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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SZ_TEST (Towards Early Molecular Diagnostics of Schizophrenia)

Teaser

Summary

Schizophrenia (SZ) is a severe mental disorder affecting more than 0.7% of the adult population. One of the most disabling and emotionally devastating illnesses known to man, SZ is also associated with considerable socioeconomic burden. In Europe, >80% of people with SZ are unemployed, a large US study found that nearly 20% of patients with SZ are homeless. In general, the chronic nature and the high degree of patient disability make SZ the fourth leading cause of disease burden across the globe with the management costs making up ~3% of the total healthcare budget in Western countries. The situation is even direr in some regions, including northern Sweden and Finland, where relative prevalence of SZ exceeds two to three times corresponding national or regional averages. Unfortunately, poorly understood aetiology and limited diagnostic arsenal make it difficult to detect and treat SZ in a timely and efficient manner. This underscores a critical need for better understanding of the mechanisms underlying this disease and development of new diagnostic possibilities allowing its early detection, ideally prior to the onset of psychosis. The SZ_TEST consortium will address these challenges by coordinating efforts of academic and industrial partners with complementary areas of expertise in genetics, epigenetics, neurodevelopment, molecular psychiatry, clinical immunology and biotech R&D. The overarching hypothesis underlying our work is that genetic vulnerabilities, neurodevelopmental defects, exposure to pathogens, immune system status and specific lifestyle choices may compound the risk of SZ and that a systematic multivariate analysis of these factors should result in substantially improved diagnostic tools.

We will work towards our main objective:
development of molecular diagnostics tools for early detection of SZ, by using relevant cohorts of human subjects, unique animal and cell models, and combining unbiased high-throughput omic screens with knowledge-based candidate marker analyses. In view of the increasing burden of SZ in Europe, the expertise and the â€œhuman capitalâ€ delivered by the SZ_TEST training network is expected to have a major impact on improving the quality of life and reducing the health care costs in Europe and worldwide.

Work performed

8 publications in peer-reviewed journals, including 6 with impact factor >5; 6 posters at conferences, acknowledging the EC/SZ_TEST support
SZ_TEST has been selected for oral presentation in a highly distinguished meeting in the field, a landmark conference on immunological disorders of the brain and mind, the Lancet Summit, Nov 2018
Industrial promotion & networking across globe â€“US-BIO, PROFILE, PANBIORA, VULCANUS, MEDLEM, AUTOIGG, ASCB/EMBO, FENS, etc.

Final results

The main objective of the project is to develop and validate molecular diagnostic tools for early detection of Schizophrenia.
For achieving the main objective, three specific objectives must be met, which state of the art progress is described below.

Elucidating developmental factors related to onset and progression of SZ with a specific emphasis on regulators of neuronal function and synaptic integrity (WP1)
Current status: There is a growing consensus that early detection of SZ, ideally before the onset of serious behavioural, emotional and cognitive dysfunctions, may improve the prognosis for the patients and minimize the societal burden. However, the existing diagnostic approaches rely predominantly on manifest psychiatric symptoms, which may develop only at advanced stages of the underlying pathological process. Improved understanding of SZ neurobiology may result in development of new pre-emptive and preventive therapies substantially delaying or completely eliminating the most severe symptoms of this disorder. With this in mind, we will focus on fundamental stages of brain development including its formation, reorganization and maintenance and investigate most promising leads poised to deliver critical insights into SZ mechanisms.

Understanding the role of immune system in SZ (WP2)
Current status: A promising but currently underexplored approach to early diagnosis of SZ involves developing tests based on blood biomarkers. Mounting evidence suggests that immune and inflammatory responses, both at pre- and postnatal stages, may reflect increased exposure and/or sensitivity to psychosocial stress or anatomical changes in the brain areas in clinically high-risk (CHR) individuals that progress to psychosis. This raises the possibility that relevant molecules released to blood have considerable diagnostic value and that the risk of transition may be associated with specific molecular signatures in blood that involves immune-inflammatory biomarkers. In this WP, we will evaluate a panel of immune and blood-born biochemical markers to identify at-risk subjects. Importantly, several common features shared between SZ and other neuropsychiatric and neurological disorders accompanied by psychosis will likely expand the overall clinical utility of this WP.

Validating molecular diagnostics for early detection of SZ (WP3)
Current status: The ultimate goal of the proposed project is to develop innovative approaches to early diagnosis of SZ and related conditions through systematic evaluation of biomarkers delivered by WP3. It is imperative to accurately predict the risk of onset of SZ in individuals with as few false positives and false negatives as possible. Earlier studies indicate that it might be difficult to deliver sufficiently reliable, specific and general diagnostics using a single biomarker. Correspondingly, multi-modal strategies have been the focus of several ongoing neuroimaging studies. However, findings from such studies have not yet been translated into clinical practice, in part due to the prohibitively expensive nature of the required imaging techniques. To address this limitation, we propose to combine analysis of clinically useful and affordable biomarkers with detailed analysis of patient-specific genetic and environmental factors to increase the accuracy of diagnostic predictions.