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Function and Brain Structure in Aging with and Without Cognitive Impairment

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Function and Brain Structure in Aging with and Without Cognitive Impairment FUNCTION AND BRAIN STRUCTURE IN AGING WITH AND WITHOUT COGNITIVE IMPAIRMENT Directors: Dr. David Bartrés Faz (Universitat de Barcelona) Dra. Imma C. Clemente Lapena (Universitat de Barcelona) Cristina Solé Padullés Programa de Doctorat en Neurociències (2001-2003) Departament de Psiquiatria i Psicobiologia Clínica Facultat de Medicina, Universitat de Barcelona FUNCTION AND BRAIN STRUCTURE IN AGING WITH AND WITHOUT COGNITIVE IMPAIRMENT Supervisors: Dr. David Bartrés Faz (University of Barcelona) Dr. Imma C. Clemente Lapena (University of Barcelona) Neuroscience Doctorate Program (2001-2003) Department of Psychiatry and Clinical Psychobiology Faculty of Medicine, University of Barcelona ii iii Dr DAVID BARTRÉS FAZ, Professor at University of Barcelona, and Dr IMMA C. CLEMENTE LAPENA, Professor at University of Barcelona, declare and confirm that they have supervised and guided the PhD thesis entitled: FUNCTION AND BRAIN STRUCTURE IN AGING WITH AND WITHOUT COGNITIVE IMPAIRMENT , presented by Cristina Solé Padullés. They hereby assert that this thesis fulfils the requirements to be defended for the Degree of Doctor. Signature, Dr David Bartrés Faz Dr Imma C. Clemente Lapena University of Barcelona University of Barcelona Barcelona, September 2007 iv Present work contains four studies that have been carried out in the Neuropsychology Research Group of the Psychiatry and Clinical Psychobiology Department at the Faculty of Medicine, University of Barcelona. This group, lead by Prof. Carme Junqué, belongs to the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS). The following studies have been partially funded by a Spanish Ministerio de Educación y Culutra research project award (SEJ2004-06710/PSIC) to D. Bartrés Faz, as well as with grants from the University of Barcelona to C. Solé Padullés. v Envellir és com escalar una gran muntanya; mentre es puja les forces minven, però la mirada és més lliure, la vista més àmplia i serena. Ingmar Bergman A la joventut aprenem, a la vellesa entenem. Marie von Ebner Eschenbach Els arbres més vells donen els fruits més dolços. Proverbi alemany vi vii Agraïments Ben entrada la primavera de l’any 2001, dos anys després d’haver acabat la carrera, tot fullejant apunts vells de neuropsicologia, vaig recordar de sobte que era allò el que m’agradava, així que se’m va posar al cap que volia formar-me en neuropsicologia i d’aquesta petita i creixent obsessió va sorgir la necessitat de posar-me en acció. Em vaig posar en contacte amb la Dra. Junqué per mail, i a base d’insistir em vaig “colar” al departament. Així és com em sentia al principi. Una afortunada que havia aconseguit entrar. Vull agrair a la Dra. Carme Junqué que m’obrís la porta del seu equip, donant-me la oportunitat de formar-me al voltant de persones de les quals he après i m’han fet possible presentar avui aquesta tesi. La primera d’elles va ser la Dra. Imma Clemente. Amb ella vaig tenir el primer contacte cara a cara amb aquest món de la recerca i em va preparar pel que m’havia d’esperar. Gràcies Imma pels teus consells, per estar sempre allà, per fer-me de directora i d’amiga, per acompanyar-me amb cotxe a buscar pacients, pel bon humor que desprens passi el que passi, per la gran ajuda que em vas donar durant el DEA, no ho oblidaré, i per aquestes estones que hem passat al laboratori de genètica ampliant gens sense parar juntament amb la Mar Matarín, ara doctora, a la qual li agraeixo que em deixés aprofitar-me de les seves mostres per aprendre genètica; li dono les gràcies també per l’amistat durant els meus primers dos anys de tesi i ara per la seva companyia des de l’altra banda de l’Atlàntic. Gràcies també al Dr. Pedro Moral i Dra. Esther Esteban, per oferir-me els recursos del laboratori d’Antropolgia de la Facultat de Biologia durant gairebé dos anys i poder fer ús, no només dels recursos d’allà, sinó també dels seus becaris Marc, Emili i Natàlia. La seva ajuda i acollida va ser en moltes estones imprescindible, sobretot en els moments d’histèria continguda quan l’ADN no s’havia amplificat o quan s’havien de fer comandes i llegir gens. Enmig de tot això hi havia una persona que des de París s’havia interessat per qui l’havia succeït com a becari de la Dra. Clemente i que, gràcies a ella, em vaig posar en contacte via mail. La Imma volia que jo tingués una “referència” i em recolzés en ell quan ho necessités, deia que estava segura que ens entendríem molt bé. I així va ser. Vull agrair al Dr. David Bartrés el seu interès en tot moment per la meva tesi, la seva