DEVELOPMENT AND IMPLEMENTATION OF THE COGDRISK DEMENTIA RISK ASSESSMENT TOOL AND INTERACTIVE WEBSITE

We developed a comprehensive risk assessment tool for dementia – Cognitive Health and Dementia Risk Assessment (CogDrisk) and a version specifically for Alzheimer’s disease called CogDrisk-AD that could be applicable in low and high-resource settings. This tool incorporates risk and protective factors identified through systematic synthesis of observational studies that report risk ratios. Risk and protective factors included in the tool were selected on the strength of evidence as well as the availability of measures that are practicable in a range of clinical and research contexts. Seventeen risk/protective factors were identified for inclusion in the dementia algorithm to estimate the risk of dementia while sixteen factors were identified for the AD model, with an overlap in the majority of the factors. CogDrisk and the CogDrisk-AD were predictive of dementia and AD when validated across four high-quality international cohort studies. To enable the CogDrisk tool to be implemented in practice our team has developed an interactive website where individuals 18 years and above can complete the CogDrisk questionnaire, obtain a personalised risk profile, and receive feedback on their risk profile. The website was developed with the capacity to collect and store data. We anticipate that the tool can be used by members of the public, in clinical settings and as a screening or outcome measure for clinical trials

L’importance des récepteurs aux glucocorticoïdes dans la physiopathologie de la maladie d’Alzheimer

Strong evidence shows that oligomeric forms of the amyloid-ß peptide (oAß) cause synapse dysfunction promoting loss of hippocampus-dependent memories in the early phase of Alzheimer’s disease (AD). AD is also associated with Hypothalamus-Pituitary-Adrenal (HPA) axis dysfunction which results in an increase of glucocorticoids (CORT) activating glucocorticoid receptors (GRs). We showed that subchronic GR antagonist in 4 month Tg2576 (Tg+) mice could rescue the synaptic deficit and memory impairment (Lanté et al., 2015).In this context, we studied the contribution of GRs to AD physiopathology. Dysregulated HPA axis was characterized by increased CORT levels at 4 and 6 months of age and by loss of CORT feedback inhibition in the Tg+ mice. We further crossed the Tg+ with GRlox/lox to produce GRlox/loxTg+ mice. These mice innately exhibited high CORT levels from weaning period and due to other several unforeseen reasons, we discontinued using this new mouse model. Instead, to identify the functional relationship between the GRs and oAß at synapses, we shifted to acute oAß treatment in neurons in vitro and ex-vivo hippocampus slices. In neuron cultures, GR levels increased in the post synaptic density upon acute oAß treatment. Further, treatment of oAß on ex-vivo hippocampus slices after either pharmacological blocking of GR or genetic ablation, prevented the oAβ-dependent LTP impairment. To conclude, our results with the Tg+ mice suggest that a neuroendocrine dysregulation occurs during the onset of AD pathology. Additionally, we have evidence for a functional relationship between oAß and GRs with GRs at the synapse playing an important role in acute Aß-induced synapto-toxicity.Les formes oligomériques du peptideβ-amyloïde (oAβ) sont toxiques pour les synapses et engendrent la perte de mémoire lors de la phase précoce de la maladie d’Alzheimer (MA). La MA est aussi associée à une dérégulation de l’axe du stress engendrant une augmentation des glucocorticoïdes (GCs) qui activent les récepteurs associés (GRs). Nous avons montré que, dans un modèle murin de la MA, les Tg2576 (Tg+), l’inhibition des GRs prévient les déficits de mémoire et de plasticité synaptique (Lanté et al. 2015). Nous avons continué à étudier le rôle des GRs dans la physiopathologie de la MA. La dérégulation de l’axe du stress dans les souris Tg+ est caractérisée par des niveaux élevés de GCs et la perte de la boucle de rétroaction négative. Aussi, nous avons croisé les souris Tg+ avec des souris GR floxées pour générer des double mutants GRlox/lox Tg+. Ces souris exhibaient plusieurs phénotypes non-anticipés et nous avons décidé de mettre fin à cette lignée de souris. Nous avons aussi analysé la relation fonctionnelle spécifique entre les GRs et oAβ à la synapse en utilisant un traitement aigu d’oAβ. Dans des cultures de neurones, ce traitement a favorisé une augmentation des niveaux de GRs à la synapse. Aussi, nous avons montré que bloquer l’activité des GRs par pharmacologie ou par ablation génétique neutralise l’effet inhibiteur d’oAβ sur la potentialisation synaptique étudiée sur tranches d’hippoccampe. En conclusion, nos résultats sur souris Tg+ suggèrent la présence d’une dérégulation en début de MA. Aussi, nous mettons en évidence une relation fonctionnelle entre oAß et GRs à la synapse, les GRs jouant en rôle clé dans la synapto-toxicité induite par oAß

