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. 2019 Apr 16;11(1):33.
doi: 10.1186/s13195-019-0487-y.

Personalized risk for clinical progression in cognitively normal subjects-the ABIDE project

Ingrid S van Maurik  1   2 , Rosalinde E R Slot  3 , Sander C J Verfaillie  3 , Marissa D Zwan  3 , Femke H Bouwman  3 , Niels D Prins  3   4 , Charlotte E Teunissen  5 , Philip Scheltens  3 , Frederik Barkhof  6   7 , Mike P Wattjes  6 , Jose Luis Molinuevo  8 , Lorena Rami  8 , Steffen Wolfsgruber  9   10 , Oliver Peters  11 , Frank Jessen  12 , Johannes Berkhof  13 , Wiesje M van der Flier  3   13 ; Alzheimer’s Disease Neuroimaging Initiative
Affiliations

Personalized risk for clinical progression in cognitively normal subjects-the ABIDE project

Ingrid S van Maurik et al. Alzheimers Res Ther. .

Abstract

Background: Biomarkers such as cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) have predictive value for progression to dementia in patients with mild cognitive impairment (MCI). The pre-dementia stage takes far longer, and the interpretation of biomarker findings is particular relevant for individuals who present at a memory clinic, but are deemed cognitively normal. The objective of the current study is to construct biomarker-based prognostic models for personalized risk of clinical progression in cognitively normal individuals presenting at a memory clinic.

Methods: We included 481 individuals with subjective cognitive decline (SCD) from the Amsterdam Dementia Cohort. Prognostic models were developed by Cox regression with patient characteristics, MRI, and/or CSF biomarkers to predict clinical progression to MCI or dementia. We estimated 5- and 3-year individualized risks based on patient-specific values. External validation was performed on Alzheimer's Disease Neuroimaging Initiative (ADNI) and an European dataset.

Results: Based on demographics only (Harrell's C = 0.70), 5- and 3-year progression risks varied from 6% [3-11] and 4% [2-8] (age 55, MMSE 30) to 38% [29-49] and 28% [21-37] (age 70, MMSE 27). Normal CSF biomarkers strongly decreased progression probabilities (Harrell's C = 0.82). By contrast, abnormal CSF markedly increased risk (5 years, 96% [56-100]; 3 years, 89% [44-99]). The CSF model could reclassify 58% of the individuals with an "intermediate" risk (35-65%) based on the demographic model. MRI measures were not retained in the models.

Conclusion: The current study takes the first steps in a personalized approach for cognitively normal individuals by providing biomarker-based prognostic models.

Keywords: Biomarkers; Cerebrospinal fluid; Magnetic resonance imaging; Progression.

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Conflict of interest statement

Ethics approval and consent to participate

The study was approved by the local Medical Ethical Committee. All patients provided written informed consent for their clinical data to be used for research purposes.

Consent for publication

Not applicable.

Competing interests

Dr. Prins serves on the advisory board of Boehringer Ingelheim and Probiodrug and on the DSMB of Abbvie’s M15-566 trial. He has provided consultancy services for Sanofi, Takeda, and Kyowa Kirin Pharmaceutical Development. NDP is the CEO and co-owner of the Alzheimer Research Center, Amsterdam, the Netherlands.

C. Teunissen serves on the advisory board of Fujirebio and Roche, received research consumables from Euroimmun, IBL, Fujirebio, Invitrogen, and Mesoscale Discovery; performed contract research for IBL, Shire, Boehringer, Roche, and Probiodrug; and received grants from the European Commission, the Dutch Research Council (ZonMW), Association of Frontotemporal Dementia/Alzheimer’s Drug Discovery Foundation, ISAO, and the Alzheimer’s Drug Discovery Foundation.

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 serves as a consultant for Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzume, and Sanofi-aventis; has received sponsoring from EU-H2020, NIHR-UCLH, NOW, SMSR, TEVA, Novartis, Toshiba; and serves on the editorial boards of Radiology, Brain, Neuroradiology, MSJ, and Neurology.

Dr. Peters is on scientific advisory boards for Roche, Kyowa Kirin, Novartis, Lilly, and Piramal. He has received funding for travel or speaker honoraria from GSK, Nutricia, and Merck Serono. He has acted as a consultant for Affiris and Roche. He has received research support from Affiris, Piramal, BMS, Eli Lilly, Pfizer, Servier, TRX Pharmaceuticals, Lundbeck, and Genentech.

Dr. Jessen has received consultation board honoraria and speakers fees from AC Immune, Lilly, GE Healthcare, Janssen, USB, Schwabe, Esai, Pfizer, Novartis, and Roche. He has received a research grant paid to his institution from Schwabe.

Dr. van der Flier performs contract research for Biogen MA Inc. Research programs of W.M.v.d.F. have been funded by ZonMW, 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, Slot, Verfaillie, Dr. Zwan, Dr. Bouwman, Dr. Wattjes, Dr. Wolfsgruber, and Dr. Berkhof declare that they have no competing interests.

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Figures

Fig. 1
Fig. 1
Probability isographs for 1-, 3-, and 5-year progression to MCI or dementia. Legend: Probability of progression within 1 (upper panel) year, 3 (middle panel) years, and 5 (lower panel) years based on Aβ (pg/mL, y-axis) and Tau (pg/mL, x-axis), stratified for individuals younger (left) and older than 65 (right)
Fig. 2
Fig. 2
Distribution of 5-year progression probabilities. Legend: Distribution of 5-year progression probabilities based on the CSF model. Green: low risk 0–35%; orange: intermediate 35–65%; red: high risk 65–100%
See this image and copyright information in PMC

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