TY - JOUR
T1 - Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study
AU - Alzheimer's Disease Neuroimaging Initiative
AU - Leung, Yuk Yee
AU - Toledo, Jon B.
AU - Nefedov, Alexey
AU - Polikar, Robi
AU - Raghavan, Nandini
AU - Xie, Sharon X.
AU - Farnum, Michael
AU - Schultz, Tim
AU - Baek, Young
AU - Deerlin, Vivianna V.
AU - Hu, William T.
AU - Holtzman, David M.
AU - Fagan, Anne M.
AU - Perrin, Richard J.
AU - Grossman, Murray
AU - Soares, Holly D.
AU - Kling, Mitchel A.
AU - Mailman, Matthew
AU - Arnold, Steven E.
AU - Narayan, Vaibhav A.
AU - Lee, Virginia M.Y.
AU - Shaw, Leslie M.
AU - Baker, David
AU - Wittenberg, Gayle M.
AU - Trojanowski, John Q.
AU - Wang, Li San
N1 - Funding Information:
H.D.S. is employed by Pfizer Global Research and Development, Groton, CT, and St. Louis, MO and therefore, Pfizer Global played a role in study design, data collection and analysis, decision to publish, and preparation of the article. Y.Y.L., J.B.T., A.N., R.P., N.R., S.X.X., M.F., T.S., Y.B., V.V.D., R.J.P., M.G., M.A.K., D.B., M.M., V.A.N., V.M.-Y.L., L.M.S., G.M.W., and L.-S.W. report no disclosures. W.T.H. has received research support from BMS, has consulted for Sanofi, and may accrue revenue in the future on patents submitted by Emory University on biomarkers for Alzheimer's disease and frontotemporal lobar degenerations. H.D.S. is a full time BMS employee and BMS shareholder. S.E.A. has grant funding paid to the University of Pennsylvania from NIH for R01AG03947802 , BrightFocus Foundation for A2012116 , University of California-San Diego for UCSDCT and 22-UPENN-RES, and the Marian S. Ware Alzheimer's Program as well as Bristol Myers Squibb, Eli Lily, Neuronetrix, Merck, Pfizer, and Johnson & Johnson. He has board memberships with Teva and Bristol Myers Squibb. He presently does consultancy work for Pain Therapeutics. He has also received payment for lectures including service on speaker's bureaus for Rush University Medical Center, Trinitas Regional Medical Center, and University of Puerto Rico. J.Q.T. may accrue revenue in the future on patents submitted by the University of Pennsylvania wherein he is co-inventor and he received revenue from the sale of Avid to Eli Lily as co-inventor on imaging-related patents submitted by the University of Pennsylvania. D.M.H. is a co-founder of C2N Diagnostics LLC, is on the scientific advisory boards of AstraZeneca, Genentech, Neurophage and C2N Diagnostics, and a consultant for Eli Lilly. Washington University receives grants to the laboratory of D.M.H. from the Tau Consortium, Cure Alzheimer's Fund, the JPB Foundation, Eli Lilly, Janssen, and C2N Diagnostics. A.M.F. is on the scientific advisory boards of IBL International and Roche and is a consultant for AbbVie.
Funding Information:
This work was sponsored by a collaborative research project between the University of Pennsylvania, the Center for Neurodegenerative Disease Research, and Janssen entity. This work was also supported by the UPenn AG-10124 . J.B.T. was supported by a grant of the Alfonso Martin Escudero Foundation. This work was supported by a grant to Washington University from Pfizer . This work was also supported by the National Institutes of Health grants P50 AG05681 , P01AG03991 , P01 AG026276 , P30 NS057105 , and the Charles and Joanne Knight Alzheimer Research Initiative . This publication was made possible by grant number UL1 RR024992 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Data collection and sharing for this project were funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) ( National Institutes of Health grant U01 AG024904 ). ADNI is funded by the National Institute on Aging , the National Institute of Biomedical Imaging and Bioengineering , and through generous contributions from the following: Alzheimer's Association; Alzheimer's Drug Discovery Foundation; BioClinica, Inc; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals, Inc; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc; GE Healthcare; Innogenetics N.V.; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education , and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by National Institutes of Health grants P30 AG010129 and K01 AG030514 .
Publisher Copyright:
© 2015 The Authors.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (. APOE) e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.
AB - Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (. APOE) e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.
KW - Alzheimer's disease
KW - Amyloid beta
KW - Biomarkers
KW - Cerebrospinal fluid
KW - Cognitive impairment
KW - Dementia
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U2 - 10.1016/j.dadm.2015.06.008
DO - 10.1016/j.dadm.2015.06.008
M3 - Article
AN - SCOPUS:84940181687
SN - 2352-8729
VL - 1
SP - 339
EP - 348
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
IS - 3
ER -