Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'

S Galluzzi; M Marizzoni; C Babiloni; D Albani; L Antelmi; C Bagnoli; D Bartres-Faz; S Cordone; M Didic; L Farotti; U Fiedler; G Forloni; N Girtler; T Hensch; J Jovicich; A Leeuwis; C Marra; J L Molinuevo; F Nobili; J Pariente; L Parnetti; P Payoux; C Del Percio; J-P Ranjeva; E Rolandi; P M Rossini; P Schönknecht; A Soricelli; M Tsolaki; P J Visser; J Wiltfang; J C Richardson; R Bordet; O Blin; G B Frisoni; PharmaCog Consortium

doi:10.1111/joim.12482

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'

J Intern Med. 2016 Jun;279(6):576-91. doi: 10.1111/joim.12482. Epub 2016 Mar 4.

Authors

S Galluzzi¹, M Marizzoni¹, C Babiloni^{2

3}, D Albani⁴, L Antelmi¹, C Bagnoli¹, D Bartres-Faz⁵, S Cordone², M Didic^{6

7}, L Farotti⁸, U Fiedler⁹, G Forloni⁴, N Girtler¹⁰, T Hensch¹¹, J Jovicich¹², A Leeuwis¹³, C Marra¹⁴, J L Molinuevo¹⁵, F Nobili¹⁰, J Pariente¹⁶, L Parnetti⁸, P Payoux¹⁶, C Del Percio¹⁷, J-P Ranjeva^{6

7}, E Rolandi¹, P M Rossini¹⁴, P Schönknecht¹¹, A Soricelli¹⁷, M Tsolaki¹⁸, P J Visser¹³, J Wiltfang^{9

19}, J C Richardson²⁰, R Bordet²¹, O Blin²², G B Frisoni^{1

23}; PharmaCog Consortium

Affiliations

¹ Laboratory of Alzheimer's Neuroimaging & Epidemiology, Saint John of God Clinical Research Centre, Brescia, Italy.
² Department of Physiology and Pharmacology, University of Rome 'La Sapienza', Rome, Italy.
³ IRCCS San Raffaele Pisana of Rome, Rome, Italy.
⁴ Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milan, Italy.
⁵ 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.
⁶ Aix-Marseille Université, INSERM, Marseille, France.
⁷ Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.
⁸ Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy.
⁹ Department of Psychiatry and Psychotherapy, Faculty of Medicine, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany.
¹⁰ Clinical Neurology, Department of Neurosciences, Rehabilitation, Ophthalmology and Maternal-Fetal Medicine, University of Genoa, Genoa, Italy.
¹¹ Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
¹² Center for Mind/Brain Sciences, University of Trento, Trento, Italy.
¹³ Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, the Netherlands.
¹⁴ Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Italy.
¹⁵ Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, and IDIBAPS, Barcelona, Catalunya, Spain.
¹⁶ INSERM, Imagerie Cérébrale et Handicaps Neurologiques, Toulouse, France.
¹⁷ SDN Istituto di Ricerca Diagnostica e Nucleare, Naples, Italy.
¹⁸ Third Neurologic Clinic, Medical School, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
¹⁹ Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-University, Goettingen, Germany.
²⁰ Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Stevenage, UK.
²¹ University of Lille, Inserm, CHU Lille, U1171 - Degenerative and Vascular Cognitive Disorders, Lille, France.
²² Mediterranean Institute of Cognitive Neurosciences, Aix Marseille University, Marseille, France.
²³ Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland.

PMID: 26940242
DOI: 10.1111/joim.12482

Abstract

Background: 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.

Objective: 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).

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: biomarkers; electroencephalography; magnetic resonance imaging; mild cognitive impairment; prodromal AD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / diagnosis*
Alzheimer Disease / diagnostic imaging
Alzheimer Disease / genetics
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoproteins E / genetics
Biomarkers / cerebrospinal fluid
Brain / diagnostic imaging
Electroencephalography
Female
Genotype
Humans
Magnetic Resonance Imaging
Male
Neuropsychological Tests
Peptide Fragments / cerebrospinal fluid
Spinal Puncture
tau Proteins / cerebrospinal fluid

Substances

Amyloid beta-Peptides
Apolipoproteins E
Biomarkers
Peptide Fragments
amyloid beta-protein (1-40)
tau Proteins