TY - JOUR
T1 - Predicting and tracking short term disease progression in amnestic mild cognitive impairment patients with prodromal Alzheimer's disease
T2 - Structural brain biomarkers
AU - Marizzoni, Moira
AU - Ferrari, Clarissa
AU - Jovicich, Jorge
AU - Albani, Diego
AU - Babiloni, Claudio
AU - Cavaliere, Libera
AU - Didic, Mira
AU - Forloni, Gianluigi
AU - Galluzzi, Samantha
AU - Hoffmann, Karl Titus
AU - Molinuevo, José Luis
AU - Nobili, Flavio
AU - Parnetti, Lucilla
AU - Payoux, Pierre
AU - Ribaldi, Federica
AU - Rossini, Paolo Maria
AU - Schönknecht, Peter
AU - Salvatore, Marco
AU - Soricelli, Andrea
AU - Hensch, Tilman
AU - Tsolaki, Magda
AU - Visser, Pieter Jelle
AU - Wiltfang, Jens
AU - Richardson, Jill C.
AU - Bordet, Régis
AU - Blin, Olivier
AU - Frisoni, Giovanni B.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - biomarkers
KW - clinical trial
KW - magnetic resonance imaging
KW - mild cognitive impairment
KW - precision medicine
UR - http://www.scopus.com/inward/record.url?scp=85065674049&partnerID=8YFLogxK
U2 - 10.3233/JAD-180152
DO - 10.3233/JAD-180152
M3 - Article
C2 - 29914031
AN - SCOPUS:85065674049
VL - 69
SP - 3
EP - 14
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - 1
ER -