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Biologically Relevant Subgroups Within the Schizophrenia Syndrome

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Biologically Relevant Subgroups Within the Schizophrenia Syndrome DOCTORAL PROGRAM IN BIOMEDICAL RESEARCH DOCTORAL THESIS BIOLOGICALLY RELEVANT SUBGROUPS WITHIN THE SCHIZOPHRENIA SYNDROME This dissertation is submitted by Alba Lubeiro Juárez for the degree of Doctor of Philosophy at the University of Valladolid Supervisor Dr. Vicente Molina Rodríguez Valladolid, Spain, 2018 PROGRAMA DE DOCTORADO EN INVESTIGACIÓN BIOMÉDICA TESIS DOCTORAL BIOLOGICALLY RELEVANT SUBGROUPS WITHIN THE SCHIZOPHRENIA SYNDROME Presentada por Alba Lubeiro Juárez para optar al grado de Doctora por la Universidad de Valladolid Dirigida por Dr. Vicente Molina Rodríguez Valladolid, España, Octubre de 2018 Título: Biologically relevant subgroups within the schizophrenia syndrome Autor: Alba Lubeiro Juárez Dirigida por: Vicente Molina Rodríguez Tutorizada por: Diego Sánchez Departamento: Departamento Pediatría e inmunología, Obstetricia y Ginecología, Nutrición y Bromatología, Psiquiatría e Historia de la Ciencia Esta tesis fue leída en la facultad de Medicina en la Universidad de Valladolid el día , estando compuesto el tribunal calificador por : Presidente: Secretario: Vocal : Obteniendo la calificación de: En Valladolid, España, a de de 201 - VII - A mi madre. - IX - A veces la enfermedad puede enseñarnos lo que tiene la vida de valioso. - Oliver Sacks - Todo lo que ocurre en el cerebro es biología y todo lo que ocurre en la mente, ocurre a través del cerebro. - Joseph le Doux - - XI - Suelta lo malo y déjalo correr, que estás en vuelo. Óyeme, ponte en talla y vámonos de aquí para el cielo. Vámonos a construir lo nuevo, a ponerlo todo boca abajo, a comer el mundo con los dedos, a romper lo negro en mil pedazos. Con amor que es todo lo que tengo y estas ganas locas de entregarlo. Para cambiar esta vida de perros, para vivir el tiempo más humano. Vueltas - Amparo Sánchez y Pascual Cantero - - XIII - Agradecimientos / Greetings A mi maestro, Vicente Molina, que me dio su confianza sin conocerme, por creer en mí y apoyarme. Por darme esta gran oportunidad y enseñarme los entresijos de la investigación. Ha sido un honor para mí poder trabajar contigo, de verdad, gracias. A las fuentes de financiación que han permitido la realización de esta Tesis Doctoral: una beca predoctoral de la Junta de Castilla y León y el Fondo Social Europeo, una beca de estancia nacional de la Universidad de Valladolid y una beca de estancia internacional de European Molecular Biology Organization (EMBO Short-term fellowship). A Diego Sánchez, Lola Ganfornina y el resto del Laboratorio Lazarillo. Por dejarnos trabajar en su laboratorio, sin condiciones. Pero sobre todo por el cariño con el que siempre me han tratado, por sus consejos y apoyo. Por su gran amor a la enseñanza, seguiré vuestro ejemplo. A mi coordinadora de doctorado en Investigación Biomédica, Teresa Pérez, por preocuparse, animarme y estar ahí para cualquier duda. A todo el personal de FIDMAG y la Universidad de Barcelona, por acogerme con los brazos abiertos. En especial a Mar Fatjó-Vilas, mi segunda maestra, María Guardiola y Carmen Almodóvar. ¡Qué tres meses más maravillosos pasé con vosotras! A veces el ideal de que el trabajo puede ser divertido y alegre, además de productivo, se cumple. To Wroclaw Medical University, Department of Genetics, specifically to Błażej Misiak, Elżbieta Szmida, Małgorzata Krzystek-Korpacka, Bartlomiej Stanczykiewicz and Filip Stramecki. Thank you for teaching me, helping me and making me feel at home in your country. A todo el equipo de Resonancia Magnética de la UVa y el Sacyl, en especial a Margarita Rodríguez, por colaborar en todo lo posible y hacer las cosas tan fáciles y por supuesto, por ser siempre encantadora conmigo. - XIV - A todo el personal del Hospital de Día de Psiquiatría. Sobre todo a Rosa, por hablarme de Vicente, sin ella no estaría aquí; a Begoña, por su colaboración y amabilidad, da gusto trabajar con personas así; y a Eva Sotelo, también por su colaboración y eficacia. A los centros que han colaborado en nuestros proyectos: Hospital Universitario de Álava (Vitoria), Hospital de Cruces (Bilbao) y Hospital 12 de Octubre (Madrid). Gracias principalmente a Aitor Palomino, Rafael Segarra, Mariana Bustillo y Javier Sanz. A Cristina Rueda, por su colaboración e implicación. Gracias a ella pudimos sacar adelante el artículo más importante de esta tesis. A los Residentes y resto de Médicos que han colaborado, de una u otra manera, en este proyecto: Marta Ayuso, Henar de la Red, Adrián Alonso, Nieves de Uribe, Rebeca Hernández, Marta Hernández, Marta García, Cristina Domínguez, Óscar Martín, Alicia Rodríguez, Laura Gallardo, Pilar del Valle, Patricia Marques, José Antonio Blanco y Fernando Uribe. Quiero hacer una mención especial a