THESE DE DOCTORAT DE L’UNIVERSITE PIERRE ET MARIE CURIE Spécialité Neurosciences Ecole doctorale Cerveau Cognition Comportement présentée par ENRICA CAVEDO NEUROIMAGING MARKERS IN CLINICAL TRIALS FOR PRE-DEMENTIA STAGES OF ALZHEIMER’S DISEASE pour obtenir le grade de DOCTEUR DE L’UNIVERSITE PIERRE ET MARIE CURIE Soutenue publiquement le 8 Decembre 2015 devant le jury composé de : Pr. Bruno Dubois Université Pierre et Marie Curie-Paris 6 Directeur de thèse Pr. Giovanni B Frisoni Hôpitaux universitaires de Genève and Co-Directeur de thèse Université de Genève, IRCCS Centro San Giovanni di Dio Fatebenefratelli Pr. Harald Hampel Université Pierre et Marie Curie-Paris 6 Co-Directeur de thèse Pr. Alexandre Krainik Centre Hospitalier Universitaire de Grenoble Rapporteur Pr. Thomas Leyhe Hôpital Psychiatrique Universitaire, Basel Rapporteur Pr. Kelly Del Tredici Université de Ulm Examinatrice Pr Jean-Christophe Corvol Université Pierre et Marie Curie-Paris 6 Examinateur Pr. Jean Mariani Université Pierre et Marie Curie-Paris 6 Examinateur “A person who never made a mistake never tried anything new” Albert Einstein 2 Acknowledgements/Remerciements/ Ringraziamenti First of all, I would like to thank the members of the Commette that have reviewed my thesis, especially Pr Leyhe and Pr Krainik for agreeing to be rapporteurs. I am really honoured to have had them as members of the Commette. I would like to thank Pr Leyhe and Pr Del Tredici for agreeing to cross Europe in order to come to my thesis dissertation. A special thanks to all the Professors that supervised me along these three years (and more): Pr Frisoni, vorrei ringraziarla per aver creduto in me, per avermi trasmesso la sua passione per la ricerca e l’interesse per la Malattia di Alzheimer. Grazie per avermi insegnato che con passione e dedizione si possono ottenere importanti risultati. Pr Dubois, je voudrais vous remercier pour vos conseils, votre soutien, confiance et nos échanges scientifiques pendant ces annèes. Pr Hampel, thank you for your tutelage, advice, and guidance during my first year at IM2A. This was the power to allow me to do my best and to obtain valuable results. Thank you for your constant positive approach from which I have learned how tackling issues. I would like to thank all the colleagues that I met during these years; from each of them I always learn something. Thanks to my Italian colleagues: Samantha, Donata, Moira, Martina, Michela, Marina, Elena. Thanks to my colleagues in Paris: Simone, Hova, Elodie, Stèphane, Remy. Un grazie speciale alla mia famiglia, perchè mi ha sempre dato la possibilità di scegliere liberamente e di sbagliare, grazie perchè mi siete sempre stati vicini ! Grazie a Rossana, perchè in tutti questi anni siamo sempre state capaci di non perderci. Grazie perchè in ogni momento di bisogno ho la certezza che tu sei pronta ad ascoltarmi. Grazie per tutti i momenti di gioia e spensieratezza trascorsi insieme durante questi anni. Ed infine grazie a Gianluca, perchè ha avuto la forza di stravolgere la sua vita per me e per permettermi di inseguire i miei sogni. Grazie perchè mi sei sempre accanto sostenendomi e dandomi la forza e sicurezza per andare avanti. Grazie per tutti i bei momenti trascorsi insieme, e grazie per averli impressi in scatti unici ed indimenticabili nella mia mente. Grazie per la tua sensibilità e delicatezza. Grazie perchè mi hai insegnato cosa vuol dire amare. 3 TABLE OF CONTENTS ACKNOWLEDGEMENTS/REMERCIEMENTS/ RINGRAZIAMENTI 3 SUMMARY 6 RESUME 7 LIST OF ABBREVIATIONS 8 I. INTRODUCTION 10 1. WHAT IS ALZHEIMER’S DISEASE? A HISTORICAL OVERVIEW 10 2. THE GLOBAL IMPACT OF ALZHEIMER’S DISEASE 13 3. DEVELOPMENT OF DIAGNOSTIC CRITERIA FOR ALZHEIMER’S DISEASE 16 4. STRUCTURAL AND FUNCTIONAL NEUROIMAGING MARKERS OF ALZHEIMER’S DISEASE 24 4.1 STRUCTURAL NEUROIMAGING MARKERS OF AD 24 4.2 FUNCTIONAL NEUROIMAGING MARKERS OF AD 32 5. BIOMARKERS IN ALZHEIMER’S DISEASE DRUG DEVELOPMENT 37 6. STRUCTURAL AND FUNCTIONAL NEUROIMAGING MARKERS AS SURROGATE OUTCOMES IN ALZHEIMER’S DISEASE CLINICAL TRIALS 42 6.1 STRUCTURAL NEUROIMAGING MARKERS IN CLINICAL TRIALS FOR AD 42 6.2 FUNCTIONAL IMAGING MARKERS IN CLINICAL TRIALS FOR AD 48 II. MAIN OBJECTIVES 52 III. EXPERIMENTAL STUDIES 54 SECTION 1: STANDARD OPERATING PROCEDURES FOR STRUCTURAL IMAGING MARKERS IN DEMENTIA 54 STUDY 1: THE ITALIAN ALZHEIMER'S DISEASE NEUROIMAGING INITIATIVE (I-ADNI): VALIDATION OF STRUCTURAL MR IMAGING 55 SECTION 2: STRUCTURAL AND FUNCTIONAL IMAGING CORRELATES OF CHOLINESTERASE INHIBITORS USE 68 STUDY 2: DONEPEZIL DECREASES ANNUAL RATE OF HIPPOCAMPAL ATROPHY IN SUSPECTED PRODROMAL ALZHEIMER'S DISEASE 69 4 STUDY 3: REDUCED REGIONAL CORTICAL THICKNESS RATE OF CHANGE IN DONEPEZIL TREATED SUBJECTS WITH SUSPECTED PRODROMAL ALZHEIMER'S DISEASE - A LONGITUDINAL