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METSY Report Summary

Project ID: 602478
Funded under: FP7-HEALTH
Country: Denmark

Periodic Report Summary 2 - METSY (Neuroimaging platform for characterisation of metabolic co-morbidities in psychotic disorders)

Project Context and Objectives:
Project Context and Introduction
The theme of this collaborative project is development and application of neuroimaging and bioinformatics tools to study lipid metabolism as a common pathogenic link between psychotic disorders and its metabolic co-morbidities. The overall objective is to identify, prioritize and evaluate multimodal blood and neuroimaging markers with diagnostic potential for prediction and monitoring of psychotic disorders and associated metabolic co-morbidities.

The concept is that: (1) Primary obesity and psychotic disorders are similar with respect to the associated changes in energy balance and co-morbidities, including metabolic syndrome (MetS). (2) The specific underlying mechanisms linking the expansion of adipose tissue to these co-morbidities are unknown. (3) Such similarities do not necessarily demonstrate causal links, but instead suggest that specific causes of and metabolic disturbances associated with obesity play a pathogenic role in the development of psychotic disorders, potentially even before obesity develops. (4) Both brain and peripheral metabolic organs use lipids as components of their integrated homeostatic system to control energy balance as well as to regulate peripheral insulin sensitivity. (5) Specific neurotransmitter systems such as endocannabinoids regulate systemic lipid metabolism. (6) Given the intrinsic complexity and widespread role of lipid metabolism, a systems biology approach which combines brain imaging with detailed metabolic characterisation is essential to identify lipid related contributing factors to psychotic disorders. (7) Knowledge of common and specific mechanisms may help in the etiopathogenic understanding, early disease detection as well as identification of subjects who may benefit from specific treatments for psychotic disorders or who may be especially vulnerable to metabolic side effects as well as in discovery of unexpected novel therapeutic avenues.

The overall objective is to identify, prioritize and evaluate multi-modal blood and neuroimaging markers with diagnostic potential for prediction and monitoring of psychotic disorders and associated metabolic co-morbidities. By combining human cohort studies, methodology developments and translational research, we aim to (1) optimise a multidisciplinary approach for combining positron emission tomography (PET) and magnetic resonance imaging (MRI) with metabolomics approaches, (2) develop a PET-method for exploring endocannabinoid pathways in early psychosis in longitudinal study setting, and (3) develop combined PET/MR biomarker methodology for psychiatric disorders by studying neurotransmitter interactions with multiple PET scan and MRI sequences.

The main objective of METSY will be met by combinations of clinical research, state-of-the-art technologies and systems biology, divided into six specific objectives:
1. To apply neuroimaging strategies to characterise structural and metabolic changes in the brain during the first stages of psychosis.
2. To apply imaging strategies to characterise the endocannabinoid pathways in the brain and relate them to lipid molecular networks.
3. To characterise genetic and lipid molecular networks as measured in biofluids in early psychosis and identify how these networks associate with patient outcomes.
4. To develop and demonstrate methodology for combined PET and MRI imaging.
5. To develop bioinformatics tools to integrate brain image information with clinical and molecular profile data.
6. To identify, prioritize and evaluate multi-modal circulating and neuroimaging markers with diagnostic potential for prediction and monitoring of psychotic disorders and associated metabolic co-morbidities.

Project Results:
Overview of Progress in the Second Reporting Period
WP1 deals with detailed multi-modal neuroimaging and neuropsychological characterisation in longitudinal studies involving patients at-risk or with first episode of psychosis. The goal in WP1 is to follow up in the same study and with analogous methodology, first-episode and at-risk subjects and matched healthy controls to extract neuroimaging information useful for characterization of the development of psychosis and associated metabolic outcomes. Harmonization of the clinical and neuroimaging data across the participants of the project is essential for achieving this goal, and it is an important milestone that has been completed during the first half of the project.

WP2 aims at quantifying the distribution volume of the CB1 receptors using positron emission tomography (PET) and it also aims to quantify peripheral endocannabinoids in 35 at-risk for psychosis (CHR) patients, 35 first-episode psychosis (FEP) patients and 35 healthy controls. The patient target has not yet been achieved for the FEP and CHR subject groups, and priority has been set for achieving the target at the baseline time point. An interesting interaction effect of the condition and the gender has been detected in the current set of PET images, and also observed in data from an earlier study. The analytical method for the analysis of circulating endocannabinoids is waiting for the sample collection to finish.

