Plasma biomarkers for Alzheimer’s disease: a field-test in a memory clinic

BACKGROUND: The key Alzheimer's disease (AD) biomarkers are traditionally measured with techniques/exams that are either expensive (amyloid-positron emission tomography (PET) and tau-PET), invasive (cerebrospinal fluid Aβ42 and p-tau181), or poorly specific (atrophy on MRI and hypometabolism on fluorodeoxyglucose-PET). Recently developed plasma biomarkers could significantly enhance the efficiency of the diagnostic pathway in memory clinics and improve patient care. This study aimed to: (1) confirm the correlations between plasma and traditional AD biomarkers, (2) assess the diagnostic accuracy of plasma biomarkers as compared with traditional biomarkers, and (3) estimate the proportion of traditional exams potentially saved thanks to the use of plasma biomarkers. METHODS: Participants were 200 patients with plasma biomarkers and at least one traditional biomarker collected within 12 months. RESULTS: Overall, plasma biomarkers significantly correlated with biomarkers assessed through traditional techniques: up to r=0.50 (p<0.001) among amyloid, r=0.43 (p=0.002) among tau, and r=-0.23 (p=0.001) among neurodegeneration biomarkers. Moreover, plasma biomarkers showed high accuracy in discriminating the biomarker status (normal or abnormal) determined by using traditional biomarkers: up to area under the curve (AUC)=0.87 for amyloid, AUC=0.82 for tau, and AUC=0.63 for neurodegeneration status. The use of plasma as a gateway to traditional biomarkers using cohort-specific thresholds (with 95% sensitivity and 95% specificity) could save up to 49% of amyloid, 38% of tau, and 16% of neurodegeneration biomarkers. CONCLUSION: The implementation of plasma biomarkers could save a remarkable proportion of more expensive traditional exams, making the diagnostic workup more cost-effective and improving patient care

Paleoclimatic control of biogeographic and sedimentary events in Tethyan and peri-Tethyan areas during the Oxfordian (Late Jurassic)

International audienceThe paleobiogeographical distribution of Oxfordian ammonites and coral reefs in northern and Central Europe, the Mediterranean area, North and East Africa, and the Middle East and Central Asia is compared with the distribution in time and space of the most important lithofacies. Interest in the Oxfordian is focused on changes in facies and in biogeographical patterns that can be interpreted as the results of climatic events. Paleotemperature trends inferred from oxygen isotopes and paleoclimatic simulations are tested against fossil and facies data. A Late Callovian–Early Oxfordian crisis in carbonate production is indicated by the widespread absence of Lower Oxfordian reefal formations. There is a gap (hiatus) in deposition on epicontinental platforms, with Middle Oxfordian deposits resting paraconformably on Upper Callovian, while shales accumulated in adjacent intracratonic basins. Simultaneously, in Mediterranean Tethys, radiolarites accumulated in deep troughs while Rosso Ammonitico facies formed on pelagic swells. However, deposition on swells was also discontinuous with numerous gaps (hiatuses) and sequences that are much reduced in thickness. Middle Callovian deposits are generally overlain by Middle Oxfordian limestones. The dearth of carbonates is consistent with a cooling event lasting about 1 My. By the middle Oxfordian a warming, leading to bgreenhouseQ type conditions, is suggested on the basis of both biogeographical (mostly coral-reef distribution) and geochemical data. Carbonates spread onto an extensive European platform while radiolarites reached a maximum development in the Mediterranean Tethys. Two distinct latitudinal belts, with seemingly different accumulation regimes, are therefore inferred. Similar latitudinal belts were also present in the late Oxfordian, when carbonates were widespread. The distribution of reefal facies in the late Oxfordian–early Kimmeridgian fits relatively well with GCMs simulations that imply low rainfall in the Tethyan Mediterranean area and slightly higher precipitation in central and northern Europe. Local salinity variations, reflecting more arid or humid conditions, may bias the paleotemperature signal inferred from Palaeogeography, Palaeoclimatology, Palaeoecology 222 (2005) 10 – 32 www.elsevier.com/locate/palaeo d 18 O values. Biogeographical and facies distributions, combined with d 18 O values, unravel the ambiguity and support a Late Callovian–Early Oxfordian cooling followed by warming in the later Oxfordian

