Biomarker Based and Individualized Prognosis for Patients with Mild Cognitive Impairment: Towards a Personalized Medicine Approach for AD
43 Pages Posted: 28 Mar 2019More...
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.
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