Home LiteratureArticle Details
PMID: 21526197 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer's disease diagnosis and prognosis.

PloS one ·Vol. 6 ·No. 4 ·2011-04-19 ·Pages e18850

Craig-Schapiro R, Kuhn M, Xiong C, Pickering EH, Liu J, Misko TP, Perrin RJ, Bales KR, Soares H, Fagan AM, Holtzman DM

Abstract

Clinicopathological studies suggest that Alzheimer's disease (AD) pathology begins ∼10-15 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset would, therefore, be invaluable for patient care and efficient clinical trial design. We utilized a targeted proteomics approach to discover novel cerebrospinal fluid (CSF) biomarkers that can augment the diagnostic and prognostic accuracy of current leading CSF biomarkers (Aβ42, tau, p-tau181). Using a multiplexed Luminex platform, 190 analytes were measured in 333 CSF samples from cognitively normal (Clinical Dementia Rating [CDR] 0), very mildly demented (CDR 0.5), and mildly demented (CDR 1) individuals. Mean levels of 37 analytes (12 after Bonferroni correction) were found to differ between CDR 0 and CDR>0 groups. Receiver-operating characteristic curve analyses revealed that small combinations of a subset of these markers (cystatin C, VEGF, TRAIL-R3, PAI-1, PP, NT-proBNP, MMP-10, MIF, GRO-α, fibrinogen, FAS, eotaxin-3) enhanced the ability of the best-performing established CSF biomarker, the tau/Aβ42 ratio, to discriminate CDR>0 from CDR 0 individuals. Multiple machine learning algorithms likewise showed that the novel biomarker panels improved the diagnostic performance of the current leading biomarkers. Importantly, most of the markers that best discriminated CDR 0 from CDR>0 individuals in the more targeted ROC analyses were also identified as top predictors in the machine learning models, reconfirming their potential as biomarkers for early-stage AD. Cox proportional hazards models demonstrated that an optimal panel of markers for predicting risk of developing cognitive impairment (CDR 0 to CDR>0 conversion) consisted of calbindin, Aβ42, and age. Using a targeted proteomic screen, we identified novel candidate biomarkers that complement the best current CSF biomarkers for distinguishing very mildly/mildly demented from cognitively normal individuals. Additionally, we identified a novel biomarker (calbindin) with significant prognostic potential.

MeSH Terms
Algorithms Alzheimer Disease/cerebrospinal fluid,complications,diagnosis,genetics Artificial Intelligence Biomarkers/cerebrospinal fluid Cognition Disorders/cerebrospinal fluid,complications Demography Female Genotype Humans Immunoassay/methods Male Middle Aged Prognosis Proportional Hazards Models ROC Curve
Chemicals
Biomarkers
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Craig-Schapiro Rebecca
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Kuhn Max
Xiong Chengjie
Pickering Eve H
Liu Jingxia
Misko Thomas P
Perrin Richard J
Bales Kelly R
Soares Holly
Fagan Anne M
Holtzman David M
References (86)
86 references, click to expand
  1. Biomarkers of Alzheimer's disease.
    Neurobiol Dis. 2009 Aug;35(2):128-40 PMID: 19010417
  2. Serum and cerebrospinal fluid cystatin C levels in vascular and Alzheimer's dementia.
    Acta Neurol Scand. 2000 Apr;101(4):279-82 PMID: 10770527
  3. Decreased beta-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease.
    JAMA. 2003 Apr 23-30;289(16):2094-103 PMID: 12709467
  4. Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study.
    Neurology. 2008 May 6;70(19):1664-71 PMID: 18401021
  5. VEGF genetic variability is associated with increased risk of developing Alzheimer's disease.
    J Neurol Sci. 2009 Aug 15;283(1-2):66-8 PMID: 19272614
  6. Glutamine synthetase, hemoglobin alpha-chain, and macrophage migration inhibitory factor binding to amyloid beta-protein: their identification in rat brain by a novel affinity chromatography and in Alzheimer's disease brain by immunoprecipitation.
    Biochim Biophys Acta. 2000 Jun 15;1479(1-2):91-102 PMID: 11004532
  7. Binding of cystatin C to Alzheimer's amyloid beta inhibits in vitro amyloid fibril formation.
    Neurobiol Aging. 2004 Sep;25(8):1033-43 PMID: 15212828
  8. Measurement of thirteen biological markers in CSF of patients with Alzheimer's disease and other dementias.
    Dement Geriatr Cogn Disord. 2006;21(1):9-15 PMID: 16244482
  9. Identification and validation of novel CSF biomarkers for early stages of Alzheimer's disease.
    Proteomics Clin Appl. 2007 Nov;1(11):1373-84 PMID: 21136637
  10. Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients.