MULTI-CENTRIC DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL 79 STUDY 4: HIPPOCAMPUS AND BASAL FOREBRAIN AS PREDICTORS OF COGNITIVE DECLINE AND TREATMENT RESPONSE IN SUSPECTED PRODROMAL ALZHEIMER’S DISEASE 107 STUDY 5: EFFECTS OF RIVASTIGMINE ON VISUAL ATTENTION IN SUBJECTS WITH AMNESTIC MILD COGNITIVE IMPAIRMENT: A SERIAL FUNCTIONAL MRI ACTIVATION PILOT-STUDY 134 IV. GENERAL DISCUSSION 164 IMPLEMENTATION OF STANDARD OPERATING PROCEDURES IN A MULTICENTRE SETTING 164 IMPLEMENTATION OF NEUROIMAGING MARKERS IN PRE-DEMENTIA PREVENTION TRIALS FOR ALZHEIMER’S DISEASE 166 CONCLUSIONS AND FUTURE PERSPECTIVES 170 ANNEX 1: SUPPLEMENTARY MATERIAL STUDY 1 175 ANNEX 2: SUPPLEMENTARY MATERIAL STUDY 5 180 LIST OF PUBLICATIONS RELATED TO THE THESIS 182 GENERAL REFERENCES 184 5 Summary The development of new drugs and the validation and standardization of neuroimaging and biological markers for Alzheimer’s Disease (AD) clinical treatment trials is expected to be one of the major goals of AD research in the upcoming years. The present thesis aims to address these critical issues. The first part of the thesis is focused on the proper application of Standard Operating Procedures (SOPs) for the structural neuroimaging protocols of acquisition and the implementation of neuroimaging markers in 10 Italian Memory Clinics. The second part of the thesis deals with the application of several structural and functional neuroimaging markers in the context of clinical trials investigation in mild cognitive impairment individuals. Results revealed that the implementation of SOPs at multicentre level reduces the variance of neuroimaging markers measurement detected by different scanners. Moreover, results from the employment of neuroimaging markers in pre-dementia trials in mild cognitive impairment individuals showed a significant impact of anticholinesterase therapies in reducing the hippocampal rate of atrophy, the cortical thinning as well as in increasing the activation of brain areas related to functional Magnetic Resonance Imaging (fMRI) face and location matching tasks. These promising results support the hypothesis that structural and functional neuroimaging markers applied in a standardized manner might be utilized as candidate surrogate outcomes in future pre- dementia trials for AD. Keywords : Alzheimer’s Disease, mild cognitive impairment, neuroimaging markers, MRI, hippocampus, cortical thickness, basal forebrain, fMRI, face and location matching tasks, standard operating procedures, clinical trials, surrogate outcomes. 6 Résumé Dans les années à venir, les principaux objectifs de la recherche pour maladie d'Alzheimer (MA) sont le développement de nouveaux médicaments ainsi que la validation et la standardisation des marqueurs de neuroimagerie et de biochimie. La présente thèse vise à aborder ces questions cruciales. La première partie de la thèse fait le point sur l’application correcte des Procédures Opérationnelles Standards (SOPs) pour l'acquisition de protocoles de neuroimagerie structurelle et l’application des marqueurs de neuroimagerie cérébrale dans 10 cliniques italiennes spécialisées dans les troubles de la mémoire. La deuxième partie traite de l'application de plusieurs marqueurs de neuroimagerie structurelle et fonctionnelle dans le cadre des études cliniques sur des patients ayant des troubles précoces de la MA. Les résultats ont révélé que la mise en œuvre des SOPs pour l’acquisition des séquences d’imagerie par résonance magnétique (IRM), au niveau multicentrique, réduit la variance des mesures des marqueurs de neuroimagerie détectées par différents scanners. En outre, les résultats de la deuxième partie de la thèse ont montré que les thérapies anticholinestérasiques ont un impact significatif : réduction de l'atrophie de l'hippocampe, de l'amincissement cortical ainsi que l'augmentation de l'activation de la voie dorsale visuelle des patients ayant des troubles précoces de la MA. Ces résultats prometteurs confirment l'hypothèse que les marqueurs de neuroimagerie structurelle et fonctionnelle appliqués avec SOPs pourraient être utilisés comme critère d'évaluation substitutif dans les études cliniques pour les patients ayant des troubles précoces de la MA. Mots clés : Maladie d’Alzheimer, IRM, marqueurs de neuroimagerie, IRM fonctionnelle, hippocampe, épaisseur corticale, cerveau antérieur basal, études cliniques, Procédures Opérationnelles Standards. 7 List of Abbreviations 18F-FDG-PET 18F-fluorodeoxyglucose-PET AD Alzheimer’s Disease ADNI Alzheimer’s Disease Neuroimaging Initiative AIBL Australian Imaging, Biomarker, and Lifestyle Flagship Study of Ageing APC Annualized Percent Change APOE Apolipoprotein E APP amyloid precursor protein Aβ1-42 42 amino acid-long form of the amyloid beta peptide BF Basal Forebrain