Importance of glucocorticoid receptors in the physiopathology of Alzheimer's disease

Les formes oligomériques du peptideβ-amyloïde (oAβ) sont toxiques pour les synapses et engendrent la perte de mémoire lors de la phase précoce de la maladie d’Alzheimer (MA). La MA est aussi associée à une dérégulation de l’axe du stress engendrant une augmentation des glucocorticoïdes (GCs) qui activent les récepteurs associés (GRs). Nous avons montré que, dans un modèle murin de la MA, les Tg2576 (Tg+), l’inhibition des GRs prévient les déficits de mémoire et de plasticité synaptique (Lanté et al. 2015). Nous avons continué à étudier le rôle des GRs dans la physiopathologie de la MA. La dérégulation de l’axe du stress dans les souris Tg+ est caractérisée par des niveaux élevés de GCs et la perte de la boucle de rétroaction négative. Aussi, nous avons croisé les souris Tg+ avec des souris GR floxées pour générer des double mutants GRlox/lox Tg+. Ces souris exhibaient plusieurs phénotypes non-anticipés et nous avons décidé de mettre fin à cette lignée de souris. Nous avons aussi analysé la relation fonctionnelle spécifique entre les GRs et oAβ à la synapse en utilisant un traitement aigu d’oAβ. Dans des cultures de neurones, ce traitement a favorisé une augmentation des niveaux de GRs à la synapse. Aussi, nous avons montré que bloquer l’activité des GRs par pharmacologie ou par ablation génétique neutralise l’effet inhibiteur d’oAβ sur la potentialisation synaptique étudiée sur tranches d’hippoccampe. En conclusion, nos résultats sur souris Tg+ suggèrent la présence d’une dérégulation en début de MA. Aussi, nous mettons en évidence une relation fonctionnelle entre oAß et GRs à la synapse, les GRs jouant en rôle clé dans la synapto-toxicité induite par oAß.Strong evidence shows that oligomeric forms of the amyloid-ß peptide (oAß) cause synapse dysfunction promoting loss of hippocampus-dependent memories in the early phase of Alzheimer’s disease (AD). AD is also associated with Hypothalamus-Pituitary-Adrenal (HPA) axis dysfunction which results in an increase of glucocorticoids (CORT) activating glucocorticoid receptors (GRs). We showed that subchronic GR antagonist in 4 month Tg2576 (Tg+) mice could rescue the synaptic deficit and memory impairment (Lanté et al., 2015).In this context, we studied the contribution of GRs to AD physiopathology. Dysregulated HPA axis was characterized by increased CORT levels at 4 and 6 months of age and by loss of CORT feedback inhibition in the Tg+ mice. We further crossed the Tg+ with GRlox/lox to produce GRlox/loxTg+ mice. These mice innately exhibited high CORT levels from weaning period and due to other several unforeseen reasons, we discontinued using this new mouse model. Instead, to identify the functional relationship between the GRs and oAß at synapses, we shifted to acute oAß treatment in neurons in vitro and ex-vivo hippocampus slices. In neuron cultures, GR levels increased in the post synaptic density upon acute oAß treatment. Further, treatment of oAß on ex-vivo hippocampus slices after either pharmacological blocking of GR or genetic ablation, prevented the oAβ-dependent LTP impairment. To conclude, our results with the Tg+ mice suggest that a neuroendocrine dysregulation occurs during the onset of AD pathology. Additionally, we have evidence for a functional relationship between oAß and GRs with GRs at the synapse playing an important role in acute Aß-induced synapto-toxicity

Study protocol for development and validation of a single tool to assess risks of stroke, diabetes mellitus, myocardial infarction and dementia: DemNCD-Risk.

