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Biomarker Based and Individualized Prognosis for Patients with Mild Cognitive Impairment: Towards a Personalized Medicine Approach for AD

43 Pages Posted: 28 Mar 2019

See all articles by Ingrid van Maurik

Ingrid van Maurik

VU University Amsterdam - Alzheimer Center Amsterdam; VU University Amsterdam - Department of Epidemiology and Biostatistics

Isabelle Bos

VU University Amsterdam - Alzheimer Center Amsterdam

Stephanie J. Vos

Maastricht University

Femke H. Bouwman

VU University Amsterdam - Alzheimer Center Amsterdam

Charlotte E. Teunissen

VU University Medical Center - Amsterdam Neuroscience

Philip Scheltens

VU University Amsterdam - Department of Neurology

Frederik Barkhof

VU University Amsterdam - Amsterdam Neuroscience; University College London - Institute of Neurology; University College London

Lutz Frolich

University of Mannheim

Johannes Kornhuber

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg

Jens Wiltfang

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy; German Center for Neurodegenerative Diseases (DZNE); Universidade de Aveiro - Institute for Research in Biomedicine (iBiMED)

Wolfgang Maier

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Oliver Peters

Charité - Universitätsmedizin Berlin - Department of Psychiatry and Psychotherapy

E. Ruther

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy

Flavio Nobili

Università degli Studi di Genova

Giovanni Frisoni

University of Geneva - Faculty of Medicine

Luiza Spiru

Carol Davila University of Medicine and Pharmacy

Yvonne Freund-Levi

Örebro University, Institute of Medical Sciences, School of Medicine

Asa K. Wallin

Lund University - Faculty of Medicine

Harald Hampel

Sorbonne University

Hilkka Soininen

University of Kuopio

M. Tsolaki

Aristotle University of Thessaloniki

F. Verhey

Maastricht University

Andy Simmons

University of London - Institute of Psychiatry, Psychology & Neuroscience (IoPPN)

I. Kloszewska

Medical University of Lodz

Patrizia Mecocci

University of Perugia - Department of Medicine

Bruno Vellas

Centre Hospitalier Universitaire Toulouse

Simon Lovestone

University of Oxford - Department of Psychiatry

S. Galluzzi

IRCCS San Giovanni di Dio Fatebenefratelli

Sanna-Kaisa Herukka

University of Eastern Finland

Isabel Santana

University of Coimbra

Ines Baldeiras

University of Coimbra

A. de Mendonça

University of Lisbon - Faculty of Medicine

Dina Silva

Universidade do Algarve

G. Chetelat

Université de Caen-Normandie

S. Egret

Université de Caen-Normandie

Sebastian Palmqvist

Lund University - Faculty of Medicine

Oskar Hansson

Lund University - Faculty of Medicine

Pieter-Jelle Visser

VU University Amsterdam - Alzheimer Center Amsterdam

Alzheimer's Disease Neuroimaging Initiative

Johannes Berkhof

VU University Amsterdam - Department of Epidemiology and Biostatistics

Wiesje M. van der Flier

VU University Amsterdam - Alzheimer Center Amsterdam

More...

Abstract

Background: Personalized biomarker-based risk predictions in patients with MCI are highly relevant in light of care planning and future disease modifying drugs. The aim of this study was to establish robust, personalized prediction models in a multi-center, multi-cohort design.

Methods: We included 2611 patients with mild cognitive impairment (MCI) (age=70±8, 44%F) via the European Medical Information Framework for Alzheimer's Disease (EMIF-AD, n=883), Alzheimer's Disease Neuroimaging Initiative (ADNI, n=829), Amsterdam Dementia Cohort (ADC, n=666) and Swedish BioFINDER study (n=233). Clinical end-point was progression to Alzheimer's disease dementia (AD). We evaluated performance of previously published models (demographic model, Hippocampal volume (HCV) model, cerebrospinal fluid (CSF) model) by determining Harrell's C, updated the models by re-estimating coefficients where necessary and evaluated concordance between predicted and observed outcomes (calibration). Finally, a model combining markers for amyloid deposition (A), tauopathy (T) and neurodegeneration (N) was constructed, in accordance with the research framework for AD.

