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CNS2023-143647

Financiado

Enfermedades del sistema nervioso

NEURODEVELOPMENTAL DISORDERS (NDS) INVOLVE A SET OF CLINICAL PHENOTYPES AND FUNCTIONALLY DISRUPTIVE SYMPTOMS THAT CAN HAVE A DEVASTATING IMPACT ON QUALITY OF LIFE. ALTHOUGH INDIVIDUAL PROFILES CAN DRASTICALLY CHANGE ACROSS NDS, AN... ver más

01/01/2023

200K€

Presupuesto del proyecto: 200K€

Líder del proyecto

UNIVERSIDAD DE SEVILLA No se ha especificado una descripción o un objeto social para esta compañía.

Total investigadores 3669

Financiación concedida El organismo AGENCIA ESTATAL DE INVESTIGACIÓN notifico la concesión del proyecto el día 2023-01-01 No tenemos la información de la convocatoria

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Líder del proyecto

UNIVERSIDAD DE SEVILLA No se ha especificado una descripción o un objeto social para esta compañía.

Total investigadores 3669

Presupuesto del proyecto 200K€

Descripción del proyecto NEURODEVELOPMENTAL DISORDERS (NDS) INVOLVE A SET OF CLINICAL PHENOTYPES AND FUNCTIONALLY DISRUPTIVE SYMPTOMS THAT CAN HAVE A DEVASTATING IMPACT ON QUALITY OF LIFE. ALTHOUGH INDIVIDUAL PROFILES CAN DRASTICALLY CHANGE ACROSS NDS, AND OFTEN EVOLVE AS INDIVIDUALS MATURE, THERE ARE IMPORTANT COMMONALITIES IN LATENT SYMPTOMATIC STRUCTURES AND NEURAL SUBSTRATES THAT CLINICALLY MANIFEST AS HIGH COMORBIDITY. GROWING EVIDENCE SUPPORTS THE HYPOTHESIS THAT THE COMPLEX GENE-ENVIRONMENTAL INTERACTIONS IN NDS LEAD TO ATYPICAL BRAIN DEVELOPMENT WHICH PLAYS A MAJOR ROLE IN THE SYMPTOMATOLOGY OF THESE CONDITIONS. UNDERSTANDING DEVIATIONS IN BRAIN MATURATION TRAJECTORIES, AS WELL AS THE ASSOCIATED GENETIC RISKS AND MOLECULAR EVENTS, HAS BECOME CRITICAL TO FULLY GRASPING THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF NDS. OVER THE LAST TWO DECADES, PSYCHIATRIC NEUROIMAGING HAS PROVIDED A UNIQUE INSIGHT INTO BRAIN STRUCTURAL ABNORMALITIES ASSOCIATED WITH NDS. HOWEVER, LIMITED EFFECT SIZES AND A LACK OF BIOLOGICAL INTERPRETATION HAVE HINDERED ITS TRANSLATIONAL CLINICAL VALUE. HERE, WE WILL EXPLOIT A NEW METHODOLOGY FOR INTEGRATING MAGNETIC RESONANCE IMAGING (MRI) AND PHENOTYPIC DATA FROM 44,648 NORMATIVE CONTROLS (NT) AND 5,742 INDIVIDUALS WITH NDS AND ASSOCIATED CONDITIONS, INCLUDING AUTISM, OBSESSIVE COMPULSIVE DISORDER, ATTENTION-DEFICIT AND HYPERACTIVITY DISORDER, FIRST EPISODE PSYCHOSIS, SCHIZOPHRENIA, LEARNING DISABILITIES AND TOURETTE SYNDROME. USING REFERENCE CHARTS OF BRAIN VOLUME IN NORMATIVE DEVELOPMENT FROM OUR RECENT WORK, WE WILL CALCULATE REGIONAL BRAIN VOLUMETRIC CENTILES, A METRIC REPRESENTING HOW MUCH THE VOLUME OF EACH REGION DEVIATES FROM THE NORMATIVE VALUES FOR ALL INDIVIDUALS IN OUR COHORTS (I.E., LARGE DEVIATIONS FROM THE 50TH CENTILE REPRESENT ATYPICAL REGIONAL VALUES). THUS, GROUNDED ON NEURODEVELOPMENTAL MODELS, CENTILES WILL REVEAL REGIONAL DEVIATIONS WHILE ACCOUNTING FOR SEX-, AGE- AND, IMPORTANTLY, SITE- (I.E., NUISANCE) EFFECTS. WE WILL DETERMINE WHETHER SPATIAL DISTRIBUTIONS OF CENTILES ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTOMIC (POST-MORTEM GENE EXPRESSION VALUES) AND MOLECULAR (METABOLISM, CELLULAR AND NEUROTRANSMITTER RECEPTORS/TRANSPORTERS DATA DERIVED FROM PET) FEATURES OF THE BRAIN. THIS WILL ALLOW US TO IDENTIFY WHETHER REGIONS WITH AN ATYPICAL TRAJECTORY IN NDS HAVE SPECIFIC MOLECULAR PROFILES SUCH AS OVER- (OR UNDER-) EXPRESSION OF GENES RELATED TO NEURODEVELOPMENT (AND PSYCHIATRIC CONDITIONS), HIGHER DENSITY OF NEUROTRANSMITTERS, ELEVATED METABOLISM, AND DISTINCT CELLULAR COMPONENTS, AMONG OTHERS. BUILDING ON THAT, WE WILL FINALLY EXPLORE THE ASSOCIATIONS BETWEEN ABNORMAL TRAJECTORIES AND ND SYMPTOMATOLOGY BY CONSIDERING BOTH NEUROPSYCHOLOGICAL BATTERIES THAT ARE SPECIFIC TO EACH ND AND THOSE THAT ARE AVAILABLE TRANSDIAGNOSTICALLY. WE ANTICIPATE THAT SPECIFIC- AND CROSS-DISEASE COMPONENTS WILL BOTH MANIFEST AS A SPATIAL PATTERN OF BRAIN REGIONAL VULNERABILITY THAT IS MEDIATED BY MOLECULAR FEATURES, AND THAT THESE COMPONENTS ARE ASSOCIATED WITH NDS SYMPTOMATOLOGY AND COMORBIDITIES. WE EXPECT THAT THIS STUDY WILL NOT ONLY PROVIDE A BETTER UNDERSTANDING OF ATYPICAL BRAIN MATURATION IN NDS BUT CAN ALSO TRIGGER A PARADIGM SHIFT WHERE PSYCHIATRISTS, NEUROLOGISTS AND CLINICIANS IN GENERAL, CAN BE FINALLY SUPPORTED BY NEUROIMAGING EVIDENCE THAT IS FIRMLY ROOTED IN BOTH NEURODEVELOPMENTAL AND MOLECULAR HYPOTHESES. TRASTORNOS DEL NEURODESARROLLO\TRANSCRIPTOMICA\IMAGEN POR RESONANCIA MAGETICA\NEUROIMAGEN PSIQUIATRICA\ESQUIZOFRENIA\MADURACION ATIPICA\MODELOS NORMATIVOS\NEUROIMAGEN GENETICA

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