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

Jorge Jovicich, Claudio Babiloni, Clarissa Ferrari, Moira Marizzoni, Davide V. Moretti, Claudio Del Percio, Roberta Lizio, Susanna Lopez, Samantha Galluzzi, Diego Albani, Libera Cavaliere, Ludovico Minati, Mira Didic, Ute Fiedler, Gianluigi Forloni, Tilman Hensch, José Luis Molinuevo, David Bartrés Faz, Flavio Nobili, Daniele OrlandiLucilla Parnetti, Lucia Farotti, Cinzia Costa, Pierre Payoux, Paolo Maria Rossini, Camillo Marra, Peter Schönknecht, Andrea Soricelli, Giuseppe Noce, Marco Salvatore, Magda Tsolaki, Pieter Jelle Visser, Jill C. Richardson, Jens Wiltfang, Régis Bordet, Olivier Blin, Giovanni B. Frisoniand

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32 Citations (Scopus)


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 (Aβ 42 /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 (<4Hz) and theta (4-8Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5Hz) 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.

Original languageEnglish
Pages (from-to)15-35
Number of pages21
JournalJournal of Alzheimer's Disease
Issue number1
Publication statusPublished - 1 Jan 2019


  • 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

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