Predicting and Tracking Short Term Disease Progression in Amnestic Mild Cognitive Impairment Patients with Prodromal Alzheimer’s Disease: Structural Brain Biomarkers
Moira Marizzoni
(1)
,
Clarissa Ferrari
(1)
,
Jorge Jovicich
(2)
,
Diego Albani
(3)
,
Claudio Babiloni
(4, 5)
,
Libera Cavaliere
(1)
,
Mira Didic
(6, 7)
,
Gianluigi Forloni
(3)
,
Samantha Galluzzi
(1)
,
Karl-Titus Hoffmann
(8)
,
José Luis Molinuevo
(9)
,
Flavio Nobili
(10)
,
Lucilla Parnetti
(11)
,
Pierre Payoux
(12)
,
Federica Ribaldi
(1, 13)
,
Paolo Maria Rossini
(14)
,
Peter Schönknecht
(8)
,
Marco Salvatore
(15)
,
Andrea Soricelli
(15)
,
Tilman Hensch
(8)
,
Magda Tsolaki
(16)
,
Pieter Jelle Visser
(17)
,
Jens Wiltfang
(18, 19, 20)
,
Jill Richardson
(21)
,
Régis Bordet
(22, 23)
,
Olivier Blin
(24, 25)
,
Giovanni Frisoni
(1, 26)
1
Istituto Centro San Giovanni di Dio Fatebenefratelli
2 UNITN - Università degli Studi di Trento = University of Trento
3 IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" = Mario Negri Institute for Pharmacological Research
4 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
5 San Raffaele Pisana IRCCS
6 INS - Institut de Neurosciences des Systèmes
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 Leipzig University / Universität Leipzig
9 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
10 UniGe - Università degli studi di Genova = University of Genoa
11 UNIPG - Università degli Studi di Perugia = University of Perugia
12 ICHN - Imagerie cérébrale et handicaps neurologiques
13 UniBs - Università degli Studi di Brescia = University of Brescia
14 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
15 SDN - Istituto di Ricerca Diagnostica e Nucleare
16 Aristotle University of Thessaloniki
17 Amsterdam UMC - Amsterdam University Medical Centers
18 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
19 Georg-August-University = Georg-August-Universität Göttingen
20 Universidade de Aveiro
21 GSK - GlaxoSmithKline [Stevenage, UK]
22 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
23 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
24 INT - Institut de Neurosciences de la Timone
25 APHM - Assistance Publique - Hôpitaux de Marseille
26 UNIGE - Université de Genève = University of Geneva
2 UNITN - Università degli Studi di Trento = University of Trento
3 IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri" = Mario Negri Institute for Pharmacological Research
4 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
5 San Raffaele Pisana IRCCS
6 INS - Institut de Neurosciences des Systèmes
7 TIMONE - Hôpital de la Timone [CHU - APHM]
8 Leipzig University / Universität Leipzig
9 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
10 UniGe - Università degli studi di Genova = University of Genoa
11 UNIPG - Università degli Studi di Perugia = University of Perugia
12 ICHN - Imagerie cérébrale et handicaps neurologiques
13 UniBs - Università degli Studi di Brescia = University of Brescia
14 Unicatt - Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma]
15 SDN - Istituto di Ricerca Diagnostica e Nucleare
16 Aristotle University of Thessaloniki
17 Amsterdam UMC - Amsterdam University Medical Centers
18 Universität Duisburg-Essen = University of Duisburg-Essen [Essen]
19 Georg-August-University = Georg-August-Universität Göttingen
20 Universidade de Aveiro
21 GSK - GlaxoSmithKline [Stevenage, UK]
22 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
23 TCDV - Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046
24 INT - Institut de Neurosciences de la Timone
25 APHM - Assistance Publique - Hôpitaux de Marseille
26 UNIGE - Université de Genève = University of Geneva
Moira Marizzoni
- Fonction : Auteur
- PersonId : 780185
- ORCID : 0000-0003-3749-2988
Jorge Jovicich
- Fonction : Auteur
- PersonId : 780184
- ORCID : 0000-0001-9504-7503
Diego Albani
- Fonction : Auteur
- PersonId : 785158
- ORCID : 0000-0002-7050-6723
Claudio Babiloni
- Fonction : Auteur
- PersonId : 780628
- ORCID : 0000-0002-5245-9839
Mira Didic
- Fonction : Auteur
- PersonId : 757436
- ORCID : 0000-0001-7067-536X
Flavio Nobili
- Fonction : Auteur
- PersonId : 785159
- ORCID : 0000-0001-9811-0897
Pierre Payoux
- Fonction : Auteur
- PersonId : 173132
- IdHAL : pierre-payoux
- ORCID : 0000-0002-1374-1620
- IdRef : 094640149
Tilman Hensch
- Fonction : Auteur
- PersonId : 780187
- ORCID : 0000-0003-2696-6017
Pieter Jelle Visser
- Fonction : Auteur
- PersonId : 785160
- ORCID : 0000-0001-8008-9727
Jens Wiltfang
- Fonction : Auteur
- PersonId : 776430
- ORCID : 0000-0003-1492-5330
Olivier Blin
- Fonction : Auteur
- PersonId : 780347
- ORCID : 0000-0003-0142-0931
Giovanni Frisoni
- Fonction : Auteur
- PersonId : 768850
- ORCID : 0000-0001-7075-7082
Résumé
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.