TY - JOUR
T1 - The EMIF-AD Multimodal Biomarker Discovery study: design, methods and cohort characteristics
AU - Bos, Isabelle
AU - Vos, Stephanie
AU - Vandenberghe, Rik
AU - Scheltens, Philip
AU - Engelborghs, Sebastiaan
AU - Frisoni, Giovanni
AU - Molinuevo, Jose
AU - Wallin, Anders
AU - Lleo, Alberto
AU - Popp, Julius
AU - Martinez-Lage, Pablo
AU - Baird, Alison
AU - Dobson, Richard
AU - Legido-Quigley, Cristina
AU - Sleegers, Kristel
AU - Van Broeckhoven, Christine
AU - Bertram, Lars
AU - ten Kate, Mara
AU - Barkhof, Frederik
AU - Zetterberg, Henrik
AU - Lovestone, Simon
AU - Streffer, Johannes
AU - Visser, Pieter Jelle
PY - 2018/7/6
Y1 - 2018/7/6
N2 - Background: There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer's disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants. Methods: Participants were selected from existing prospective multicenter and single-center European studies. Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (A beta) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF). Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF. Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA. Visual rating and volumetric measures were assessed on MRI. Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling. Results: We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 67.9 (SD 8.3) years. The percentage A beta+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups. Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects. For 759 (62%) individuals, clinical follow-up data were available. In each diagnostic group, the APOE e4 allele was more frequent amongst A beta+ individuals (p < 0.001). Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p< 0.001). A beta+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0.001) and MCI (p < 0.001) groups. Conclusions: The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of A beta and APOE epsilon 4 in AD pathogenesis. The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers. All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog.
AB - Background: There is an urgent need for novel, noninvasive biomarkers to diagnose Alzheimer's disease (AD) in the predementia stages and to predict the rate of decline. Therefore, we set up the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study. In this report we describe the design of the study, the methods used and the characteristics of the participants. Methods: Participants were selected from existing prospective multicenter and single-center European studies. Inclusion criteria were having normal cognition (NC) or a diagnosis of mild cognitive impairment (MCI) or AD-type dementia at baseline, age above 50 years, known amyloid-beta (A beta) status, availability of cognitive test results and at least two of the following materials: plasma, DNA, magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF). Targeted and untargeted metabolomic and proteomic analyses were performed in plasma, and targeted and untargeted proteomics were performed in CSF. Genome-wide SNP genotyping, next-generation sequencing and methylation profiling were conducted in DNA. Visual rating and volumetric measures were assessed on MRI. Baseline characteristics were analyzed using ANOVA or chi-square, rate of decline analyzed by linear mixed modeling. Results: We included 1221 individuals (NC n = 492, MCI n = 527, AD-type dementia n = 202) with a mean age of 67.9 (SD 8.3) years. The percentage A beta+ was 26% in the NC, 58% in the MCI, and 87% in the AD-type dementia groups. Plasma samples were available for 1189 (97%) subjects, DNA samples for 929 (76%) subjects, MRI scans for 862 (71%) subjects and CSF samples for 767 (63%) subjects. For 759 (62%) individuals, clinical follow-up data were available. In each diagnostic group, the APOE e4 allele was more frequent amongst A beta+ individuals (p < 0.001). Only in MCI was there a difference in baseline Mini Mental State Examination (MMSE) score between the A groups (p< 0.001). A beta+ had a faster rate of decline on the MMSE during follow-up in the NC (p < 0.001) and MCI (p < 0.001) groups. Conclusions: The characteristics of this large cohort of elderly subjects at various cognitive stages confirm the central roles of A beta and APOE epsilon 4 in AD pathogenesis. The results of the multimodal analyses will provide new insights into underlying mechanisms and facilitate the discovery of new diagnostic and prognostic AD biomarkers. All researchers can apply for access to the EMIF-AD MBD data by submitting a research proposal via the EMIF-AD Catalog.
KW - Alzheimer's disease
KW - Biomarkers
KW - Multimodal
KW - Proteomics
KW - Genomics
KW - Metabolomics
KW - Plasma
KW - Magnetic resonance imaging
KW - DNA
KW - Cerebrospinal fluid
KW - CEREBROSPINAL-FLUID BIOMARKERS
KW - MILD COGNITIVE IMPAIRMENT
KW - BLOOD-BASED BIOMARKERS
KW - ALZHEIMERS-DISEASE
KW - CSF BIOMARKERS
KW - DEMENTIA
KW - ATROPHY
KW - DIAGNOSIS
KW - MRI
U2 - 10.1186/s13195-018-0396-5
DO - 10.1186/s13195-018-0396-5
M3 - Article
C2 - 29980228
SN - 1758-9193
VL - 10
JO - Alzheimer's Research & Therapy
JF - Alzheimer's Research & Therapy
M1 - 64
ER -