Predicting and tracking short term disease progression in amnestic mild cognitive impairment patients with prodromal Alzheimer's disease: Structural brain biomarkers

Moira Marizzoni, Clarissa Ferrari, Jorge Jovicich, Diego Albani, Claudio Babiloni, Libera Cavaliere, Mira Didic, Gianluigi Forloni, Samantha Galluzzi, Karl Titus Hoffmann, José Luis Molinuevo, Flavio Nobili, Lucilla Parnetti, Pierre Payoux, Federica Ribaldi, Paolo Maria Rossini, Peter Schönknecht, Marco Salvatore, Andrea Soricelli, Tilman HenschMagda Tsolaki, Pieter Jelle Visser, Jens Wiltfang, Jill C. Richardson, Régis Bordet, Olivier Blin, Giovanni B. Frisoni

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17 Citations (Scopus)


Background: Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. Objective: To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. Methods: APOE ϵ4 specific CSF Aβ 42 /P-tau cut-offs were used to identify MCI with prodromal AD (Aβ 42 /P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ 42 /P-tau status, time, and Aβ 42 /P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Results: Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients who declined faster (interaction, p = 0.003). Lateral ventricle volume and medial temporal lobe measures were the biomarkers most sensitive to disease progression (interaction, p≤0.042). Enrichment through ventricular volume reduced the sample size that a clinical trial would require from 13 to 76%, depending on structural outcome variable. The biomarker needing the lowest sample size was the hippocampal subfield GC-ML-DG (granule cells of molecular layer of the dentate gyrus) (n = 82 per arm to demonstrate a 20% atrophy reduction). Conclusion: MRI structural biomarkers can enrich prodromal AD with fast progressors and significantly decrease group size in clinical trials of disease modifying drugs.

Original languageEnglish
Pages (from-to)3-14
Number of pages12
JournalJournal of Alzheimer's Disease
Issue number1
Publication statusPublished - 1 Jan 2019


  • Alzheimer's disease
  • biomarkers
  • clinical trial
  • magnetic resonance imaging
  • mild cognitive impairment
  • precision medicine

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