    J Alzheimers Dis. 2009;16(2):389-97 PMID: 19221428
  11. Core candidate neurochemical and imaging biomarkers of Alzheimer's disease.
    Alzheimers Dement. 2008 Jan;4(1):38-48 PMID: 18631949
  12. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study.
    Lancet Neurol. 2006 Mar;5(3):228-34 PMID: 16488378
  13. CSF markers for incipient Alzheimer's disease.
    Lancet Neurol. 2003 Oct;2(10):605-13 PMID: 14505582
  14. Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment.
    Acta Neuropathol. 2010 Jun;119(6):669-78 PMID: 20232070
  15. Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment.
    Arch Neurol. 2007 Mar;64(3):366-70 PMID: 17353378
  16. Increased intrathecal levels of the angiogenic factors VEGF and TGF-beta in Alzheimer's disease and vascular dementia.
    Neurobiol Aging. 2002 Mar-Apr;23(2):237-43 PMID: 11804709
  17. Macrophage migration inhibitory factor in mild cognitive impairment and Alzheimer's disease.
    J Psychiatr Res. 2009 May;43(8):749-53 PMID: 19038405
  18. Cerebrospinal fluid beta-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease.
    Arch Neurol. 1999 Jun;56(6):673-80 PMID: 10369305
  19. Alzheimer's beta-amyloid peptide blocks vascular endothelial growth factor mediated signaling via direct interaction with VEGFR-2.
    J Neurochem. 2010 Jan;112(1):66-76 PMID: 19818105
  20. Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI.
    Neurology. 2006 Aug 8;67(3):467-73 PMID: 16894109
  21. Increase of SCF plasma concentration during donepezil treatment of patients with early Alzheimer's disease.
    Int J Neuropsychopharmacol. 2009 Nov;12(10):1319-26 PMID: 19580698
  22. Meningeal derived cerebrospinal fluid proteins in different forms of dementia: is a meningopathy involved in normal pressure hydrocephalus?
    J Neurol Neurosurg Psychiatry. 2004 Nov;75(11):1614-6 PMID: 15489398
  23. Beta-amyloid induces neuronal apoptosis via a mechanism that involves the c-Jun N-terminal kinase pathway and the induction of Fas ligand.
    J Neurosci. 2001 Oct 1;21(19):7551-60 PMID: 11567045
  24. Increased plasma urotensin-II and carotid atherosclerosis are associated with vascular dementia.
    J Atheroscler Thromb. 2009 Jun;16(3):179-87 PMID: 19638714
  25. Longitudinal study of CSF biomarkers in patients with Alzheimer's disease.
    PLoS One. 2009 Jul 17;4(7):e6294 PMID: 19609443
  26. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease.
    EMBO Mol Med. 2009 Nov;1(8-9):371-80 PMID: 20049742
  27. The tissue plasminogen activator-plasminogen proteolytic cascade accelerates amyloid-beta (Abeta) degradation and inhibits Abeta-induced neurodegeneration.
    J Neurosci. 2003 Oct 1;23(26):8867-71 PMID: 14523088
  28. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study.
    Neurology. 2007 Aug 14;69(7):631-9 PMID: 17698783
  29. Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease.
    Neuropathol Appl Neurobiol. 2001 Oct;27(5):339-42 PMID: 11679085
  30. Cystatin C reduces the in vitro formation of soluble Abeta1-42 oligomers and protofibrils.
    Scand J Clin Lab Invest. 2007;67(2):179-90 PMID: 17365997
  31. YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer's disease.
    Biol Psychiatry. 2010 Nov 15;68(10):903-12 PMID: 21035623
  32. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans.
    Ann Neurol. 2006 Mar;59(3):512-9 PMID: 16372280
  33. Mild cognitive impairment: clinical characterization and outcome.
    Arch Neurol. 1999 Mar;56(3):303-8 PMID: 10190820
  34. Fibrinogen gamma-A chain precursor in CSF: a candidate biomarker for Alzheimer's disease.
    BMC Neurol. 2007 Jun 12;7:14 PMID: 17565664
  35. Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders.
    J Alzheimers Dis. 2006 Aug;9(3):293-348 PMID: 16914840
  36. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease.
