title: Reduced Regional Cortical Thickness Rate of Change in Donepezil-Treated Subjects With Suspected Prodromal Alzheimer's Disease.
abstract: OBJECTIVE
  Cortical thinning, previously identified during prodromal stages of Alzheimer's disease (AD), is a "candidate" biomarker implemented in AD clinical therapy trials. We investigated the effect of donepezil treatment on cortical thickness in mild cognitively impaired subjects with the amnestic syndrome of the hippocampal type, a prodromal at-risk group for progression to AD dementia.
  
  
  METHODS
  Data were from a longitudinal analysis of a community-based multicenter suspected prodromal AD cohort diagnosed by the Free and Cued Selective Reminding Test (81 donepezil vs 92 placebo) enrolled in a double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day). The study started in November 2006 and concluded in August 2010. All subjects underwent 2 brain structural magnetic resonance imaging (MRI) scans, at baseline and at the end of the trial. Structural MRI images had been processed using the automated pipeline for longitudinal segmentation and surface reconstruction implemented in FreeSurfer. The primary outcome measure of this post hoc study was the annualized percentage change (APC) of cortical thickness.
  
  
  RESULTS
  The donepezil group exhibited reduced APC cortical thinning compared to placebo in the rostral anterior cingulate (right: P = .048; left: P = .032), the orbitofrontal (right: P = .012; left: P < .048), and the right inferior frontal (P = .022) cortices and in the right insula (P = .010). These results were not statistically significant after Bonferroni correction likely due to insufficient power for cortical thickness measurements in the study group powered for the predefined hippocampus outcome.
  
  
  CONCLUSIONS
  Our findings support the hypothesis that cortical thickness is a reliable candidate surrogate outcome in early predementia AD trials. In addition, donepezil treatment may have an impact on cortical structure/morphology in areas innervated by the medial and lateral cholinergic pathways.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT00403520.
authors: Université Pierre et Marie Curie, 47 Blvd de l'Hôpital, 75013 Paris, France. enrica.cavedo@gmail.com.|Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.|INSERM U1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France .|CATI multicenter neuroimaging platform (cati-neuroimaging.com), Paris, France .|IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors: Enrica
authors: E
authors: Cavedo
authors: Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.|INSERM U1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France .
authors: Bruno
authors: B
authors: Dubois
authors: Inserm, U1127, F-75013, Paris, France.|CNRS, UMR 7225 ICM, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France.|Inria, Aramis project-team, Centre de Recherche Paris-Rocquencourt, France.
authors: Olivier
authors: O
authors: Colliot
authors: Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.|INSERM U1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France .|AXA Research Fund & UPMC, Paris, France.
authors: Simone
authors: S
authors: Lista
authors: Department of Neuropsychology, Hôpital Neurologique Pierre Wertheimer, Lyon, France.
authors: Bernard
authors: B
authors: Croisile
authors: Hôpital Neurologique Pierre Wertheimer, Lyon, France.
authors: Guy Louis
authors: GL
authors: Tisserand
authors: CHRU, Gui de Chauliac, Montpellier, France.
authors: Jacques
authors: J
authors: Touchon
authors: CHRU, Gui de Chauliac, Montpellier, France.
authors: Alain
authors: A
authors: Bonafe
authors: Centre Mémoire/Centre de Recherche Clinique-Gérontopôle, Hôpital Casselardit, Toulouse, France.
authors: Pierre J
authors: PJ
authors: Ousset
authors: Hôpital General, Dijon, France.
authors: Olivier
authors: O
authors: Rouaud
authors: Hôpital General, Dijon, France.
authors: Fréderic
authors: F
authors: Ricolfi
authors: Lyon 1 University, Hospices Civils de Lyon, Hôpital neurologique, Service de Neurologie D, Lyon, France.
authors: Alain
authors: A
authors: Vighetto
authors: Université de Lille, Inserm U1171, CHU, Centre Mémoire, 59000, Lille, France.
authors: Florence
authors: F
authors: Pasquier
authors: IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Brescia, Italy.
authors: Samantha
authors: S
authors: Galluzzi
authors: Université de Lille, Inserm U1171, Service de Neuroradiologie, Hôpital Roger Salengro, Lille, France.
authors: Christine
authors: C
authors: Delmaire
authors: Hôpital de la Timone, Marseille, France.
authors: Mathieu
authors: M
authors: Ceccaldi
authors: Hôpital de la Timone, Marseille, France.
authors: Nadine
authors: N
authors: Girard
authors: INSERM U1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France .|CENIR, Neuroimaging Unit, ICM, Hôpital de la Salpêtriere, Paris, France.
authors: Stéphane
authors: S
authors: Lehericy
authors: Eisai SAS, La Defense 2 Cedex, France.
authors: Françoise
authors: F
authors: Duveau
authors: Inserm, U1127, F-75013, Paris, France.|CNRS, UMR 7225 ICM, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France.|Inria, Aramis project-team, Centre de Recherche Paris-Rocquencourt, France.
authors: Marie
authors: M
authors: Chupin
authors: Neurologie de la Mémoire et du Langage, Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France.
authors: Marie
authors: M
authors: Sarazin
authors: Inserm, U1127, F-75013, Paris, France.|CNRS, UMR 7225 ICM, 75013, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France.|Institut du Cerveau et de la Moelle Épinière, ICM, F-75013, Paris, France.|Neuroradiology Department, Hôpital de la Salpêtriere, Paris, France.
authors: Didier
authors: D
authors: Dormont
authors: Institut de la Mémoire et de la Maladie d'Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.|INSERM U1127, Institut du Cerveau et de la Moelle Épinière (ICM), Paris, France.|Sorbonne Universités, Université Pierre et Marie Curie-Paris 6, Paris, France .|AXA Research Fund & UPMC, Paris, France.
authors: Harald
authors: H
authors: Hampel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000188:drug therapy*; D000647:Amnesia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging* / Q000187:drug effects; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging / Q000188:drug therapy*; D018450:Disease Progression; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000494:pharmacology*; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D062706:Prodromal Symptoms
chemical_list: D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil