Abstract
Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.
| Original language | English |
|---|---|
| Pages (from-to) | 940-950 |
| Number of pages | 11 |
| Journal | Alzheimer's and Dementia |
| Volume | 15 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 2019 |
Keywords
- Alzheimer's disease
- Brain functional dynamics
- Precision medicine
- Subjective memory complaints
- fMRI
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Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease. / INSIGHT-preAD Study Group; Alzheimer Precision Medicine Initiative (APMI).
In: Alzheimer's and Dementia, Vol. 15, No. 7, 07.2019, p. 940-950.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Differential default mode network trajectories in asymptomatic individuals at risk for Alzheimer's disease
AU - INSIGHT-preAD Study Group
AU - Alzheimer Precision Medicine Initiative (APMI)
AU - Chiesa, Patrizia A.
AU - Cavedo, Enrica
AU - Vergallo, Andrea
AU - Lista, Simone
AU - Potier, Marie Claude
AU - Habert, Marie Odile
AU - Dubois, Bruno
AU - Thiebaut de Schotten, Michel
AU - Hampel, Harald
AU - Bakardjian, Hovagim
AU - Benali, Habib
AU - Bertin, Hugo
AU - Bonheur, Joel
AU - Boukadida, Laurie
AU - Boukerrou, Nadia
AU - Chiesa, Patrizia
AU - Colliot, Olivier
AU - Dubois, Marion
AU - Epelbaum, Stéphane
AU - Gagliardi, Geoffroy
AU - Genthon, Remy
AU - Houot, Marion
AU - Kas, Aurélie
AU - Lamari, Foudil
AU - Levy, Marcel
AU - Metzinger, Christiane
AU - Mochel, Fanny
AU - Nyasse, Francis
AU - Poisson, Catherine
AU - Revillon, Marie
AU - Santos, Antonio
AU - Andrade, Katia Santos
AU - Sole, Marine
AU - Surtee, Mohmed
AU - de Schotten, Michel Thiebaud
AU - Younsi, Nadjia
AU - Afshar, Mohammad
AU - Aguilar, Lisi Flores
AU - Akman-Anderson, Leyla
AU - Arenas, Joaquín
AU - Avila, Jesus
AU - Babiloni, Claudio
AU - Baldacci, Filippo
AU - Batrla, Richard
AU - Benda, Norbert
AU - Black, Keith L.
AU - Bokde, Arun L.W.
AU - Bonuccelli, Ubaldo
AU - Broich, Karl
AU - O'Bryant, Sid E.
N1 - Funding Information: This publication is within the framework of the Program “MIDAS” led by the Sorbonne University Foundation and sponsored by MSDAVENIR. Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the ?Investissement d'Avenir? (ANR-10-AIHU-06). The study was promoted in collaboration with the ?CHU de Bordeaux? (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/Lilly. The research leading to these results was supported by the Colam Initiatives and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. This publication benefited from the support of the Program ?PHOENIX? led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. Michel Thiebaut de Schotten is supported by the ?AgenceNationale de la Recherche? (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). H.H. is supported by the AXA Research Fund, the ?Fondation partenariale Sorbonne Universit?? and the ?Fondation pour la Recherchesur Alzheimer,? Paris, France. Ce travail a b?n?fici? d'une aide de l'Etat ?Investissements d'avenir? ANR-10-IAIHU-06. The research leading to these results has received funding from the program ?Investissements d'avenir? ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Author contributions: P.A.C. E.C. B.D. H.H. and M.T.S. have contributed to the conception and design of the study. P.A.C. E.C. M.C.P. M.O.H. and M.T.S. have contributed to acquisition and analysis of data. P.A.C. A.V. E.C. S.L. M.T.S. and H.H. have contributed to drafting and revising a significant portion of the manuscript. Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Patent number: 8916388. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Patent number: 8298784. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20120196300. ?In vitro multiparameter determination method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100062463. ?In vitro method for the diagnosis and early diagnosis of neurodegenerative disorders. Publication number: 20100035286. ?In vitro procedure for diagnosis and early diagnosis of neurodegenerative diseases. Publication number: 20090263822. ?In vitro method for the diagnosis of neurodegenerative diseases. Patent number: 7547553. ?Cerebrospinal fluid diagnostic in vitro method for diagnosis of dementias and neuroinflammatory diseases. Publication number: 20080206797. ?In vitro method for the diagnosis of neurodegenerative diseases. Publication number: 20080199966. ?Neurodegenerative markers for psychiatric conditions. Publication number: 20080131921., INSIGHT-preAD Study Group: Hovagim Bakardjian, Habib Benali, Hugo Bertin, Joel Bonheur, Laurie Boukadida, Nadia Boukerrou, Enrica Cavedo, Patrizia Chiesa, Olivier Colliot, Bruno Dubois, Marion Dubois, St?phane Epelbaum, Geoffroy Gagliardi, Remy Genthon, Marie-Odile Habert, Harald Hampel, Marion Houot, Aur?lie Kas, Foudil Lamari, Marcel Levy, Simone Lista, Christiane Metzinger, Fanny Mochel, Francis Nyasse, Catherine Poisson, Marie-Claude Potier, Marie Revillon, Antonio Santos, Katia Santos Andrade, Marine Sole, Mohmed Surtee, Michel Thiebaud de Schotten, Andrea Vergallo, Nadjia Younsi. INSIGHT-preAD Scientific Committee Members: Dubois B, Hampel H, Bakardjian H, Colliot O, Habert MO, Lamari F, Mochel F, Potier