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

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 journalArticle

Abstract

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 languageEnglish
JournalJournal of Alzheimer's Disease
DOIs
Publication statusPublished - Jun 9 2018

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Disease Progression
Alzheimer Disease
Biomarkers
Sample Size
Lateral Ventricles
Cerebrospinal Fluid
Clinical Trials
Dentate Gyrus
Temporal Lobe
Cognitive Dysfunction
Patient Selection
Atrophy
Early Diagnosis
Linear Models
Pharmaceutical Preparations

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Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease. / Consortium, PharmaCog; Marizzoni, Moira; Ferrari, Clarissa; Jovicich, Jorge; Albani, Diego; Babiloni, Claudio; Cavaliere, Libera; Didic, Mira; Forloni, Gianluigi; Galluzzi, Samantha; Hoffmann, Karl-Titus; Molinuevo, José Luis; Nobili, Flavio; Parnetti, Lucilla; Payoux, Pierre; Ribaldi, Federica; Rossini, Paolo Maria; Schönknecht, Peter; Soricelli, Andrea; Hensch, Tilman; Tsolaki, Magda; Visser, Pieter Jelle; Wiltfang, Jens; Richardson, Jill C; Bordet, Régis; Blin, Olivier; Frisoni, Giovanni B.

In: Journal of Alzheimer's Disease, 09.06.2018.

Research output: Contribution to journalArticle

Consortium, P, Marizzoni, M, Ferrari, C, Jovicich, J, Albani, D, Babiloni, C, Cavaliere, L, Didic, M, Forloni, G, Galluzzi, S, Hoffmann, K-T, Molinuevo, JL, Nobili, F, Parnetti, L, Payoux, P, Ribaldi, F, Rossini, PM, Schönknecht, P, Soricelli, A, Hensch, T, Tsolaki, M, Visser, PJ, Wiltfang, J, Richardson, JC, Bordet, R, Blin, O & Frisoni, GB 2018, 'Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease', Journal of Alzheimer's Disease. https://doi.org/10.3233/JAD-180152
Consortium, PharmaCog ; Marizzoni, Moira ; Ferrari, Clarissa ; Jovicich, Jorge ; Albani, Diego ; Babiloni, Claudio ; Cavaliere, Libera ; Didic, Mira ; Forloni, Gianluigi ; Galluzzi, Samantha ; Hoffmann, Karl-Titus ; Molinuevo, José Luis ; Nobili, Flavio ; Parnetti, Lucilla ; Payoux, Pierre ; Ribaldi, Federica ; Rossini, Paolo Maria ; Schönknecht, Peter ; Soricelli, Andrea ; Hensch, Tilman ; Tsolaki, Magda ; Visser, Pieter Jelle ; Wiltfang, Jens ; Richardson, Jill C ; Bordet, Régis ; Blin, Olivier ; Frisoni, Giovanni B. / Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease. In: Journal of Alzheimer's Disease. 2018.
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abstract = "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.",
author = "PharmaCog Consortium and Moira Marizzoni and Clarissa Ferrari and Jorge Jovicich and Diego Albani and Claudio Babiloni and Libera Cavaliere and Mira Didic and Gianluigi Forloni and Samantha Galluzzi and Karl-Titus Hoffmann and Molinuevo, {Jos{\'e} Luis} and Flavio Nobili and Lucilla Parnetti and Pierre Payoux and Federica Ribaldi and Rossini, {Paolo Maria} and Peter Sch{\"o}nknecht and Andrea Soricelli and Tilman Hensch and Magda Tsolaki and Visser, {Pieter Jelle} and Jens Wiltfang and Richardson, {Jill C} and R{\'e}gis Bordet and Olivier Blin and Frisoni, {Giovanni B}",
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TY - JOUR

T1 - Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer's Disease

AU - Consortium, PharmaCog

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 - 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 - 2018/6/9

Y1 - 2018/6/9

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 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.

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 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.

U2 - 10.3233/JAD-180152

DO - 10.3233/JAD-180152

M3 - Article

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

ER -