Findings: During 3±2 years follow up, 838 (32%) MCI patients showed clinical progression to AD dementia. For the demographic and HCV model, the pooled effect for model performance was equal to the original models (Harrell's c=0·63[0·60-0·66] and 0·68[0·65-0·72]). The CSF model performed suboptimal (Harrell's c=0·70[0·66-0·73] vs. original 0·75[0·72-0·78]), but improved after re-estimating the coefficients (Harrell's c=0·77[0·75-0·80]). In all models, inclusion of center-specific effects did not improve model performance. Finally, the ATN model had highest performance (Harrell's c=0·79[0·77-0·81]). On calibration of the models, we found that the predicted probabilities were comparable to observed progression, up to more than five years of follow-up.

Interpretation: We generated personalized risk models that accommodate different measurement methods and are robust across cohorts, illustrating their clinical applicability. The models aid to interpret CSF and HCV results in individual MCI patients, facilitating the implementation of the ATN framework for personalization of prognosis.

Funding: ZonMW-Memorabel (ABIDE; projectnr. 733050201).

Declaration of Interest: Dr. Teunissen has functioned in advisory boards of Fujirebio and Roche, received nonfinancial support in the form of research consumables from ADxNeurosciences and Euroimmun, performed contract research or received grants from Probiodrug, Janssen Prevention Center, Boehringer, Brains Online, Axon Neurosciences, EIP Pharma, and Roche.

Dr. Scheltens has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal, and MERCK. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma.

Dr. Barkhof is supported by the NIHR biomedical research centre at UCLH.

Dr. Frolich: research funding, consultancy fees or speech honoraria from Allergan, Avid-Eli Lilly, Avanir, Avraham Pharmaceuticals, Axon Neuroscience, Axovant, Biogen, Boehringer Ingelheim, Eisai, Functional Neuromodulation, GE Health Care, Lundbeck, MerckSharpe&Dohme, Novartis, Pfizer, Piramal Imaging, Roche, Schwabe Pharma.

Dr. Wiltfang has acquired research support (for the institution) from Immungenetics, TECAN-IBL.

Consultancy fees from Lilly, Roche Pharma, MSD SHARP & DOHME, Boehringer-Ingelheim, Abbot EPD. Speech honoraria Roche Pharma, Helios Klinikum Wuppertal, Vitos Kurhessen-Bad Emstal, Pfizer, Janssen, AGNP, Actelion. Patents: PCT/EP 2011 001724: New formulations for diagnosis of Alzheimer's disease . PCT/EP 2015 052945: Biosensor for conformation and secondary structure analysis

Dr. Harald Hampel serves as Senior Associate editor for Journal Alzheimer’s & Dementia; he received lecture fees from Biogen, Roche, Eisai, 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, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics and Roche Diagnostics.

H.H. is supported by AXA research Fund “Fondation partenariale Sorbonne Université” and “Fondation pour la Recherche sur Alzheimer” Paris France. Ce travail a bénéficié d'un aid de l’Etat “Investissements d’avenir” AN -10-IAIHU-06. The research leading to these results has received funding from the program “Investissements d’avenir” AN -10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6).

H.H. is co-inventor in the following patents as a scientific expert and has received no royalties:
• In Vitro Multiparameter Determination Method for The Diagnosis and a 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 a Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463

• In Vitro Method for The Diagnosis and a Early Diagnosis of Neurodegeneratie Disorders Publication Number: 20100035286

• In Vitro Procedure for Diagnosis and Early Diagnosis of Neurogenative Diseases Publication Number: 20090263822

• In Vitro Method for The Diagnosis of Neurodegenerative Dieases Patent Number: 7547553

• CSF 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

• Neurodegenrative Markers foe Psychiatric Conditions Publication Number: 20080131921

Dr. Vellas reports grants and personal fees from Biogen, MSD, Lily and Roche, outside the submitted work.

Dr. Lovestone has, within the past 5 years, held research grants with funding from multiple industry partners through the IMI funding scheme and also with Astra Zeneca. He is currently an employee of Janssen R&D.

