Periodic Reporting for period 2 - SZ_TEST (Towards Early Molecular Diagnostics of Schizophrenia)
Período documentado: 2019-01-01 hasta 2022-06-30
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. 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 knowledge for diagnostic improvements allowing its early detection, ideally prior to the onset of psychosis. SZTEST, a consortium supported by Research and Innovation Staff Exchange (RISE) program, has addressed these challenges by coordinating efforts of academic and industrial partners with complementary areas of expertise in genetics, transcriptomics, neurodevelopment, molecular psychiatry, clinical immunology and biotech R&D. The overarching hypothesis underlying our work is that a systematic multivariate analysis of disease-contributing factors should result in improved diagnostic tools and potentially contribute to better therapies.
The SZTEST project aimed to investigate the following:
1) what are the molecular mechanisms driving SZ
2) can we develop biomarkers for early detection of SZ
3) is a peripheral blood test for SZ diagnostics feasible?
SZTEST brought together 11 partners from research and industry sectors across Europe. Overall, >130 secondments were carried out as a part of this program, involving >40 fellows at both ER and ESRs levels. A key output of SZTEST has been publication of 28 high-quality scientific papers, with several additional manuscripts still in preparation or in revision. The consortium has also allowed us to establish new collaborations addressing important aspects of SZ R&D.
Furthermore, SZTEST organized 6 very successful international events at the interface between academia and industry, which have been extensively publicized. Several SZTEST alumni made excellent career moves in the US and Europe.
The SZTEST project aimed to investigate the following:
1) what are the molecular mechanisms driving SZ
2) can we develop biomarkers for early detection of SZ
3) is a peripheral blood test for SZ diagnostics feasible?
SZTEST brought together 11 partners from research and industry sectors across Europe. Overall, >130 secondments were carried out as a part of this program, involving >40 fellows at both ER and ESRs levels. A key output of SZTEST has been publication of 28 high-quality scientific papers, with several additional manuscripts still in preparation or in revision. The consortium has also allowed us to establish new collaborations addressing important aspects of SZ R&D.
Furthermore, SZTEST organized 6 very successful international events at the interface between academia and industry, which have been extensively publicized. Several SZTEST alumni made excellent career moves in the US and Europe.
Twenty eight publications in peer-reviewed journals with average impact factor >7.868 (as of June 2022); 4 successful PhD defences with at least 6 additional PhD defences to follow; >20 poster or oral presentations at conferences and meetings, including ASCB/EMBO, FENS, The Society for Neuroscience, The Nordic Neuroscience, The Sigrid Juselius Symposium acknowledging the EC/SZTEST support. SZTEST was 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 –US-BIO, PROFILE, PANBIORA, VULCANUS, MEDLEM, AUTOIGG, others.
Industrial promotion & networking across globe –US-BIO, PROFILE, PANBIORA, VULCANUS, MEDLEM, AUTOIGG, others.
The main objective of the project is to develop and validate molecular diagnostic tools for early detection of Schizophrenia. To this end, we developed three lines of research summarized 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 focused on fundamental stages of brain development including its formation, reorganization and maintenance and investigated the 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 evaluated a panel of metabolic and immune blood-born biochemical markers to identify FEP at-risk subjects. Importantly, several common features shared between SZ and other neuropsychiatric and neurological disorders accompanied by psychosis that were observed 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 used blood-biomarker-based approach for development of clinically useful and affordable biomarker candidates with potential to increase the accuracy of current diagnostic predictors.
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 focused on fundamental stages of brain development including its formation, reorganization and maintenance and investigated the 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 evaluated a panel of metabolic and immune blood-born biochemical markers to identify FEP at-risk subjects. Importantly, several common features shared between SZ and other neuropsychiatric and neurological disorders accompanied by psychosis that were observed 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 used blood-biomarker-based approach for development of clinically useful and affordable biomarker candidates with potential to increase the accuracy of current diagnostic predictors.