5 research outputs found
Intelligent digital tools for screening of brain connectivity and dementia risk estimation in people affected by mild cognitive impairment: the AI-Mind clinical study protocol
No full text| openaire: EC/H2020/964220/EU//AI-MindMore than 10 million Europeans show signs of mild cognitive impairment (MCI), a transitional stage between normal brain aging and dementia stage memory disorder. The path MCI takes can be divergent; while some maintain stability or even revert to cognitive norms, alarmingly, up to half of the cases progress to dementia within 5 years. Current diagnostic practice lacks the necessary screening tools to identify those at risk of progression. The European patient experience often involves a long journey from the initial signs of MCI to the eventual diagnosis of dementia. The trajectory is far from ideal. Here, we introduce the AI-Mind project, a pioneering initiative with an innovative approach to early risk assessment through the implementation of advanced artificial intelligence (AI) on multimodal data. The cutting-edge AI-based tools developed in the project aim not only to accelerate the diagnostic process but also to deliver highly accurate predictions regarding an individual's risk of developing dementia when prevention and intervention may still be possible. AI-Mind is a European Research and Innovation Action (RIA H2020-SC1-BHC-06-2020, No. 964220) financed between 2021 and 2026. First, the AI-Mind Connector identifies dysfunctional brain networks based on high-density magneto- and electroencephalography (M/EEG) recordings. Second, the AI-Mind Predictor predicts dementia risk using data from the Connector, enriched with computerized cognitive tests, genetic and protein biomarkers, as well as sociodemographic and clinical variables. AI-Mind is integrated within a network of major European initiatives, including The Virtual Brain, The Virtual Epileptic Patient, and EBRAINS AISBL service for sensitive data, HealthDataCloud, where big patient data are generated for advancing digital and virtual twin technology development. AI-Mind's innovation lies not only in its early prediction of dementia risk, but it also enables a virtual laboratory scenario for hypothesis-driven personalized intervention research. This article introduces the background of the AI-Mind project and its clinical study protocol, setting the stage for future scientific contributions.Peer reviewe
Genome-wide determinants of mortality and motor progression in Parkinson’s disease
No full textThere are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD
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Effects of organophosphates on neural and purified liver tissue transglutaminase
No full textTransglutaminase 2 (TGase 2) is a multifunctional calcium dependent enzyme that catalyzes protein modifications. TGase 2 is essential in neuronal cell differentiation and it has been reported that certain organophosphates are able to inhibit this process, and the organophosphate phenyl saligenin compound also disrupts TGase 2 activity. It has also been shown that the organophosphates chlorpyrifos (CPF) and chlorpyrifos oxon (CPFO), which cause developmental neurotoxicity, provoke several changes in differentiating rat C6 glioma cells at different levels. The aims of this thesis were to analyse the effects of CPF and CPFO on the TGases present in differentiating rat C6 glioma cells, to develop a new method for the purification of TGase 2 from guinea pig liver, to study possible direct interactions between TGase 2 and esterase inhibitors and to analyze a possible pathway for the externalisation of TGase 2.
In the presence of sodium butyrate, rat C6 glial cells differentiated into an astrocyte phenotype. Differentiation of the cells was associated with an increase in the activity, protein levels and gene expression of TGase 2. Differentiation in the presence of CPF or CPFO generated an increase in the activity of TGase 2, a decrease in its levels of gene expression but had no effect on the protein levels. These effects could be associated with a direct interaction between the organophosphates and TGase 2.
Chromatographic methods were developed to purify TGase 2 from guinea pig liver and the most effective one was a combination of ion exchange chromatography, protamine sulfate precipitation and hydrophobic interaction chromatography (HIC). The level of purity and yield obtained were superior to that of previously published methods. Furthermore, the final step of HIC could be applied directly to commercially available TGase 2 for the production of a highly purified TGase 2 sample.
When TGase 2 purified in this manner was assayed in the presence of CPF and CPFO, enzyme activity was observed to increase significantly, suggesting a direct interaction with TGase 2. By contrast, phenyl saligenin phosphate was found to inhibit TGase activity in vitro, which suggests a direct effect that may involve a different binding site and/or mechanism to CPF or CPFO. The aspartyl protease inhibitor pepstatin A was also able to inhibit directly TGase activity in vitro.
The final part of the project involved a short study of the potential association of TGase 2 with exosomes, in order to determine whether the latter might present a means of externalization of this enzyme. Exosomes purified from mouse N2a neuroblastoma cells were found to contain TGase 2, but its localization within the vesicles remains unclear
Depression: Can we predict who will relapse?
No full textThis thesis addresses risk factors and proposed mechanisms to explain relapse to depression. Volume 1 comprises three parts: Part 1 is a literature review consisting of meta-reviews of systematic and non-systematic reviews of studies reporting on risk factors for relapse to depression, and a systematic-review of neuroimaging and experimental studies investigating risk factors for relapse and potential mechanisms of action of these risk factors. The reviews found that only residual symptoms of depression at the end of treatment and childhood maltreatment were sufficiently evidenced as predictors of relapse and neither have great clinical utility. A number of psychological and neuropsychological factors were suggested to play a role in conferring risk for relapse. Considering the inter-relationships between these factors the reviews were used to propose a conceptual framework which may be used to help guide future research into relapse to depression in adults. Part 2 is an empirical paper in which data were analysed from service users of a primary care mental health service to identify risk factors for relapse and for the presence of residual symptoms, and survival analysis methods were used to determine when relapses occur most often and what factors impact survival. In addition, a prospective cohort study was formed to investigate the relationship between cognitive control and depressive symptoms. The findings confirmed that cognitive control can be used to predict residual symptoms of depression post-treatment and therefore potentially to predict relapse. Part 3 is a critical appraisal focussing on the theoretical reasons as to why studying relapse in a manner as used in the prospective study is so important and discusses the logistical difficulties conducting such research in the current context of NHS services and of the D.Clin.Psy research project. Methodological decisions made that impacted upon the research process are discussed and reflective conclusions are offered
