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With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer's disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of change in DS-associated AD (DS-AD). The current study reports its cross-sectional analysis of the first 90 subjects enrolled. Plasma biomarkers phosphorylated tau protein (p-tau), neurofilament light chain (NfL), amyloid β peptides (Aβ1-40, Aβ1-42), and glial fibrillary acidic protein (GFAP) were undertaken with previously published methods. The clinical data from the baseline visit include demographics as well as the cognitive measures under the Severe Impairment Battery (SIB) and Down Syndrome Mental Status Examination (DS-MSE). Biomarker distributions are described with strong statistical associations observed with participant age. The biomarker data contributes to understanding DS-AD across the spectrum of disease. Collectively, the biomarker data show evidence of DS-AD progression beginning at approximately 40 years of age. Exploring these data across the full LIFE-DSR longitudinal study population will be an important resource in understanding the onset, progression, and clinical profiles of DS-AD pathophysiology.

BackgroundMolecular tweezers (MTs) are broad-spectrum inhibitors of abnormal protein aggregation. A lead MT, called CLR01, has been demonstrated to inhibit the aggregation and toxicity of multiple amyloidogenic proteins in vitro and in vivo. Previously, we evaluated the effect of CLR01 in the 3 × Tg mouse model of Alzheimer's disease, which overexpresses mutant human presenilin 1, amyloid β-protein precursor, and tau and found that subcutaneous administration of the compound for 1 month led to a robust reduction of amyloid plaques, neurofibrillary tangles, and microgliosis. CLR01 also has been demonstrated to inhibit tau aggregation in vitro and tau seeding in cell culture, yet because in Alzheimer's disease (AD) and in the 3 × Tg model, tau hyperphosphorylation and aggregation are thought to be downstream of Aβ insults, the study in this model left open the question whether CLR01 affected tau in vivo directly or indirectly.MethodsTo determine if CLR01 could ameliorate tau pathology directly in vivo, we tested the compound similarly using the P301S-tau (line PS19) mouse model. Mice were administered 0.3 or 1.0 mg/kg per day CLR01 and tested for muscle strength and behavioral deficits, including anxiety- and disinhibition-like behavior. Their brains then were analyzed by immunohistochemical and biochemical assays for pathological forms of tau, neurodegeneration, and glial pathology.ResultsCLR01 treatment ameliorated muscle-strength deterioration, anxiety-, and disinhibition-like behavior. Improved phenotype was associated with decreased levels of pathologic tau forms, suggesting that CLR01 exerts a direct effect on tau in vivo. Limitations of the study included a relatively short treatment period of the mice at an age in which full pathology is not yet developed. In addition, high variability in this model lowered the statistical significance of the findings of some outcome measures.ConclusionsThe findings suggest that CLR01 is a particularly attractive candidate for the treatment of AD because it targets simultaneously the two major pathogenic proteins instigating and propagating the disease, amyloid β-protein (Aβ), and tau, respectively. In addition, our study suggests that CLR01 can be used for the treatment of other tauopathies in the absence of amyloid pathology.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

This study presents a comparison between triaxial test results and constitutive model simulations for saturated sand subjected to a wide range of stress, relative density and both monotonic and cyclic loadings. This is a preliminary part of a project which is focussed on developing models for the behaviour of unsaturated soils under cyclic loading. There are currently limited experimental data of the cyclic behaviour of unsaturated soils due in part to the difficulty of controlling stress state, degree of initial saturation and uniformity of samples in experiments and their interpretation is challenging due to the mathematical complexity in constitutive models. This study attempts to bridge the abovementioned gap by creating an experimentally validated constitutive model for dynamic loading on saturated sand and then to extend this for unsaturated sands. The paper reports results from a series of monotonic triaxial tests and cyclic triaxial tests on saturated sand. Specimens of 100mm diameter, 200mm height and 54mm diameter, 110mm height have been prepared with different void ratios. These samples have been subjected to a wide range of deviatoric stress in both monotonic and cyclic tests. The results from these tests on saturated Sydney sand are presented and used to demonstrate the ability of the constitutive model. As the constitutive model has been developed for variable saturation demonstration of its success with saturated sand for which considerable data is available is the first stage in simulating the cyclic behaviour of the unsaturated sand.

