title: Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.
abstract: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest.
  
  
  
  To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study).
  
  
  
  A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1-42 (Aβ42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated.
  
  
  
  Prodromal AD was found in 55 aMCI patients defined by low Aβ42 in the cerebrospinal fluid (Aβ positive). Compared to the aMCI group with high Aβ42 levels (Aβ negative), Aβ positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03).
  
  
  
  These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Galluzzi
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Marizzoni
authors.affiliation: Department of Physiology and Pharmacology, University of Rome 'La Sapienza', Rome, Italy.|IRCCS San Raffaele Pisana of Rome, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Babiloni
authors.affiliation: Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Albani
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Antelmi
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Bagnoli
authors.affiliation: Department of Psychiatry and Clinical Psychobiology, Faculty of Medicine, University of Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Bartres-Faz
authors.affiliation: Department of Physiology and Pharmacology, University of Rome 'La Sapienza', Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cordone
authors.affiliation: Aix-Marseille Université, INSERM, Marseille, France.|Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Didic
authors.affiliation: Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Farotti
authors.affiliation: Department of Psychiatry and Psychotherapy, Faculty of Medicine, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Fiedler
authors.affiliation: Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Forloni
authors.affiliation: Clinical Neurology, Department of Neurosciences, Rehabilitation, Ophthalmology and Maternal-Fetal Medicine, University of Genoa, Genoa, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Girtler
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hensch
authors.affiliation: Center for Mind/Brain Sciences, University of Trento, Trento, Italy.
authors.forename: J
authors.initials: J
authors.lastname: Jovicich
authors.affiliation: Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Leeuwis
authors.affiliation: Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Marra
authors.affiliation: Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, and IDIBAPS, Barcelona, Catalunya, Spain.
authors.forename: J L
authors.initials: JL
authors.lastname: Molinuevo
authors.affiliation: Clinical Neurology, Department of Neurosciences, Rehabilitation, Ophthalmology and Maternal-Fetal Medicine, University of Genoa, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Nobili
authors.affiliation: INSERM, Imagerie Cérébrale et Handicaps Neurologiques, Toulouse, France.
authors.forename: J
authors.initials: J
authors.lastname: Pariente
authors.affiliation: Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Parnetti
authors.affiliation: INSERM, Imagerie Cérébrale et Handicaps Neurologiques, Toulouse, France.
authors.forename: P
authors.initials: P
authors.lastname: Payoux
authors.affiliation: SDN Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Del Percio
authors.affiliation: Aix-Marseille Université, INSERM, Marseille, France.|Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.
authors.forename: J-P
authors.initials: JP
authors.lastname: Ranjeva
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Rolandi
authors.affiliation: Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Italy.
authors.forename: P M
authors.initials: PM
authors.lastname: Rossini
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Schönknecht
authors.affiliation: SDN Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Soricelli
authors.affiliation: Third Neurologic Clinic, Medical School, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Tsolaki
authors.affiliation: Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, the Netherlands.
authors.forename: P J
authors.initials: PJ
authors.lastname: Visser
authors.affiliation: Department of Psychiatry and Psychotherapy, Faculty of Medicine, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany.|Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Goettingen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Wiltfang
authors.affiliation: Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
authors.forename: J C
authors.initials: JC
authors.lastname: Richardson
authors.affiliation: University of Lille, Inserm, CHU Lille, U1171 - Degenerative and Vascular Cognitive Disorders, Lille, France.
authors.forename: R
authors.initials: R
authors.lastname: Bordet
authors.affiliation: Mediterranean Institute of Cognitive Neurosciences, Aix Marseille University, Marseille, France.
authors.forename: O
authors.initials: O
authors.lastname: Blin
authors.affiliation: Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.|Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland.
authors.forename: G B
authors.initials: GB
authors.lastname: Frisoni
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000000981:diagnostic imaging; D004569:Electroencephalography; D005260:Female; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D013129:Spinal Puncture; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D015415:Biomarkers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D016875:tau Proteins
keywords: biomarkers; electroencephalography; magnetic resonance imaging; mild cognitive impairment; prodromal AD