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J Alzheimers Dis. 2018 Oct 29. doi: 10.3233/JAD-180158. [Epub ahead of print]

Two-Year Longitudinal Monitoring of Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease Using Topographical Biomarkers Derived from Functional Magnetic Resonance Imaging and Electroencephalographic Activity.

Author information

1
Center for Mind/Brain Sciences, University of Trento, Italy.
2
Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Rome, Italy.
3
Department of Neuroscience, IRCCS-Hospital San Raffaele Pisana of Rome and Cassino, Rome and Cassino, Italy.
4
Unit of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
5
Lab Alzheimer's Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
6
Alzheimer's Epidemiology and Rehabilitation in Alzheimer's disease Operative Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
7
IRCCS SDN, Napoli, Italy.
8
Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
9
Aix-Marseille Université, INSERM, INS UMR_S 1106, Marseille, France; Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.
10
APHM, Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France.
11
Department of Psychiatry and Psychotherapy, LVR-Hospital Essen, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
12
Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
13
Alzheimer's disease and other cognitive disorders unit, Neurology Service, ICN Hospital Clinic i Universitari and Pasqual Maragall Foundation Barcelona, Spain.
14
Department of Medicine, Medical Psychology Unit, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
15
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
16
Department of Neuroscience (DINOGMI), Neurology Clinic, University of Genoa, Italy.
17
U.O. Clinica Neurologica, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
18
Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy.
19
ToNIC, Toulouse NeuroImaging Center, Université de Toulouse, Inserm, UPS, France.
20
Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Policlinic A. Gemelli Foundation-IRCCS, Rome, Italy.
21
1st University Department of Neurology, AHEPA Hospital, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Makedonia, Greece.
22
Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands.
23
Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, UK.
24
Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Goettingen, Germany.
25
University of Lille, Inserm, CHU Lille, U1171 - Degenerative and vascular cognitive disorders, Lille, France.
26
Aix Marseille University, UMR-CNRS 7289, Service de Pharmacologie Clinique, AP-HM, Marseille, France.
27
Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland.

Abstract

Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD"; n = 81) or "negative" (n = 63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ42/P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group×Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p <  0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (<4 Hz) and theta (4-8 Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time×Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to "negative" aMCI patients based on 5 serial recording sessions over 2 years.

KEYWORDS:

Alpha rhythms; PharmaCog project; amnesic mild cognitive impairment; biomarkers; clinical trial; electroencephalography; functional magnetic resonance imaging; oddball event-related potentials; prodromal Alzheimer’s disease; resting state

PMID:
30400088
DOI:
10.3233/JAD-180158

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