This paper presents the stress–strain behaviour of three structured clays subjected to a number of stepwise changes in strain rate during shearing in a triaxial apparatus. Undrained compression tests were performed on clay specimens in both undisturbed and reconstituted states. As a result, it has been possible to identify the influence of structure on the rate-dependent response of the clays. Step changes in applied shearing strain rates for all tests resulted in predominately isotache-type behaviour within the range of strains from very small strains to large strains at failure. At very small strains, evidence of a limiting elastic modulus was established for both the stiff sedimentary and artificially cemented soil, which is consistent with published literature on other structured geomaterials. The stress–strain behaviour of all three materials was affected by both the degradation of structure with increasing strain and applied strain rate. The influence of structure on the time-dependent behaviour of the clays is discussed by comparing the response of undisturbed and reconstituted specimens and following normalisation by the equivalent pressure. Results indicate that the rate sensitivity evolves with increasing strains and reaches a maximum at strain levels associated with peak shearing resistance. [ABSTRACT FROM AUTHOR]

Rolling dynamic compaction (RDC) is a soil compaction technique, which is capable of improving thick layers of soil at a relatively fast operating speed. The paper presents the results of laboratory experiments conducted on 1:13 scale models of the four-sided, 8 and 12 t, Broons BH-1300 and BH-1300 HD impact rollers, respectively, to study the performance of the scale model at four different operating speeds. A series of laboratory tests is undertaken using transparent soils and the particle image velocimetry (PIV) technique to investigate the effectiveness of the models. The transparent soil employed in this study consists of fused quartz and a pore fluid that matched the refractive index of the fused quartz. A one-particle thick layer of coloured fused quartz is embedded in the centre plane of the transparent soil to visualize soil internal displacements and a digital camera is used to capture the speckled pattern during the scale model testing process. The results show that the heavier module induces greater soil displacements at each operating speed. The optimal operating speed is approximately 299 mm/s for both module weights. The most significant soil displacements occur within the first 20 passes and no obvious ground improvement is observed after 35 passes. The results of this study demonstrate the unique capability of transparent soil to study soil displacements induced by the ground improvement scale models. Key words: rolling dynamic compaction, impact roller, ground improvement, transparent soil, particle image velocimetry. Le compactage dynamique par roulement (CDR) est une technique de compactage du sol, capable d'ameliorer des couches epaisses de sol a une vitesse de fonctionnement relativement rapide. L'article presente les resultats d'experiences de laboratoire menees sur des modeles a l'echelle 1:13 des rouleaux d'impact Broons BH-1300 et BH-1300 HD a quatre cotes, de 8 et 121, respectivement, afin d'etudier les performances du modele reduit a quatre vitesses de fonctionnement differentes. Une serie d'essais en laboratoire est realisee a l'aide de sols transparents et de la technique de velocimetrie par images de particules (PIV) afin d'etudier l'efficacite des modeles. Le sol transparent utilise dans cette etude se compose de quartz fondu et d'un fluide interstitiel dont l'indice de refraction correspond a celui du quartz fondu. Une couche de quartz fondu colore d'une epaisseur d'une particule est incorporee dans le plan central du sol transparent pour visualiser les deplacements internes du sol et un appareil photo numerique est utilise pour capturer le motif mouchete pendant le processus d'essai du modele reduit. Les resultats montrent que le module le plus lourd induit des deplacements de sol plus importants a chaque vitesse de fonctionnement. La vitesse optimale de fonctionnement est d'environ 299 mm/s pour les deux poids de modules. Les deplacements du sol les plus importants se produisent au cours des 20 premiers passages et aucune amelioration evidente du sol n'est observee apres 35 passages. Les resultats de cette etude demontrent la capacite unique du sol transparent permettant d'etudier les deplacements du sol induits par les modeles d'amelioration du sol a l'echelle. [Traduit par la Redaction] Mots-cles : compaction dynamique par roulement, rouleau a impact, amelioration du sol, sol transparent, velocimetrie par image de particules., Introduction The stability and serviceability of foundations are highly dependent on the bearing capacity and settlement of the underlying soil. With the global increase in population and the consequent growing [...]