < 0.05). The higher tertile of pGFAP was associated with greater change in MMSE score and poor cognitive outcome during follow-up both in FTD (1.40 points annually, hazard ratio [HR] 3.82, P < 0.005) and in AD (1.20 points annually, HR 2.26, P < 0.005). Conclusions: pGFAP and pNfL levels differ in FTD and AD, and their combination is useful for distinguishing between the two diseases. pGFAP could also be used to track disease severity and predict greater cognitive decline during follow-up in patients with FTD

Differential levels of Neurofilament Light protein in cerebrospinal fluid in patients with a wide range of neurodegenerative disorders

Altres ajuts: "Marató TV3" grant (20141210, 044412, 20143710).Cerebrospinal fluid (CSF) biomarkers are useful in the diagnosis and the prediction of progression of several neurodegenerative diseases. Among them, CSF neurofilament light (NfL) protein has particular interest, as its levels reflect neuroaxonal degeneration, a common feature in various neurodegenerative diseases. In the present study, we analyzed NfL levels in the CSF of 535 participants of the SPIN (Sant Pau Initiative on Neurodegeneration) cohort including cognitively normal participants, patients with Alzheimer disease (AD), Down syndrome (DS), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). We evaluated the differences in CSF NfL accross groups and its association with other CSF biomarkers and with cognitive scales. All neurogenerative diseases showed increased levels of CSF NfL, with the highest levels in patients with ALS, FTD, CBS and PSP. Furthermore, we found an association of CSF NfL levels with cognitive impairment in patients within the AD and FTD spectrum and with AD pathology in DLB and DS patients. These results have implications for the use of NfL as a marker in neurodegenerative diseases