Coral-sponge-microencruster-microbialite associations in the Upper Jurassic reef: quantitative characterization of a case study from Eastern Sardinia (Italy)

The Late Jurassic records one of the largest reefal expansions of the Phanerozoic, with major diffusion and differentiation in the Tethys realm (WOOD, 1999; KIESSLING, 2002; CECCA et al., 2005). Several depositional and compositional models about Upper Jurassic reef types (see INSALACO et al.,1997; LEINFELDER et al., 2002, 2005; RUSCIADELLI et al., 2011 for a revision) have been published but little knowledge is available about the Eastern Sardinian reefs. This study focuses on the compositional and sedimentological characterization of the Upper Tithonian reef complex presently exposed in the area of Cala Gonone (Orosei Gulf) (Fig.1). The Upper Jurassic carbonate succession of Eastern Sardinia consists of three Bathonian-Callovian to Berriasian (DIENI & MASSARI, 1985; JADOUL et al., 2010 and references therein) carbonate depositional systems developed on the southern Europe passive margin (Fig.1): 1) the first (Dorgali Fm.) is characterized by ooidal grainstone, accumulated above wave base on structural highs (Variscan basement), capped by an Upper Bathonian-Callovian condensed succession with a few Fe-phosphatic hardgrounds; 2) a low-angle Oxfordian-upper Tithonian depositional system: the shallow ramp deposition (Tului Fm.) is characterized by basal oolitic facies overlain by prograding coral-stromatoporoid reefs, interfingering with outer ramp-basinal peloidal packstone-wackestone (S\u2019Adde and Baunei Fms.); 3) the third depositional carbonate system (Bardia Fm.) developed after an Early Tithonian regressive trend, locally marked by carbonate breccias indicative of subaerial exposure. The lower part of the Bardia Fm. (upper Tithonian) is locally characterized by gentle slopes (3-15\ub0) with bioclastic-coral-sponge facies associations (LANFRANCHI et al., 2011). This progradational unit is followed by up to 400-500 m of back reef and inner platform shallow water carbonates.REEF COMPONENTS AND FACIES Compositional and sedimentological analysis of the Bardia reef has been carried out through the combination of \u201cmacroscopic\u201d (outcrop-scale) and \u201cmicroscopic\u201d (microfacies-scale) observations on exceptionally exposed saw-cut quarry walls, over a surface of a few hundreds square metres in three different locations. The external surface of each macroscopically detectable component has been emphasized on the quarry walls (Fig.2). The areal distribution of each portion has been stored as vector images, defining frequency, density and area occupied by the reef components. Microfacies and paleontological analyses have been performed on 280 thin sections. Reef components were grouped into three broad categories: 1) macroscopically detectable organisms (mainly corals, sponges, bivalves, gastropods, echinoderms); 2) microscopically detectable components (microencrusters and microbialites); 3) fine- to coarse bioclastic debris and mud-supported facies. Corals show different degree of reworking, from in life-position skeletons more than 2.5 m2 in size to centimetre-sized rubble. The 49 recognized genera of corals have been classified according to external morphology and corallite type. Calcified sponges (Stromatoporoids) are a few centimetres to tens of centimetres in size, occurring as isolated specimens and in densely-packed assemblages. Siliceous sponges and spiculae are replaced respectively by precipitated automicrite and calcite spar. Microbialite and microencruster organisms form domal, columnar or irregular accretionary crusts, few millimetres to several centimetres in thickness. Frequently, crusts bind neighbouring skeletons of large biota, developing metre-scale bioconstructions. These components combine in various proportions within and among quarries, reflecting abrupt lateral and vertical changes of environmental conditions. Quarry 1 is characterized by large branched and massive coral colonies partially or totally encrusted by centimetre thick microencruster crusts and well-washed bioclastic facies, indicating sediment reworking in a high\u2013energy environment. This facies abruptly passes laterally into a densely packed massive microsolenid coral and calcareous sponge assemblage and microbialite and microencruster (Tubiphytes. and other nubeculariids) boundstone. Microsolenid assemblages are commonly interpreted to have formed in deeper water (LATHULI\uc8RE & GILL, 1995; GILL et al., 2004) or alternatively related to poorly illuminated shallow-water cave environments, and adapted to low-sedimentation, low-energy and nutrient-rich conditions (INSALACO, 1996; DUPRAZ & STRASSER, 2002). Quarry 2 is characterized by progressive vertical variations from facies dominated by densely packed platy and flat coral colonies (microsolenids and others) to facies dominated by calcareous sponges and loosely packed phaceloid coral colonies. Microbialite and microencrusters (Tubiphytes and other nubeculariids) envelope and bind