ajuda incondicional des de París i els seus alegres mails. Així es va anar convertint en una persona molt propera i certament la Imma va aconseguir que fós un referència per tirar endavant la tesi. Ja des de París el Dr. Bartrés va dissenyar el que seria la meva tesi i un cop aquí, l’estiu del 2003, em va posar en contacte amb una gran quantitat d’avis del Vallès, especialment de Castellar del Vallès, que van formar part de la mostra de la seva tesi. I cotxe amunt, cotxe avall em va introduir en diversos CAP d’on, per fi, i gràcies a l’interès i col.laboració dels Dr. Antoni Moya, Dr. Josep Sánchez-Aldeguer, Dra. Carme Bel i Dra. Isabel Martínez vaig obtenir una bona part de la mostra a estudiar. M’agradaria tornar a agrair al David la seva passió contagiosa per la recerca, per obrir nous projectes, la seva ajuda els dilluns a la tarda quan havíem de passejar l’aparell d’estimulació magnètica per tot l’Hospital Clínic, per supervisar les sessions de ressonància magnètica, per ensenyar-me i compartir el seus coneixements, que no són pocs. Als col·legues de la meva promoció, Blanca, Anna, Xavi, Marta i Mònica; a les veïnes del laboratori de Neurofisiologia Vanesa, Sílvia, Míriam per compartir les queixes, alegries, i frustracions, que també n’hi ha i força; als “grans” com Mar Ariza, Roser, Pep, Dra. Segarra i Dra. Colell per ser grans consellers. També al grup de Neurologia de l’Hospital Clínic, especialment al Dr. Josep Valls Solé, pel seu entusiasme i amabilitat. Sense ell hagués estat impossible realitzar els dos primers estudis. També al Dr. Jose Luis Molinuevo i al seu gran equip: Dra. Lorena Rami, Dra. Amparo Villar, Bea, Guada per la gran injecció de pacients que ens ha permès acabar els estudis i pel seu interès en els treballs que aquí presentaré. A la Dra. Fina Martí per la seva acollida i ajuda en un tema que, si bé no estrictament de la meva tesi, m’ha ofert la possibilitat de recollir algun coneixement d’una altra patologia com el Parkinson. No m‘oblido de la Dra. Núria Bargalló per la seva feina i interès allà baix al soterrani i al Dr. Carles Falcón per enviar-nos puntualment les imatges de RM i estar sempre disponible per qualsevol dubte. A la Dra. MªTeresa Colomina per la seva col·laboració, amistat i acollida des del principi de la meva incorporació, per les idees que gràcies a ella vam incorporar en alguns estudis. Gràcies també a les noves promocions de doctorat, Giusi, Naroa, Davinia, Sara i Benji, pel nou aire fresc que ha entrat al departament, pel flux d’informació que ara circula i l’ajuda desinteressada. Per la vostra alegria, bon humor i honestedat. Moltes gràcies i ànims per la vostra tesi. viii Al Dr. Pere Vendrell, per la seva predisposició a resoldre dubtes de tot tipus, a la Dra. Wilma Penzo, pels detalls comestibles que deixava sovint a la nevera. Moltes gràcies a la Pilar Bouzas, per ser com és, per la seva discreció, eficàcia, paciència i somriure permanent. Gràcies també a la meva família, papes, Anna, Natàlia, Joan, Tin i Alvarito per la vostra paciència i per intentar entendre (no sé si ho heu aconseguit) el que he estat fent durant gairebé 6 anys, per quan em preguntàveu “Com va la tesi?”, “Quan la presentes?” i entendre que no tenia resposta. I per molts d’altres que us heu interessat per la tesi i fins i tot m’heu fet explicar els resultats d’algun estudi en un context com “estar de vacances banyant-te al mar” (¿te acuerdas Nati?); pel vostre interès en una cosa que us queda tan llunyana. A tota la gent gran que ha participat en aquests quatre estudis, sobretot aquells que pateixen Alzheimer i a les seves famílies. Als meus avis i padrins, especialment a la iaia, que no ha vist el final de tot això. Al David, perquè he tingut la gran sort de conèixe’t precisament aquí, com a director i com a persona. Per la teva manera de ser, la teva sinceritat, la teva bondat, perquè des de que t’he conegut has estat la meva referència (la Imma ho va encertar) i finalment per la petita que m’ha donat la motivació i l’empenta final per acabar la tesi: la Georgina. ix Al David x xi Contents Page Foreword xiii Glossary of Abbreviations xiv 1. INTRODUCTION 1 1.1 Neuroscience of cognitive aging 1 1.1.1 Age-related cognitive and cerebral changes 1 1.1.2 Mild cognitive impairment 7 1.1.3 Alzheimer’s disease 10 1.1.4 Functional neuroimaging in aging 13 1.1.5 Transcranial magnetic stimulation 19 1.1.5.1 Transcranial magnetic stimulation: basic principles 19 1.1.5.2 Cognitive studies with TMS 22 1.1.6 Genetic correlates of brain function 27 1.1.7 Cognitive Reserve and brain function in normal and pathological aging conditions 29 1.1.7.1 Cognitive reserve 29 1.1.7.2 Cognitive Reserve influence on brain function 31 1.2 Approach and objectives 33 2.
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