Plasma neuregulin 1 as a synaptic biomarker in Alzheimer's disease: a discovery cohort study

BACKGROUND: Synaptic dysfunction is an early core feature of Alzheimer's disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. OBJECTIVE: To measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers. METHODS: This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI, n = 27) and at dementia stage (n = 35), non-AD dementia (n = 26, Aβ-negative), non-AD MCI (n = 19), and neurological controls (n=20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aβ 42/Aβ 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25. RESULTS: Plasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P < 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (β = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aβ-positive patients (β = -0.197-0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 (β = 0.278-0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aβ-positive patients (all, β = -0.188, P = 0.038; Aβ+: β = -0.255, P = 0.038). CONCLUSION: Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD

A Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging

OBJECTIVE: To elaborate a new algorithm to establish a standardized method to define cuff-offs for CSF biomarkers of Alzheimer's disease (AD) by validating the algorithm against CSF classification derived from PET imaging. METHODS: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cut-offs for CSF amyloid-β peptide (Aβ) biomarkers. These Aβ cut-offs were then used to determine cut-offs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients. RESULTS: A total of 6,922 subjects with CSF biomarkers data were included (mean (SD) age: 70.6 (8.5) years, 51.0% women). In the ADNI study population (n=497), the agreement between classification based on our algorithm and one based on amyloid/tau PET imaging was high with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n=6,425), the proportion of persons with AD ranged from 25.9% to 43.5%. DISCUSSION: The proposed novel, pragmatic method to determine CSF biomarkers cut-offs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification

Plos Med

Background The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level

Development of an additive manufacturing process based on expansive materials for large parts

Les travaux scientifiques abordés dans le cadre de la thèse portent sur le développement d'un nouveau procédé d'impression 3D à partir de matériaux expansifs permettant la réalisation de pièces de forme complexe de grandes dimensions. Ce procédé est appelé FAM (Foam Additive Manufacturing) et exploité avec des moyens robotisés il sera mise en oeuvre pour des cas d’applications dans les domaines de la construction et du nautisme. Cette technologie FAM consiste à déposer le long d’une trajectoire un polymère à l’état liquide qui va s’expanser et se solidifier en seulement quelques secondes. Sur ce premier cordon de matière solidifiée de nouvelles couches de matière vont pouvoir être imprimées, et ainsi de suite jusqu'à la pièce finale. Les objectifs de la thèse sont de développer des modèles numériques pour simuler le procédé de fabrication additive en maitrisant l’expansion du matériau, identifier les paramètres influents, développer la chaîne numérique et optimiser le processus de fabrication. Après l'identification des paramètres intrinsèques d'expansion du matériau, les modèles qui ont été développés permettent d'obtenir la géométrie des cordons déposés et les champs de température vis-à-vis de la vitesse de dépose de matière couche par couche.Grâce à ces modèles numériques, il est possible d'analyser l'influence des paramètres opératoires sur les différents observables et donc d'avoir une meilleure compréhension des phénomènes impliqués afin de proposer une solution de stratégie optimisée d'impression 3d pour garantir la géométrie 3D de la pièce, la santé matière et la fabricabilité en fonction du moyen d'impression.Scientific work focuses on the development of a new 3D printing process from expansive materials, allowing the production of large-shaped complex parts. This process is called FAM (Foam Additive Manufacturing) and operated with robotic means it will be used for application cases in the fields of construction and boating. This FAM technology consists in depositing along a trajectory a polymer in the liquid state which will expand and solidify in just a few seconds. On this first layer of solidified material, new layers of material will be able to be printed, and so on until the final part. The objectives of the thesis are to develop digital models to simulate the additive manufacturing process by controlling the expansion of the material, identify the influencing parameters, develop the digital chain and optimize the manufacturing process. After identifying the intrinsic parameters of expansion of the material, the models that have been developed make it possible to obtain the geometry of the deposited beads and the temperature fields with respect to the rate of deposition of material layer by layer. For producte digital models, it is possible to analyze the influence of the operating parameters on the different observables and therefore to have a better understanding of the phenomena involved in order to propose an optimized 3d printing strategy solution to guarantee 3D geometry of the part, the material health and the manufacturability according to the printing machinery

High-sensitivity quantification of acetylcholine and choline in human cerebrospinal fluid with a validated LC-MS/MS method

International audienceAcetylcholine is the neurotransmitter of the parasympathetic nervous system, synthesized from choline and involved in several neurodegenerative diseases. Exploration of cholinergic neurotransmission in the human central nervous system is limited by the lack of a sensitive and specific method for the determination of acetylcholine and choline expression. We developed an hydrophilic interaction liquid chromatography – mass spectrometry method for the quantification of both molecules in human cerebrospinal fluid samples. An extensive selectivity study towards endogenous interfering compounds, in particular γ-butyrobetain, was performed and the method was validated according to the European Medicine Agency and Food and Drug Administration guidelines for the validation of bioanalytical methods. The performance of the method was excellent with a lower limit of quantification at 5 ng/L (34.2 pmol/L) for acetylcholine and 5 μg/L for choline, a precision in the range 1.3–11.9% and an accuracy between 85.2 and 113.1%. This suitability of the method for the quantification of acetylcholine and choline in clinical samples was demonstrated with the analysis of patient cerebrospinal fluid samples. Altogether, this validated method allows the simultaneous quantitative analysis of acetylcholine and choline in human cerebrospinal fluid with high sensitivity and selectivity. It will allow to better characterize the cholinergic neurotransmission in human pathologies and to study the effects of drugs acting on this system

On site deployment of 3D printing for the building construction – The case of Yhnova

The University of Nantes has developed a 3D printing technique (BatiPrint3DTM) dedicated to the construction of the walls of a house. This innovative on site construction technique is based on the deposition of two layers of expansive foam used as a formwork for a third concrete layer. It allows to build at the same time the structure and the insulation. This new construction technology has first been developed at the laboratory, but rapidly, we decided to deploy it on site, in order to demonstrate its technical viability. We present the technology Batiprint3DTM and the demonstrator YhnovaTM, a 95m2 social dwelling built for the social landlord Nantes Métropole Habitat (NMH)

The implementation of a methodology for robotic repair operations on composite structures

International audienc