    Nature. 2009 Oct 15;461(7266):916-22 PMID: 19829371
  37. Cystatin C inhibits amyloid-beta deposition in Alzheimer's disease mouse models.
    Nat Genet. 2007 Dec;39(12):1440-2 PMID: 18026100
  38. Sparse partial least squares regression for simultaneous dimension reduction and variable selection.
    J R Stat Soc Series B Stat Methodol. 2010 Jan;72(1):3-25 PMID: 20107611
  39. Age-related differences in NFkappaB translocation and Bcl-2/Bax ratio caused by TNFalpha and Abeta42 promote survival in middle-age neurons and death in old neurons.
    Exp Neurol. 2008 Sep;213(1):93-100 PMID: 18625500
  40. Differential activation of tumor necrosis factor receptors distinguishes between brains from Alzheimer's disease and non-demented patients.
    J Alzheimers Dis. 2010;19(2):621-30 PMID: 20110607
  41. Cerebrospinal fluid proteomic biomarkers for Alzheimer's disease.
    Ann Neurol. 2007 Feb;61(2):120-9 PMID: 17167789
  42. Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function.
    Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3227-32 PMID: 9501245
  43. Low serum VEGF levels are associated with Alzheimer's disease.
    Acta Neurol Scand. 2007 Jul;116(1):56-8 PMID: 17587256
  44. Increased cerebrospinal fluid fas (Apo-1) levels in Alzheimer's disease. Relationship with IL-6 concentrations.
    Brain Res. 2000 Jun 30;869(1-2):216-9 PMID: 10865077
  45. Relationship of calbindin D28K-immunoreactive cells and neuropathological changes in the hippocampal formation of Alzheimer's disease.
    Neuropathology. 2001 Sep;21(3):162-7 PMID: 11666012
  46. Relationships between biomarkers in aging and dementia.
    Neurology. 2009 Oct 13;73(15):1193-9 PMID: 19822868
  47. Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients.
    Neuroreport. 2002 Apr 16;13(5):611-5 PMID: 11973456
  48. Serum cystatin C and the risk of Alzheimer disease in elderly men.
    Neurology. 2008 Sep 30;71(14):1072-9 PMID: 18824671
  49. Local and systemic GM-CSF increase in Alzheimer's disease and vascular dementia.
    Acta Neurol Scand. 2001 Mar;103(3):166-74 PMID: 11240564
  50. Specific reduction of calcium-binding protein (28-kilodalton calbindin-D) gene expression in aging and neurodegenerative diseases.
    Proc Natl Acad Sci U S A. 1990 Jun;87(11):4078-82 PMID: 2140897
  51. Genotype and plasma concentration of cystatin C in patients with late-onset Alzheimer disease.
    Dement Geriatr Cogn Disord. 2007;23(4):251-7 PMID: 17310123
  52. The role of macrophage migration inhibitory factor in Alzheimer's disease.
    Mol Med. 2010 Mar;16(3-4):116-21 PMID: 20200619
  53. Evidence for calcium-reducing and excito-protective roles for the calcium-binding protein calbindin-D28k in cultured hippocampal neurons.
    Neuron. 1991 Jan;6(1):41-51 PMID: 1670921
  54. Fas and Fas ligand are associated with neuritic degeneration in the AD brain and participate in beta-amyloid-induced neuronal death.
    Neurobiol Dis. 2003 Apr;12(3):182-93 PMID: 12742739
  55. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.
    Neurology. 2006 Aug 8;67(3):446-52 PMID: 16894106
  56. Ageing and amyloid-beta peptide deposition contribute to an impaired brain tissue plasminogen activator activity by different mechanisms.
    Neurobiol Dis. 2007 Aug;27(2):164-73 PMID: 17566751
  57. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.
    Neurology. 1984 Jul;34(7):939-44 PMID: 6610841
  58. Combining correlated diagnostic tests: application to neuropathologic diagnosis of Alzheimer's disease.
    Med Decis Making. 2004 Nov-Dec;24(6):659-69 PMID: 15534346
  59. Cystatin C modulates cerebral beta-amyloidosis.
    Nat Genet. 2007 Dec;39(12):1437-9 PMID: 18026102
  60. Calbindin-D28k immunoreactivity and selective vulnerability to ischemia in the dentate gyrus of the developing rat.
    Brain Res. 1993 Mar 26;606(2):309-14 PMID: 8490723
  61. Vascular endothelial growth factor gene variability is associated with increased risk for AD.
    Ann Neurol. 2005 Mar;57(3):373-80 PMID: 15732116
  62. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade.
