Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease: Structural Brain Biomarkers

PharmaCog Consortium, 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, Andrea Soricelli, Tilman HenschMagda Tsolaki, Pieter Jelle Visser, Jens Wiltfang, Jill C Richardson, Régis Bordet, Olivier Blin, Giovanni B Frisoni

Research output: Contribution to journalArticlepeer-review


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 ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/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 Aβ42/P-tau status, time, and Aβ42/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 languageItalian
Pages (from-to)3-14
JournalJournal of Alzheimer's Disease
Publication statusPublished - Jun 9 2019

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