Abstract
Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study
| Original language | English |
|---|---|
| Pages (from-to) | 897-905 |
| Number of pages | 9 |
| Journal | Neurology |
| Volume | 79 |
| Issue number | 9 |
| DOIs | |
| State | Published - Aug 28 2012 |
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In: Neurology, Vol. 79, No. 9, 28.08.2012, p. 897-905.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Plasma multianalyte profiling in mild cognitive impairment and Alzheimer Disease
AU - Hu, William T.
AU - Holtzman, David M.
AU - Fagan, Anne M.
AU - Shaw, Leslie M.
AU - Perrin, Richard
AU - Arnold, Steven E.
AU - Grossman, Murray
AU - Xiong, Chengjie
AU - Craig-Schapiro, Rebecca
AU - Clark, Christopher M.
AU - Pickering, Eve
AU - Kuhn, Max
AU - Chen, Yu
AU - Van Deerlin, Vivianna M.
AU - McCluskey, Leo
AU - Elman, Lauren
AU - Karlawish, Jason
AU - Chen-Plotkin, Alice
AU - Hurtig, Howard I.
AU - Siderowf, Andrew
AU - Swenson, Frank
AU - Lee, Virginia M.Y.
AU - Morris, John C.
AU - Trojanowski, John Q.
AU - Soares, Holly
N1 - Funding Information: W. Hu receives research support from the Viretta Brady Discovery Fund. D. Holtzman serves on scientific advisory boards for Satori Pharmaceuticals and EnVivo Pharmaceuticals; may accrue revenue on pending patents re: Methods for measuring the metabolism of neurally derived biomolecules in vivo; Use of anti-AB antibody to treat traumatic brain injury; Methods to treat Alzheimer's disease or other amyloid beta accumulation associated disorders; Humanized antibodies that sequester abeta peptide; Diagnostic for early stage Alzheimer's disease; and Predictive diagnostic for Alzheimer's disease; serves as a consultant to Merck Serono, Eli Lilly and Company, Takeda Pharmaceutical Company Limited, Abbott, Comentis, Inc., Eisai Inc., and AstraZeneca; is cofounder of and receives board of directors compensation from C2N Diagnostics LLC; receives research support from AstraZeneca, Pfizer Inc., Eli Lilly and Company, Elan Corporation, Forest Laboratories, Inc., the NIH, Cure Alzheimer's Fund, and Fidelity Foundation; has received compensation from Washington University from license revenue received for licensing of patent applications to C2N Diagnostics LLC; and may receive future royalty payments for Washington University licensing patents to C2N Diagnostics, LLC, and Eli Lilly and Company. A. Fagan serves on the speakers' bureau for the Alzheimer's Association. L. Shaw and R. Perrin report no disclosures. S. Arnold is a consultant to NIMH Geriatrics Branch and a member of the advisory board to Rush University Medical Center, was a compensated guest lecturer at Vanderbilt University, and was an expert witness to Cozen O'Connor and Reed-Smith. M. Grossman is a consultant to Allon Therapeutics, Forest Labs, and Pfizer Pharmaceuticals; a study section member at the NIH; a member of the editorial board for Wolters Kluwer Health; and a compensated lecturer at Sacred Heart Hospital. C. Xiong and R. Craig-Schapiro report no disclosures. C. Clark is deceased; disclosures are not included for this author. E. Pickering is an employee of Pfizer Global Research and Development. M. Kuhn is an employee of Pfizer Global Research and Development. Y. Chen is an employee of Pfizer Global Research and Development. V. Van Deerlin reports no disclosures. L. McCluskey was an expert witness to Gallagher & Rowan and Kilcoyne & Nesbitt. L. Elman, J.H.T. Karlawish, and A. Chen-Plotkin report no disclosures. H. Hurtig is a consultant to UpToDate. A. Siderowf is supported by a Morris K. Udall Parkinson's Disease Research Center of Excellence grant from NINDS ( NS-053488 ), and has been supported by SAP4100027296 , a health research grant awarded by the Department of Health of the Commonwealth of Pennsylvania from the Tobacco Master Settlement Agreement under Act 2001-77. He has received consulting fees from Teva Neuroscience, Supernus Pharmaceuticals, Schering-Plough, and Merck Serono. He has received speaking honorarium from Teva Neuroscience. F. Swenson is an employee of Pfizer Global Research and Development. V.M.