large biota. Platy growth forms are generally interpreted as a response to poor illumination (INSALACO, 1996). Consequently the whole association seems to be compatible with poorly illuminated water, low sedimentation rate in a low energy environment. Quarry 3 records large scale bedding (from 1 m to several metres) defined by six intervals dominated respectively by 1) bivalves; 2) dasycladacean algae; 3) reworked massive thamnasterioid coral colonies; 4) thin phaceloid corals and calcareous sponges in growth position; 5) branched ramose coral colonies and calcareous sponges; 6) reworked massive plocoid coral colonies and gastropods. Large biota within intervals 3, 4 and 5 are largely encrusted by different microencrusters such as Koskinobulina, Thaumatoporella, light-dependent Lithocodium-Bacinella, and microbial accrectionary crust. Coral assemblages and microencruster association reveal a progressive increasing of the energy regime and sediment reworking in well-lit waters (INSALCO, 1996; SCHIMD & LEINFELDER, 2002), while the presence of bivalve, algae and gastropod floatstone represents the temporary shifting to \u201cperi-reefal\u201d environments. Despite variability of facies associations in the three quarries, a paleoecological evolution from quarry 1 to quarry 3 emerges, reflecting the change from moderate energy environment with more protected, poorly illuminated cave environment (quarry 1), through a low energy, poorly illuminated environment characterized by low sedimentation rate (quarry 2), to a high energy, well illuminated environment, characterized by high sedimentation rate and reworking (quarry 3). The relative position of the studied quarries along an ideal depositional profile remains speculative, although a medium-scale progradational trend, from distal to proximal setting, seems to be compatible with the long-scale stratigraphic trend of the Bardia Fm. Spectacular outcrop conditions, amount of data collected, biota taxonomic classifications and the observed stratigraphic evolution provide the solid base for paleo-biogeographical comparisons with other Upper Jurassic Tethyan reef complexes. REFERENCES CECCA F., GARIN M., MARCHAND D., LATHUILIERE B. & BARTOLINI A. (2005). Paleoclimatic control of biogeographic and sedimentary events in Tethyan and peri-Tethyan areas during the Oxfordian (Late Jurassic). Pal.Pal.Pal., 222, 10\u201332. DIENI I. & MASSARI F. (1985). Mesozoic of Eastern Sardinia. In: Cherchi A. (ed.), 19th European Micropaleontological Colloquium. Sardinia, October 1-10. Micropaleontological researches in Sardinia. Guidebook, 66-77. DUPRAZ C. & STRASSER A. (2002) Nutritional modes in coral-microbialite reefs (Jurassic, Oxfordian, Switzerland): evolution of trophic structure as a response to environmental change. Palaios 17, 449-471. GILL G., SANTANTONIO M. & LATHUILI\uc8RE B. (2004). The depth of pelagic deposits in the Tethyan Jurassic and the use of corals: an example from the Apennines. Sedimentary Geology, 166, (3-4), 311\u2013334. INSALACO E. (1996) Upper Jurassic microsolenids biostromes of northern and central Europe: facies and depositional environment. Pal. Pal. Pal., 121, 169\u2013194. INSALACO E., HALLAM A. & ROSEN B.R. (1997). Oxfordian (Upper Jurassic) coral reefs in western Europe: reef types and conceptual depositional model. Sedimentology 44, 707\u2013734. JADOUL F., LANFRANCHI A., CASELLATO C.E., BERRA F. & ERBA E. (2010). I sistemi carbonatici giurassici della Sardegna orientale (Golfo di Orosei). In Geol.F.Trips of ISPRA and Societ\ue0 Geologica Italiana Vol. 2, 122 pp. KIESSLING,W. (2002). Secular variations in the Phanerozoic reef systems. In: Kiessling,W., Fl\ufcgel, E., Golonka, J. (Eds.), Phanerozoic Reef Patterns: SEPM, Spec. Publ., 72, 625\u2013690. LATHULI\uc8RE B. & GILL G. (1995). Some new suggestions on functional morphology in pennular corals. In: B Lathuili\ue8re, J Geister (Eds.), Coral Reefs in Past, Present and Future. Proceeding of the 2nd European Meeting of the International Society for Reef Studies, Publications du Service G\ue9ologique du Luxembourg, 29, 259\u2013264 LANFRANCHI A., BERRA F. & JADOUL F. (2011). Compositional changes in sigmoidal carbonate clinoforms (Late Tithonian, eastern Sardinia, Italy): insights from quantitative microfacies analyses. Sedimentology 58, 2039\u20132060 LEINFELDERR.R., SCHLAGINTWEIT F., WERNER W., EBLI O., NOSE,M., SCHMID D.U. & HUGHES G.W. (2005). Signi\ufb01cance of stromatoporoids in Jurassic reefs and carbonate platforms\u2014concepts and implications. Facies 51, 287\u2013325. LEINFELDER R.R., SCHMID D.U., NOSE M. & WERNER W. (2002). Jurassic reef patterns. The expression of a changing globe. In: Kiessling, W., Fl\ufcgel, E., Golonka, J. (Eds.), Phanerozoic Reef Patterns: SEPM Spec Publ, 72,. 465\u2013520. RUSCIADELLI G., RICCI C., LATHUILI\uc8RE B. (2011) The Ellipsactinia Limestones of the Marsica area (Central Apennines): A reference zonation model for Upper Jurassic Intra-Tethys reef complexes. Sed. Geol., 233, 69\u201387 WOOD, R.A. (1999). Reef Evolution. Oxford University Press