Benjamín Cea y Aldara Álvarez, con quien he compartido momentos de trabajo pero también inquietudes, preocupaciones, risas y alegrías. ¡Ojalá podamos mantener nuestra amistad durante mucho tiempo! A todos los Ingenieros que han participado en los artículos incluidos en esta tesis, Rodrigo de Luis, Javier Gómez, Alejandro Bachiller, Jesús Poza, Roberto Hornero y Pablo Núñez, sin vosotros nada de esto sería posible, me siento afortunada de haber podido trabajar juntos. Alejandro, fuiste un gran apoyo en los inicios de este camino, gracias por ser tan majo y tener siempre una sonrisa. Javier, gracias por explicarme conceptos “ingenieriles” con tanta paciencia, por ayudarme en lo posible y estar disponible en cualquier momento. A los estudiantes de Medicina cuyos trabajos fin de grado han estado entrelazados con parte del trabajo de esta tesis: Óscar Soto, Jorge Blanco, Daniel Ortega, Miguel Jiménez e Isabel Blanco. A Vanessa Suazo, por sus consejos y ayuda en la primera etapa de mi formación. A mis actuales compañeros, Sabela y Álvaro, que me han acompañado y apoyado en esta última parte de la tesis y hacen que me sienta parte de un equipo de verdad. - XV - A la banda sonora que me ha acompañado durante esta tesis: Amparo Sánchez, Celtas Cortos, Eskorzo, Depedro, La M.O.D.A, Kase O, Natalia Lafourcade, Lila Downs, Leonard Cohen, Bob Dylan, Gregory Porter y muchos más. To my friends Tita and Kuba. I feel fortunate to have met you. I will never forget the three great months we were together in Wroclaw. We must keep in touch despite the distance between our homes. A mis amigos Pucelanos, en primer lugar a Clara, compañera de camino desde hace muchos años, sin tu ejemplo y ayuda quizá no habría llegado aquí. Ahora las dos lo hemos conseguido, ¡somos doctoras!. En segundo lugar a Nati, María, David y Sara. Gracias por estar, por las cenas, los bailes, las risas y, en general, los buenos momentos. Qué suerte tengo de teneros cerca. Por último, a Christopher, por su ayuda con las correcciones del inglés. A mis amigos Leoneses “Los Jetas”, con los que recorrí las primeras etapas de mi formación universitaria. Porque nuestras pequeñas y grandes escapadas me han dado fuerzas para realizar esta tesis y lo mejor, permiten que sigamos unidos. A mi padre y abuelos, por darme los recursos y el apoyo para poder estudiar. A mi familia no de sangre, pero sí de corazón, por orden de llegada a mi vida: Celia, Santi, Laura, Samuel, Inés y Manolo. Algunos formáis parte de estos artículos como “conejillos de indias”. Gracias por vuestro apoyo, por estar a mi lado siempre y porque la vida es mejor teniéndoos cerca. A Julio, porque tú haces que la vida se me vuelva de colores. Esto es un logro compartido, de ambos. A mi madre, por enseñarme a vivir, a ser valiente, a luchar, a levantarme en cada tropiezo. Por transmitirme el amor de la cultura y la educación. Esta tesis es por y para ti. A los controles y pacientes que dieron su tiempo para formar parte de este proyecto. Y en general, a todos los pacientes que sufren o han sufrido enfermedades mentales y a sus familiares. Este es mi pequeño granito de arena. - XVII - Abstract Diagnostic criteria for schizophrenia are based on signs and symptoms and do not take into account biological abnormalities. Therefore, current diagnoses are subjective and unspecific, promoting enormous differences in clinical presentations among patients with the same diagnosis. On the other hand, lots of biological processes have been studied in relation to schizophrenia. Some of the findings support neurotransmitters alterations, neuroanatomical changes, connectivity disruptions, immune dysregulation, genetic or environmental risk factors. Nevertheless, research findings are inconclusive, very heterogeneous and difficult to replicate. Thus, schizophrenia aetiology is not well understood in spite of the huge efforts made by researches. Different evidence suggests that schizophrenia is not a homogeneous disease but a syndrome comprising patients with different biological disruptions. In order to cope with this heterogeneity, the low replication rate of research findings and the lack of biological validity of current diagnosis is necessary to incorporate new research approaches that can eventually translate in a change in psychiatric diagnosis. In the present thesis, we aimed to explore the existence of biological subgroups within schizophrenia patients by using data from structural and functional brain connectivity as well as a genetic information. It includes five articles with sample sizes from 27 to 121 schizophrenia patients and 27 to 144 healthy controls. All patients were diagnosed according to DSM-IV or V criteria and their symptoms were scored using the Positive and Negative Syndrome Scale (PANSS). Structural connectivity was assessed in two different ways. Firstly, using structural magnetic resonance
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