-Y. Lee has received funding for travel and honoraria from Takeda Pharmaceutical Company Ltd.; has received speaker honoraria from Pfizer Inc., BMS, and Merck; may accrue revenue on patents re: Modified avidin-biotin technique, Method of stabilizing microtubules to treat Alzheimer's disease, Method of detecting abnormally phosphorylated tau, Method of screening for Alzheimer's disease or disease associated with the accumulation of paired helical filaments, Compositions and methods for producing and using homogeneous neuronal cell transplants, Rat comprising straight filaments in its brain, Compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, Diagnostic methods for Alzheimer's disease by detection of multiple MRNAs, Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, Compositions and methods for producing and using homogenousneuronal cell transplants, Method of identifying, diagnosing and treating alpha-synuclein positive neurodegenerative disorders, Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, Microtubule stabilizing therapies for neurodegenerative disorders, and Treatment of Alzheimer's and related diseases with an antibody; and receives research support from the NIH NIA PO1 AG 17586-10, PO1 AG-032953, NINDS P50 NS053488-02, NIA UO1 AG029213-01; and from the Marian S. Ware Alzheimer Program. J. Morris serves on scientific advisory boards for AstraZeneca, Bristol-Myers Squibb, Genentech, Inc., Merck Serono, Novartis, Pfizer Inc, Schering-Plough Corp., Eli Lilly and Company, Wyeth, and Elan Corporation; and receives research support from Elan Corporation, Wyeth, Eli Lilly and Company, Novartis, Pfizer Inc, Avid Radiopharmaceuticals, the NIH, and the Dana Foundation. J. Trojanowski has received funding for travel and honoraria from Takeda Pharmaceutical Company Ltd.; has received speaker honoraria from Pfizer Inc.; may accrue revenue on patents re: Modified avidin-biotin technique, Method of stabilizing microtubules to treat Alzheimer's disease, Method of detecting abnormally phosphorylated tau, Method of screening for Alzheimer's disease or disease associated with the accumulation of paired helical filaments, Compositions and methods for producing and using homogeneous neuronal cell transplants, Rat comprising straight filaments in its brain, Compositions and methods for producing and using homogeneous neuronal cell transplants to treat neurodegenerative disorders and brain and spinal cord injuries, Diagnostic methods for Alzheimer's disease by detection of multiple MRNAs, Methods and compositions for determining lipid peroxidation levels in oxidant stress syndromes and diseases, Compositions and methods for producing and using homogenous neuronal cell transplants, Method of identifying, diagnosing and treating alpha-synuclein positive neurodegenerative disorders, Mutation-specific functional impairments in distinct tau isoforms of hereditary frontotemporal dementia and parkinsonism linked to chromosome-17: genotype predicts phenotype, Microtubule stabilizing therapies for neurodegenerative disorders, and Treatment of Alzheimer's and related diseases with an antibody; and receives research support from the NIH (NIA P01 AG 09215-20 [PI], NIA P30 AG 10124-18 [PI], NIA PO1 AG 17586-10 [Project 4 Leader], NIA 1PO1 AG-19724-07 [Core C Leader], NIA 1 U01 AG 024904-05 [Co-PI Biomarker Core Laboratory], NINDS P50 NS053488-02 [PI], NIA UO1 AG029213-01 [Co-I]; RC2NS069368 [PI], RC1AG035427 [PI], and NIA P30AG036468 [PI]), and the Marian S. Ware Alzheimer Program. H. Soares is an employee of Bristol-Myers Squibb. Go to Neurology.org for full disclosures.
PY - 2012/8/28
Y1 - 2012/8/28
N2 - Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study
AB - Objectives: While plasma biomarkers have been proposed to aid in the clinical diagnosis of Alzheimer disease (AD), few biomarkers have been validated in independent patient cohorts. Here we aim to determine plasma biomarkers associated with AD in 2 independent cohorts and validate the findings in the multicenter Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: Using a targeted proteomic approach, we measured levels of 190 plasma proteins and peptides in 600 participants from 2 independent centers (University of Pennsylvania, Philadelphia; Washington University, St. Louis, MO), and identified 17 analytes associated with the diagnosis of very mild dementia/mild cognitive impairment (MCI) or AD. Four analytes (apoE, B-type natriuretic peptide, C-reactive protein, pancreatic polypeptide) were also found to be altered in clinical MCI/AD in the ADNI cohort (n = 566). Regression analysis showed CSF Aβ42 levels and t-tau/Aβ42 ratios to correlate with the number of APOE4 alleles and plasma levels of B-type natriuretic peptide and pancreatic polypeptide. Conclusion: Four plasma analytes were consistently associated with the diagnosis of very mild dementia/MCI/AD in 3 independent clinical cohorts. These plasma biomarkers may predict underlying AD through their association with CSF AD biomarkers, and the association between plasma and CSF amyloid biomarkers needs to be confirmed in a prospective study
UR - http://www.scopus.com/inward/record.url?scp=84866106602&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e318266fa70
DO - 10.1212/WNL.0b013e318266fa70
M3 - Article
C2 - 22855860
AN - SCOPUS:84866106602
SN - 0028-3878
VL - 79
SP - 897
EP - 905
JO - Neurology
JF - Neurology
IS - 9
ER -