Dr. Hansson has acquired research support (for the institution) from Roche, GE Healthcare, Biogen, AVID Radiopharmaceuticals, Fujirebio, and Euroimmun. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Biogen, Roche, and Fujirebio.

Dr. van der Flier performs contract research for Biogen MA Inc. Research programs of W.M.v.d.F. have been funded by ZonMW, Health Holland, Pasman stichting, NWO, EU-FP7, EU-JPND, Alzheimer Nederland, Cardiovasculair Onderzoek Nederland, stichting Dioraphte, Gieskes-Strijbis fonds, Boehringer Ingelheim, Piramal Neuroimaging, Roche BV, Janssen Stellar, and Combinostics.

All funding is paid to her institution.

Van Maurik, Bos. Vos, Bouwman, Kornhuber, Maier, Peters, Rüther, Nobili, Frisoni, Spiru, FreundLevi, Wallin, Soininen, Tsolaki, Verhey, Simmons, Kloszewska , Mecocci, Galluzzi, Herukka, Santana, Baldeiras, de Mendonça, Silva, Chetelat, Egret, Palmqvist, Visser and Berkhof report no conflict of interests.

Ethical Approval: All participant gave written informed consent and institutional review boards approved the study. This study is reported in accordance with the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guideline.

Suggested Citation

van Maurik, Ingrid and Bos, Isabelle and Vos, Stephanie J. and Bouwman, Femke H. and Teunissen, Charlotte E. and Scheltens, Philip and Barkhof, Frederik and Frolich, Lutz and Kornhuber, Johannes and Wiltfang, Jens and Maier, Wolfgang and Peters, Oliver and Ruther, E. and Nobili, Flavio and Frisoni, Giovanni and Spiru, Luiza and Freund-Levi, Yvonne and Wallin, Asa K. and Hampel, Harald and Soininen, Hilkka and Tsolaki, M. and Verhey, F. and Simmons, Andy and Kloszewska, I. and Mecocci, Patrizia and Vellas, Bruno and Lovestone, Simon and Galluzzi, S. and Herukka, Sanna-Kaisa and Santana, Isabel and Baldeiras, Ines and de Mendonça, A. and Silva, Dina and Chetelat, G. and Egret, S. and Palmqvist, Sebastian and Hansson, Oskar and Visser, Pieter-Jelle and Initiative, Alzheimer's Disease Neuroimaging and Berkhof, Johannes and van der Flier, Wiesje M., Biomarker Based and Individualized Prognosis for Patients with Mild Cognitive Impairment: Towards a Personalized Medicine Approach for AD (March 26, 2019). Available at SSRN: https://ssrn.com/abstract=3360114

Ingrid Van Maurik (Contact Author)

VU University Amsterdam - Alzheimer Center Amsterdam ( email )

Amsterdam
Netherlands

VU University Amsterdam - Department of Epidemiology and Biostatistics ( email )

De Boelelaan 1117
Amsterdam, North Holland 1081 HV
Netherlands

Isabelle Bos

VU University Amsterdam - Alzheimer Center Amsterdam

Amsterdam
Netherlands

Stephanie J. Vos

Maastricht University

P.O. Box 616
Maastricht, 6200MD
Netherlands

Femke H. Bouwman

VU University Amsterdam - Alzheimer Center Amsterdam

Amsterdam
Netherlands

Charlotte E. Teunissen

VU University Medical Center - Amsterdam Neuroscience

Amsterdam
Netherlands

Philip Scheltens

VU University Amsterdam - Department of Neurology

Amsterdam
Netherlands

Frederik Barkhof

VU University Amsterdam - Amsterdam Neuroscience

Amsterdam
Netherlands

University College London - Institute of Neurology

Queen Square
London WC1N 3BG
United Kingdom

University College London

Gower Street
London, WC1E 6BT
United Kingdom

Lutz Frolich

University of Mannheim

Universitaetsbibliothek Mannheim
Zeitschriftenabteilung
Mannheim, 68131
Germany

Johannes Kornhuber

University of Erlangen-Nuremberg-Friedrich Alexander Universität Erlangen Nürnberg