    Lancet Neurol. 2010 Jan;9(1):119-28 PMID: 20083042
  63. VEGF gene and phenotype relation with Alzheimer's disease and mild cognitive impairment.
    Rejuvenation Res. 2006 Winter;9(4):485-93 PMID: 17105389
  64. The FAS gene, brain volume, and disease progression in Alzheimer's disease.
    Alzheimers Dement. 2010 Mar;6(2):118-24 PMID: 19766542
  65. The induction of the TNFalpha death domain signaling pathway in Alzheimer's disease brain.
    Neurochem Res. 2003 Feb;28(2):307-18 PMID: 12608703
  66. Vascular endothelial growth factor (VEGF) affects processing of amyloid precursor protein and beta-amyloidogenesis in brain slice cultures derived from transgenic Tg2576 mouse brain.
    Int J Dev Neurosci. 2009 Oct;27(6):517-23 PMID: 19589380
  67. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease.
    J Alzheimers Dis. 2005 Apr;7(2):125-33; discussion 173-80 PMID: 15851850
  68. Hemorheological mechanisms in Alzheimer's disease.
    Microcirculation. 2007 Aug;14(6):627-34 PMID: 17710633
  69. A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer's disease versus normal aging and frontotemporal dementia.
    Dement Geriatr Cogn Disord. 2007;24(6):434-40 PMID: 17971664
  70. A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer's disease.
    Proteomics. 2003 Aug;3(8):1486-94 PMID: 12923774
  71. Plasminogen activator activity is inhibited while neuroserpin is up-regulated in the Alzheimer disease brain.
    J Neurochem. 2009 Apr;109(2):303-15 PMID: 19222708
  72. Cystatin C protects neuronal cells from amyloid-beta-induced toxicity.
    J Alzheimers Dis. 2010;19(3):885-94 PMID: 20157244
  73. Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease.
    Brain Res Mol Brain Res. 2003 Oct 21;118(1-2):140-6 PMID: 14559363
  74. Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia.
    Stroke. 2005 Dec;36(12):2637-41 PMID: 16269641
  75. Protective effect of transforming growth factor-beta 1 on beta-amyloid neurotoxicity in rat hippocampal neurons.
    Mol Pharmacol. 1996 Feb;49(2):319-28 PMID: 8632765
  76. The Clinical Dementia Rating (CDR): current version and scoring rules.
    Neurology. 1993 Nov;43(11):2412-4 PMID: 8232972
  77. Fibrinogen and beta-amyloid association alters thrombosis and fibrinolysis: a possible contributing factor to Alzheimer's disease.
    Neuron. 2010 Jun 10;66(5):695-709 PMID: 20547128
  78. Oxidative imbalance and cathepsin D changes as peripheral blood biomarkers of Alzheimer disease: a pilot study.
    FEBS Lett. 2005 May 23;579(13):2759-66 PMID: 15907478
  79. Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin.
    Alzheimer Dis Assoc Disord. 1998 Sep;12(3):215-27 PMID: 9772027
  80. Intra-individual stability of CSF biomarkers for Alzheimer's disease over two years.
    J Alzheimers Dis. 2007 Nov;12(3):255-60 PMID: 18057559
  81. Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer's disease.
    J Exp Med. 2007 Aug 6;204(8):1999-2008 PMID: 17664291
  82. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.
    Arch Neurol. 2007 Mar;64(3):343-9 PMID: 17210801
  83. Chromogranin peptides in Alzheimer's disease.
    Exp Gerontol. 2004 Jan;39(1):101-13 PMID: 14724070
  84. Metalloproteinase shedding of Fas ligand regulates beta-amyloid neurotoxicity.
    Curr Biol. 2002 Sep 17;12(18):1595-600 PMID: 12372252
  85. Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B.
    Ann Neurol. 2004 Mar;55(3):306-19 PMID: 14991808
  86. Increasing CSF phospho-tau levels during cognitive decline and progression to dementia.
    Neurobiol Aging. 2008 Oct;29(10):1466-73 PMID: 17512092
Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0018850
Published
2011-04-19
Epub
2011-00-19
Pages
e18850
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3079734
Subset
IM
Grants
NIA NIH HHS · P01 AG026276 · United States
NCATS NIH HHS · UL1 TR000448 · United States
NINDS NIH HHS · P30 NS057105 · United States
NIA NIH HHS · P50 AG05681 · United States
NIA NIH HHS · P01 AG003991 · United States
NIA NIH HHS · P50 AG005681 · United States
NIA NIH HHS · P01 AG03991 · United States
NCRR NIH HHS · UL1 RR024992 · United States
External Links
PubMed source DOI: 10.1371/journal.pone.0018850 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2