title: Predictors of cognitive decline and treatment response in a clinical trial on suspected prodromal Alzheimer's disease.
abstract: We determined the value of hippocampus (Hp) and basal forebrain (BF) volumes for predicting cognitive decline and treatment response in a double-blind, randomized, placebo-controlled phase 4 trial at 28 academic centers (France) in patients with amnestic mild cognitive impairment (MCI) receiving Donepezil 10 mg daily or placebo over 12 months, and 6 months open label follow-up. Outcome measures were the rates of global and domain specific cognitive decline as non-primary efficacy endpoint. The intention-to-treat (ITT) sample analyzed comprised 215 cases. Baseline Hp volume was a significant predictor of rates of change in global cognitive function in linear mixed effects models. This effect was independent of treatment. BF volume was not associated with rates of global or domain specific cognitive decline. Rates of delayed free recall decline were higher in MCI cases treated with donepezil compared to placebo. Only Hp, but not BF volume was a useful predictor of cognitive decline in suspected prodromal AD patients. Both Hp and BF volumes were poor predictors of treatment response, questioning previous approaches on predicting treatment response without placebo control.
  
  
  
  clinicalTrials.gov Identifier NCT00403520.
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) - Rostock/Greifswald, Rostock, Germany; Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany. Electronic address: stefan.teipel@med.uni-rostock.de.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Teipel
authors.affiliation: Institut de la Memoire et de la Maladie d'Alzheimer (IM2A), Departement de Neurologie, Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France; INSERM U1127, Institut du Cerveau et de la Moelle Epiniere (ICM), Paris, France; Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France; CATI Multicenter Neuroimaging Platform, France; IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Cavedo
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE) - Rostock/Greifswald, Rostock, Germany; Department of Psychosomatic Medicine, University of Rostock, Rostock, Germany.
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Grothe
authors.affiliation: Institut de la Memoire et de la Maladie d'Alzheimer (IM2A), Departement de Neurologie, Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France; INSERM U1127, Institut du Cerveau et de la Moelle Epiniere (ICM), Paris, France; Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France; AXA Research Fund & UPMC Chair, Paris, France.
authors.forename: Simone
authors.initials: S
authors.lastname: Lista
authors.affiliation: IRCCS Istituto Centro San Giovanni di Dio-Fatebenefratelli, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Galluzzi
authors.affiliation: 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.forename: Olivier
authors.initials: O
authors.lastname: Colliot
authors.affiliation: 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.forename: Marie
authors.initials: M
authors.lastname: Chupin
authors.affiliation: Institut de la Memoire et de la Maladie d'Alzheimer (IM2A), Departement de Neurologie, Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France; IHU-A-ICM - Paris Institute of Translational Neurosciences, Paris, France.
authors.forename: Hovagim
authors.initials: H
authors.lastname: Bakardjian
authors.affiliation: 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.forename: Didier
authors.initials: D
authors.lastname: Dormont
authors.affiliation: Institut de la Memoire et de la Maladie d'Alzheimer (IM2A), Departement de Neurologie, Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France; INSERM U1127, Institut du Cerveau et de la Moelle Epiniere (ICM), Paris, France; Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Institut de la Memoire et de la Maladie d'Alzheimer (IM2A), Departement de Neurologie, Hôpital de la Pitie-Salpêtriere, AP-HP, Paris, France; INSERM U1127, Institut du Cerveau et de la Moelle Epiniere (ICM), Paris, France; Sorbonne Universites, Universite Pierre et Marie Curie-Paris 6, Paris, France; AXA Research Fund & UPMC Chair, Paris, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000523:psychology; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000523:psychology; D003430:Cross-Sectional Studies; D018450:Disease Progression; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007189:Indans / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging / Q000639:trends; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use; D010880:Piperidines / Q000627:therapeutic use; D011237:Predictive Value of Tests; D062706:Prodromal Symptoms; D016896:Treatment Outcome
chemical_list: D007189:Indans; D018697:Nootropic Agents; D010880:Piperidines; D000077265:Donepezil
keywords: Basal forebrain; Biomarkers; Cholinergic system; Cholinesterase inhibitors; Cognitive decline; Hippocampus; MCI; MRI; Prediction; Prodromal Alzheimer's disease; Therapy