WP3 has pursued molecular characterization of the cohorts included in WP1. Blood samples of 86 subjects from the THL/Helsinki cohort were analysed in parallel with two metabolomics mass-spectrometry instruments at Steno Diabetes Center. A pipeline of metabolomic profiling, pre-processing, statistical analysis and machine learning-based modeling were developed in collaboration with WP5 and WP6. Full analysis of the first data set available to WP3 led to the first collaborative publication (D7.3), and the results were presented at the 5th Biennial Schizophrenia Research Society Conference (SIRS) and at the 16th International Conference on Systems Biology. Latest results from the newly-run samples were presented at the 40th International Symposium on Capillary Chromatography and the 13th GCxGC Symposium.

WP4 has developed methods and software tools for combined PET and MR image acquisition, processing and analysis. The major goal of the WP4 – a standardized pre-processing chain for PET/MR image analysis – was completed (D4.3) during the reporting period and will be used for the analysis of data available from WP2. A harmonized and aligned processing chain for the data will ensure comparability and reproducibility of the results.

WP5 pursues the integration of image data with other phenotypic data, including from ‘omics’ analyses, aiming to extract the signals of potential diagnostic value. A prototype for implementation for the diagnostic tool disease state index was developed (D5.1). The METSY knowledge portal was expanded by adapting the data model of the BioXM knowledge management environment to allow integration of clinical, neurobiological and metabolic patient data from the METSY project. Several brain atlases and ontologies used in the METSY project as well as in neurobiological and brain connectivity research were imported into the knowledge infrastructure. A machine learning pipeline was developed for dimensionality reduction and used in the first collaborative METSY publication (D7.3). Further, the dimensionality reduction approach was coupled with partial correlation network-based association analysis to integrate and visualize multi-modal data (D5.2 & D3.2).

WP6 will validate the multi-modal circulating and neuroimage markers which are sensitive to metabolic disturbances in the brain of at-risk or psychotic patients. The independent prospective sample series from WPs 1-3 has not yet been completed, and the current work in this WP has been focused on the quality control, priorization and validation of the findings from existing data. Algorithmic first-step validation tools were developed in collaboration with WP3 and WP5 to assess the quality of the metabolomic features produced by the non-targeted metabolomics platforms. Quality control of the high-dimensional profiles is an essential first step in the biomarker selection process, ensuring that the observations are not confounded by technical artefacts from the sample collection process, sample preparation or from the measurement instrument. This measure is later also useful assessing the technical reliability of the selected biomarkers.

WP7 promotes scientific and public awareness about the METSY project and co-morbidities, and addresses tasks related to the exploitation of METSY findings. The public website of the project – – is online and has been updated for presentations and advances in the project (D7.1). The first major collaborative publication of METSY findings (D7.3) has been accepted for publication and is in press now. The first FEC proposal for the METSY technology exploitation (D7.4) was completed. The manuscript of the first opinion paper outlining the METSY bioinformatics platform (D7.5) has been drafted collaboratively by the consortium, and the publication plan has been agreed upon.

WP8 provides management and coordination for the project. The coordinating participant has distributed interim payments to METSY partners, chaired and supported annual plenary meetings, and prepared and submitted management reports. Following changes in affiliations of two work package leaders, the current coordinator, Steno Diabetes Center, has done additional work with the METSY Project Officer to change the coordinator of the project and to add a new beneficiary to the project, making sure that the project can progress as planned.

Potential Impact:
Expected Final Results and Scientific, Societal and Socio-Economic Impact
The expected impacts of METSY are (1) etiopathogenic understanding, (2) new validated multi-modal markers for early disease detection and monitoring, (3) new tools for the identification of subjects who may benefit from specific treatment (4) discovery of new avenues for disease prevention and therapy, and (5) new tools and processes for applying brain imaging in personalised medicine.

Three lead user groups can be identified that benefit from METSY’s impact: healthcare professionals, the citizens, and European industry and decision makers. For healthcare professionals the impacts are in improvements in the healthcare system. Additionally, the project is expected to generate new scientific knowledge about the pathophysiology behind different biomarkers in psychosis and its metabolic co-morbidities.

For the citizens, the impacts lie in better tools to predict the health-related outcomes in psychosis, leading to better treatment options and ultimately to improved quality of life. For the European industry and decision makers METSY’s results give input for development and exploitation of products based on innovative methods developed in the project, thereby increasing global competitiveness.

List of Websites:

Reported by

Steno Diabetes Center A/S


Life Sciences
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