MC, Thiebaut de Schotten M. Contributors to the Alzheimer precision medicine initiative?working group (APMI?WG): Mohammad Afshar (Paris), Lisi Flores Aguilar (Montr?al), Leyla Akman-Anderson (Sacramento), Joaqu?n Arenas (Madrid), Jesus Avila (Madrid), Claudio Babiloni (Rome), Filippo Baldacci (Pisa), Richard Batrla (Rotkreuz), Norbert Benda (Bonn), Keith L. Black (Los Angeles), Arun L.W. Bokde (Dublin), Ubaldo Bonuccelli (Pisa), Karl Broich (Bonn), Francesco Cacciola (Siena), Filippo Caraci (Catania), Juan Castrillo ? (Derio), Enrica Cavedo (Paris), Roberto Ceravolo (Pisa), Patrizia A. Chiesa (Paris), Jean-Christophe Corvol (Paris), Augusto Claudio Cuello (Montr?al), Jeffrey L. Cummings (Las Vegas), Herman Depypere (Gent), Bruno Dubois (Paris), Andrea Duggento (Rome), Enzo Emanuele (Robbio), Valentina Escott-Price (Cardiff), Howard Federoff (Irvine), Maria Teresa Ferretti (Z?rich), Massimo Fiandaca (Irvine), Richard A. Frank (Malvern), Francesco Garaci (Rome), Hugo Geerts (Berwyn), Filippo S. Giorgi (Pisa), Edward J. Goetzl (San Francisco), Manuela Graziani (Roma), Marion Haberkamp (Bonn), Marie-Odile Habert (Paris), Harald Hampel (Paris), Karl Herholz (Manchester), Felix Hernandez (Madrid), Dimitrios Kapogiannis (Baltimore), Eric Karran (Cambridge), Steven J. Kiddle (Cambridge), Seung H. Kim (Seoul), Yosef Koronyo (Los Angeles), Maya Koronyo-Hamaoui (Los Angeles), Todd Langevin (Minneapolis-Saint Paul), St?phane Leh?ricy (Paris), Alejandro Luc?a (Madrid), Simone Lista (Paris), Jean Lorenceau (Paris), Dalila Mango (Rome), Mark Mapstone (Irvine), Christian Neri (Paris), Robert Nistic? (Rome), Sid E. O'Bryant (Fort Worth), Giovanni Palermo (Pisa), George Perry (San Antonio), Craig Ritchie (Edinburgh), Simone Rossi (Siena), Amira Saidi (Rome), Emiliano Santarnecchi (Siena), Lon S. Schneider (Los Angeles), Olaf Sporns (Bloomington), Nicola Toschi (Rome), Steven R. Verdooner (Sacramento), Andrea Vergallo (Paris), Nicolas Villain (Paris), Lindsay A. Welikovitch (Montr?al), Janet Woodcock (Silver Spring), Erfan Younesi (Esch-sur-Alzette). Funding Information: H.H. is supported by the AXA Research Fund, the “Fondation partenariale Sorbonne Université” and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Ce travail a bénéficié d'une aide de l'Etat “Investissements d'avenir” ANR-10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d'avenir” ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). Funding Information: The study was promoted by INSERM in collaboration with ICM, IHU-A-ICM, and Pfizer and has received a support within the “Investissement d'Avenir” (ANR-10-AIHU-06). The study was promoted in collaboration with the “CHU de Bordeaux” (coordination CIC EC7), the promoter of Memento cohort, funded by the Foundation Plan-Alzheimer. The study was further supported by AVID/ Lilly . Funding Information: The research leading to these results was supported by the Colam Initiatives and the “Fondation pour la Recherchesur Alzheimer,” Paris, France. Funding Information: Competing financial interests: H.H. serves as a Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd, Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, and Oryzon Genomics, Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd, GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. H.H. is a coinventor in the following patents as a scientific expert and has received no royalties: Funding Information: Michel Thiebaut de Schotten is supported by the “AgenceNationale de la Recherche” (grant number ANR-13- JSV4-0001-01) and a European Research Council Consolidator Investigator Award (ERC-2018-COG 818521). Publisher Copyright: © 2019
PY - 2019/7
Y1 - 2019/7
N2 - Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.
AB - Introduction: The longitudinal trajectories of functional brain dynamics and the impact of genetic risk factors in individuals at risk for Alzheimer's disease are poorly understood. Methods: In a large-scale monocentric cohort of 224 amyloid stratified individuals at risk for Alzheimer's disease, default mode network (DMN) resting state functional connectivity (FC) was investigated between two serial time points across 2 years. Results: Widespread DMN FC changes were shown in frontal and posterior areas, as well as in the right hippocampus. There were no cross-sectional differences, however, apolipoprotein E ε4 (APOE ε4) carriers demonstrated slower increase in FC in frontal lobes. There was no impact of individual brain amyloid load status. Discussion: For the first time, we demonstrated that the pleiotropic biological effect of the APOE ε4 allele impacts the dynamic trajectory of the DMN during aging. Dynamic functional biomarkers may become useful surrogate outcomes for the development of preclinical targeted therapeutic interventions.
KW - Alzheimer's disease
KW - Brain functional dynamics
KW - Precision medicine
KW - Subjective memory complaints
KW - fMRI
UR - http://www.scopus.com/inward/record.url?scp=85065804629&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2019.03.006
DO - 10.1016/j.jalz.2019.03.006
M3 - Article
C2 - 31113760
AN - SCOPUS:85065804629
VL - 15
SP - 940
EP - 950
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 7
ER -