INTRODUCTION: Current efforts to reduce dementia focus on prevention and risk reduction by targeting modifiable risk factors. As dementia and cardiometabolic non-communicable diseases (NCDs) share risk factors, a single risk-estimating tool for dementia and multiple NCDs could be cost-effective and facilitate concurrent assessments as compared with a conventional single approach. The aim of this study is to develop and validate a new risk tool that estimates an individuals risk of developing dementia and other NCDs including diabetes mellitus, stroke and myocardial infarction. Once validated, it could be used by the public and general practitioners. METHODS AND ANALYSIS: Ten high-quality cohort studies from multiple countries were identified, which met eligibility criteria, including large representative samples, long-term follow-up, data on clinical diagnoses of dementia and NCDs, recognised modifiable risk factors for the four NCDs and mortality data. Pooled harmonised data from the cohorts will be used, with 65% randomly allocated for development of the predictive model and 35% for testing. Predictors include sociodemographic characteristics, general health risk factors and lifestyle/behavioural risk factors. A subdistribution hazard model will assess the risk factors contribution to the outcome, adjusting for competing mortality risks. Point-based scoring algorithms will be built using predictor weights, internally validated and the discriminative ability and calibration of the model will be assessed for the outcomes. Sensitivity analyses will include recalculating risk scores using logistic regression. ETHICS AND DISSEMINATION: Ethics approval is provided by the University of New South Wales Human Research Ethics Committee (UNSW HREC; protocol numbers HC200515, HC3413). All data are deidentified and securely stored on servers at Neuroscience Research Australia. Study findings will be presented at conferences and published in peer-reviewed journals. The tool will be accessible as a public health resource. Knowledge translation and implementation work will explore strategies to apply the tool in clinical practice

Identification of an acute functional cross-talk between amyloid-β and glucocorticoid receptors at hippocampal excitatory synapses

International audienc

Study protocol for development and validation of a single tool to assess risks of stroke, diabetes mellitus, myocardial infarction and dementia: DemNCD-Risk

Introduction Current efforts to reduce dementia focus on prevention and risk reduction by targeting modifiable risk factors. As dementia and cardiometabolic non-communicable diseases (NCDs) share risk factors, a single risk-estimating tool for dementia and multiple NCDs could be cost-effective and facilitate concurrent assessments as compared with a conventional single approach. The aim of this study is to develop and validate a new risk tool that estimates an individual's risk of developing dementia and other NCDs including diabetes mellitus, stroke and myocardial infarction. Once validated, it could be used by the public and general practitioners. Methods and analysis Ten high-quality cohort studies from multiple countries were identified, which met eligibility criteria, including large representative samples, long-term follow-up, data on clinical diagnoses of dementia and NCDs, recognised modifiable risk factors for the four NCDs and mortality data. Pooled harmonised data from the cohorts will be used, with 65% randomly allocated for development of the predictive model and 35% for testing. Predictors include sociodemographic characteristics, general health risk factors and lifestyle/behavioural risk factors. A subdistribution hazard model will assess the risk factors' contribution to the outcome, adjusting for competing mortality risks. Point-based scoring algorithms will be built using predictor weights, internally validated and the discriminative ability and calibration of the model will be assessed for the outcomes. Sensitivity analyses will include recalculating risk scores using logistic regression. Ethics and dissemination Ethics approval is provided by the University of New South Wales Human Research Ethics Committee (UNSW HREC; protocol numbers HC200515, HC3413). All data are deidentified and securely stored on servers at Neuroscience Research Australia. Study findings will be presented at conferences and published in peer-reviewed journals. The tool will be accessible as a public health resource. Knowledge translation and implementation work will explore strategies to apply the tool in clinical practice