Schloßplatz 4
Erlangen, Bavaria 91054
Germany

Jens Wiltfang

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy ( email )

Germany

German Center for Neurodegenerative Diseases (DZNE) ( email )

von Siebold Strasse 3a
Goettingen, 37075
Germany

Universidade de Aveiro - Institute for Research in Biomedicine (iBiMED) ( email )

Aveiro
Portugal

Wolfgang Maier

University of Bonn - Department of Neurodegenerative Disease and Gerontopsychiatry

Bonn, 53127
Germany

Oliver Peters

Charité - Universitätsmedizin Berlin - Department of Psychiatry and Psychotherapy

Charitéplatz 1
Berlin, 10117
Germany

E. Ruther

University of Goettingen (Gottingen), Faculty of Medicine, University Medical Centre, Department of Psychiatry and Psychotherapy

Germany

Flavio Nobili

Università degli Studi di Genova

Via Vivaldi 5
Genova, 16126
Italy

Giovanni Frisoni

University of Geneva - Faculty of Medicine

102 Bd Carl-Vogt
Genève, CH - 1205
Switzerland

Luiza Spiru

Carol Davila University of Medicine and Pharmacy

Bulevardul Eroii Sanitari 8
Bucharest
Romania

Yvonne Freund-Levi

Örebro University, Institute of Medical Sciences, School of Medicine

Sweden

Asa K. Wallin

Lund University - Faculty of Medicine

Box 117
SE-221 00 Lund
Sweden

Harald Hampel

Sorbonne University

UFR 927, 4 Place Jussieu
Paris, F-75252
France

Hilkka Soininen

University of Kuopio

PL 1627
Kuopio, 70211
Finland

M. Tsolaki

Aristotle University of Thessaloniki

Thessaloniki
Greece

F. Verhey

Maastricht University

P.O. Box 616
Maastricht, 6200MD
Netherlands

Andy Simmons

University of London - Institute of Psychiatry, Psychology & Neuroscience (IoPPN)

United Kingdom

I. Kloszewska

Medical University of Lodz

Lodz
Poland

Patrizia Mecocci

University of Perugia - Department of Medicine

Severi Square, 1
University of Perugia
Perugia, I-06129
Italy

Bruno Vellas

Centre Hospitalier Universitaire Toulouse

France

Simon Lovestone

University of Oxford - Department of Psychiatry

Warneford Hospital
Warneford Ln
Oxford, OX3 7JX
United Kingdom

S. Galluzzi

IRCCS San Giovanni di Dio Fatebenefratelli

Brescia
Italy

Sanna-Kaisa Herukka

University of Eastern Finland

PO Box 111
Joensuu, 80100
Finland

Isabel Santana

University of Coimbra

Avenida Dias da Silva, 165
Coimbra, 3004-512
Portugal

Ines Baldeiras

University of Coimbra

Avenida Dias da Silva, 165
Coimbra, 3004-512
Portugal

A. De Mendonça

University of Lisbon - Faculty of Medicine

Avenida Professor Egas Moniz
Lisboa, 1649-028
Portugal

Dina Silva

Universidade do Algarve

Campus de Gambelas
Faro, Algarve 8005
Portugal

G. Chetelat

Université de Caen-Normandie

Caen
France

S. Egret

Université de Caen-Normandie

Caen
France

Sebastian Palmqvist

Lund University - Faculty of Medicine

Box 117
SE-221 00 Lund
Sweden

Oskar Hansson

Lund University - Faculty of Medicine

Box 117
SE-221 00 Lund
Sweden

Pieter-Jelle Visser

VU University Amsterdam - Alzheimer Center Amsterdam

Amsterdam
Netherlands

Johannes Berkhof

VU University Amsterdam - Department of Epidemiology and Biostatistics

De Boelelaan 1117
Amsterdam, North Holland 1081 HV
Netherlands

Wiesje M. Van der Flier

VU University Amsterdam - Alzheimer Center Amsterdam

Amsterdam
Netherlands

No contact information is available for Alzheimer's Disease Neuroimaging Initiative

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