Poleward along-shore current pulses on the inner shelf of the Bay of Biscay

We analyzed strong events of coastal poleward along-shore currents above 10 cm s−1 and up to more than 50 cm s−1 on the inner shelf (50-80 m depth) of the Bay of Biscay (BoB) from the Spanish coast to the Brittany coast. We used data from four acoustic Doppler current profilers (ADCPs) deployed from July 2009 to August 2011. The goal of this study was to analyze current variability at meso- and subinertial scales and their generation mechanisms. These currents occurred all year long and were classified into three types. Events occurring principally in the southern part of the BoB were classified as southern events. Bay-scale events were defined when strong poleward currents were detected over all the shelf, typically stronger on the Spanish and the southern Brittany shelves. Strong events were characterized by depth averaged current velocities over 40 cm s−1 in the southern part of the BoB. At short time lags, the along-shore currents were clearly related to along-shore wind stress at upstream locations. An explanation is provided for longer time lags in terms of coastal trapped wave (CTW) dynamics. The first CTW mode phase speeds were in agreement with the propagation speeds of the fastest events (> 5 m s−1), while inner shelf modes could explain the slowest events (∼ 1-3 m s−1). The cross-shelf density gradient and the extension of the IPC were also associated with strong coastal poleward along-shore currents. The duration of the events, the vertical structure of the currents and the associated coastal trapped waves were studied in relation with the stratification

Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease

Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD