Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.
BACKGROUND
Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome.


RESULTS
CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.


CONCLUSIONS
Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.
Division of Neuropathology, Washington University School of Medicine, St. Louis, Missouri, United States of America. rperrin@path.wustl.edu
Richard J
RJ
Perrin
Rebecca
R
Craig-Schapiro
James P
JP
Malone
Aarti R
AR
Shah
Petra
P
Gilmore
Alan E
AE
Davis
Catherine M
CM
Roe
Elaine R
ER
Peskind
Ge
G
Li
Douglas R
DR
Galasko
Christopher M
CM
Clark
Joseph F
JF
Quinn
Jeffrey A
JA
Kaye
John C
JC
Morris
David M
DM
Holtzman
R Reid
RR
Townsend
Anne M
AM
Fagan
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000175:diagnosis*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D002556:Cerebrospinal Fluid Proteins / Q000032:analysis*; D003704:Dementia / Q000175:diagnosis; D018450:Disease Progression; D042241:Early Diagnosis; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012372:ROC Curve; D012720:Severity of Illness Index; D053719:Tandem Mass Spectrometry
D015415:Biomarkers; D002556:Cerebrospinal Fluid Proteins
Neurochem Int. 2009 Sep;55(4):219-25
19524112
Curr Mol Med. 2010 Apr;10(3):259-66
20236058
BMC Neurosci. 2007 Jan 29;8:11
17261189
Anal Chem. 2006 Apr 1;78(7):2171-81
16579595
Eur J Biochem. 1990 Apr 30;189(2):423-9
2110898
Proteomics Clin Appl. 2007 Nov;1(11):1373-84
21136637
J Neuroimmunol. 1991 Apr;32(1):19-28
1705945
Exp Neurol. 2008 Oct;213(2):315-25
18625222
J Neurosci. 2007 Nov 14;27(46):12516-30
18003830
J Alzheimers Dis. 2009;16(2):389-97
19221428
Ann Neurol. 2005 Sep;58(3):436-41
16130094
Neurology. 2007 Oct 16;69(16):1569-79
17761554
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):13713-8
19666512
Ann Neurol. 2003 Jan;53(1):81-90
12509851
J Alzheimers Dis. 2009;18(1):105-11
19625752
Cancer Sci. 2005 Mar;96(3):183-90
15771622
J Alzheimers Dis. 2010;20 Suppl 2:S487-98
20413848
Ann N Y Acad Sci. 2000;920:245-8
11193158
Neuron. 2009 Aug 13;63(3):287-303
19679070
Biometals. 2008 Jun;21(3):367-72
18060472
J Neurochem. 2006 Jul;98(1):78-88
16805798
Brain. 2006 Nov;129(Pt 11):3042-50
17071923
Alzheimer Dis Assoc Disord. 2005 Apr-Jun;19(2):55-66
15942322
Clin Diagn Lab Immunol. 2002 May;9(3):598-604
11986266
Lancet Neurol. 2006 Mar;5(3):228-34
16488378
Acta Neuropathol. 2010 Jun;119(6):669-78
20232070
Proteomics. 2007 Oct;7(20):3651-60
17880003
Arch Neurol. 2007 Mar;64(3):366-70
17353378
Nat Med. 2007 Nov;13(11):1359-62
17934472
Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11566-71
9751706
J Neurochem. 2009 Jul;110(2):496-508
19490362
Science. 1990 Dec 7;250(4986):1423-6
2124002
Jpn J Clin Oncol. 1991 Aug;21(4):251-5
1719260
J Biol Chem. 2004 Jan 30;279(5):3627-34
14597614
Neuron. 2008 Oct 23;60(2):247-57
18957217
Neuron. 2008 Mar 27;57(6):858-71
18367087
Nature. 2010 Feb 18;463(7283):968-72
20139964
J Alzheimers Dis. 2010;20(2):659-68
20164549
Neurology. 2006 Aug 8;67(3):467-73
16894109
Curr Alzheimer Res. 2005 Apr;2(2):191-6
15974918
Glia. 2006 Feb;53(3):241-7
16265666
Glia. 2005 Sep;51(4):266-78
15816038
Exp Gerontol. 2000 Jul;35(4):473-9
10959035
Hypertension. 2010 Feb;55(2):277-83, 6p following 283
20008675
Int Immunol. 1989;1(5):551-4
2489042
Neurosci Lett. 2005 May 20-27;380(1-2):105-10
15854760
J Neurosci. 2005 Feb 23;25(8):1894-903
15728829
Nat Genet. 2009 Oct;41(10):1088-93
19734902
Genomics. 1994 Jul 1;22(1):162-71
7959763
J Neurochem. 2003 May;85(3):662-9
12694392
Alzheimer Dis Assoc Disord. 2008 Jan-Mar;22(1):47-53
18317246
J Neurochem. 2004 Jun;89(5):1260-70
15147519
Ann Neurol. 2009 Jul;66(1):48-54
19360898
Biochemistry. 2008 Jan 29;47(4):1176-85
18171086
Acta Neuropathol. 2007 Feb;113(2):163-75
17024494
EMBO Mol Med. 2009 Nov;1(8-9):371-80
20049742
Matrix Biol. 2009 Sep;28(7):406-15
19520159
Neurobiol Aging. 2008 Jul;29(7):961-8
17321007
BMC Neurol. 2007 Nov 05;7:38
17983474
Neurology. 2007 Aug 14;69(7):631-9
17698783
Free Radic Biol Med. 1999 Jun;26(11-12):1508-12
10401616
J Biol Chem. 2001 Mar 9;276(10):7320-6
11058599
J Cell Sci. 2005 Mar 15;118(Pt 6):1267-77
15741237
Brain Res. 1993 Dec 3;629(2):245-52
7509248
Neuron. 2007 Sep 6;55(5):786-98
17785185
J Neurosci Res. 2010 Jan;88(1):64-72
19598241
Scand J Clin Lab Invest. 2007;67(2):179-90
17365997
Science. 1994 May 27;264(5163):1336-40
8191290
J Neurosci. 2003 Nov 26;23(34):10800-8
14645472
Biol Psychiatry. 2010 Nov 15;68(10):903-12
21035623
Lancet. 1998 Jul 25;352(9124):287
9690413
Ann Neurol. 2006 Mar;59(3):512-9
16372280
FASEB J. 2007 Apr;21(4):968-75
17215481
Cell. 1988 Feb 26;52(4):487-501
3257719
Inflamm Res. 2000 Jun;49(6):305-10
10939621
Mol Neurodegener. 2008 Oct 21;3:16
18939994
J Alzheimers Dis. 2006 Aug;9(3):293-348
16914840
Curr Med Chem. 2005;12(20):2293-315
16181134
J Neuroinflammation. 2006 Sep 27;3:27
17005052
Nat Rev Immunol. 2009 Jan;9(1):62-70
19104500
Nat Genet. 2007 Dec;39(12):1440-2
18026100
J Biol Chem. 2004 Jul 16;279(29):30469-73
15123717
N Engl J Med. 2007 Nov 15;357(20):2016-27
18003958
Cell Death Differ. 2008 May;15(5):879-88
18239671
J Mol Neurosci. 2001 Oct;17(2):101-18
11816784
J Nucl Med. 2009 Sep;50(9):1464-70
19690025
Dis Markers. 2005;21(2):93-101
15920296
Nature. 1990 Aug 23;346(6286):751-4
1697039
Mol Cancer Res. 2009 Nov;7(11):1756-70
19887559
Mol Cell Neurosci. 2002 Nov;21(3):393-409
12498782
Front Cell Neurosci. 2007 Dec 31;1:1
18946519
Ann Neurol. 2007 Feb;61(2):120-9
17167789
Biochem Biophys Res Commun. 2007 Oct 26;362(3):626-32
17727818
Brain Pathol. 2009 Jan;19(1):48-57
18429966
Neurology. 2008 Jun 3;70(23):2212-8
18448869
Am J Pathol. 1997 Dec;151(6):1571-5
9403708
Neurology. 2009 Jan 6;72(1):50-5
19122030
Mech Ageing Dev. 2001 Nov;122(16):1971-83
11589915
Curr Opin Chem Biol. 1998 Feb;2(1):31-9
9667917
J Neurosci. 2009 May 6;29(18):5974-84
19420263
J Biol Chem. 2007 Dec 7;282(49):35831-41
17916554
Endocr J. 2010;57(4):275-86
20203425
Cell Mol Biol (Noisy-le-grand). 2005 Sep 05;51(2):201-14
16171556
J Neurosci. 2008 Sep 24;28(39):9857-69
18815270
Int J Biochem Cell Biol. 2009 Jun;41(6):1361-70
19130896
J Biol Chem. 1993 Dec 5;268(34):25803-10
8245017
Biol Psychiatry. 2009 Jun 1;65(11):927-34
19268916
Brain Res. 1996 Nov 4;738(2):265-74
8955522
Neurol Res. 2006 Mar;28(2):155-63
16551433
Arch Neurol. 2001 Sep;58(9):1395-402
11559310
Biochem J. 1989 Dec 1;264(2):347-55
2604721
Hippocampus. 2008;18(10):1051-63
18570185
Proc Natl Acad Sci U S A. 2004 Aug 10;101(32):11785-90
15280543
Am J Pathol. 2008 Jul;173(1):130-43
18556781
Dementia. 1995 Nov-Dec;6(6):306-11
8563783
JAMA. 2003 Apr 23-30;289(16):2094-103
12709467
Am J Pathol. 2008 Jul;173(1):25-9
18583323
Exp Neurol. 2005 Dec;196(2):273-81
16154129
Mol Biol Cell. 2006 Aug;17(8):3651-63
16760430
Neurosci Lett. 1995 Mar 31;188(3):202-4
7609909
J Neurosci. 2009 Mar 11;29(10):3252-8
19279262
Brain Res. 1992 May 8;579(2):337-41
1378350
J Neuropathol Exp Neurol. 1999 Jul;58(7):719-28
10411342
J Neurochem. 2001 Nov;79(4):903-13
11723183
J Neurochem. 2002 Apr;81(1):178-84
12067231
Am J Pathol. 1995 Aug;147(2):238-44
7639323
Brain Res. 2000 Jan 24;853(2):344-51
10640633
Neurobiol Dis. 2004 Mar;15(2):387-93
15006709
Dev Neurobiol. 2009 Jul;69(8):518-29
19365814
J Neurochem. 1997 Nov;69(5):1904-11
9349534
J Biol Chem. 2009 Oct 30;284(44):30177-86
19723623
J Biol Chem. 2003 Feb 21;278(8):6521-31
12473676
Proteomics. 2003 Jan;3(1):36-44
12548632
Neurology. 2009 Oct 13;73(15):1193-9
19822868
Med Hypotheses. 2004;63(1):115-7
15193361
Neuroreport. 2002 Apr 16;13(5):611-5
11973456
Cent Nerv Syst Agents Med Chem. 2009 Jun;9(2):119-31
20021345
J Biol Chem. 2004 Feb 6;279(6):4221-33
14638689
Biochem J. 1995 Jul 1;309 ( Pt 1):315-20
7619073
Brain Res Mol Brain Res. 2002 Dec 30;109(1-2):128-33
12531522
Neurobiol Aging. 1997 Jul-Aug;18(4):351-7
9330961
Hippocampus. 2008;18(4):349-63
18064706
J Biol Chem. 2000 Nov 3;275(44):34260-5
10954708
J Immunol. 2007 Jun 15;178(12):8158-67
17548654
J Clin Invest. 2008 Jan;118(1):133-48
18079966
J Biol Chem. 2009 Feb 20;284(8):5195-207
19049969
Neurology. 2006 Nov 14;67(9):1581-5
17101887
Traffic. 2009 May;10(5):572-89
19192245
Curr Chem Biol. 2009 May 1;3(2):138-145
19890475
Eur Rev Med Pharmacol Sci. 2009 Sep-Oct;13(5):397-9
19961048
J Proteome Res. 2008 Feb;7(2):720-30
18186601
Biochim Biophys Acta. 2008 Dec;1780(12):1441-7
18706485
Am J Pathol. 2003 Jun;162(6):2041-57
12759259
Science. 1997 Oct 10;278(5336):294-8
9323209
Trends Neurosci. 2009 Dec;32(12):619-28
19796831
J Mol Neurosci. 2009 Feb;37(2):151-9
18607778
Neurology. 1984 Jul;34(7):939-44
6610841
Am J Pathol. 1994 Sep;145(3):640-9
8080046
Cell Mol Neurobiol. 2004 Aug;24(4):517-33
15233376
Neurosci Lett. 2005 Jun 3;380(3):219-22
15862889
Ann Neurol. 2009 Feb;65(2):176-83
19260027
Free Radic Biol Med. 2002 Aug 1;33(3):337-49
12126755
Nat Genet. 2007 Dec;39(12):1437-9
18026102
Lancet. 1998 Apr 11;351(9109):1105-6
9660591
J Comp Neurol. 2004 Jul 26;475(3):289-302
15221946
Neurobiol Aging. 2011 Feb;32(2):272-9
19282067
EMBO J. 2009 Oct 7;28(19):3027-39
19713936
Mol Cell Neurosci. 2001 Jan;17(1):151-66
11161476
J Neurochem. 1996 Jun;66(6):2429-35
8632166
Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9593-6
7937812
Proc Natl Acad Sci U S A. 2005 Nov 15;102(46):16771-6
16260723
Prion. 2008 Jan-Mar;2(1):23-7
19164917
Neuroscience. 1992;46(1):1-8
1594095
Neuroreport. 1997 Oct 20;8(15):3183-8
9351640
Cereb Cortex. 2010 Jun;20(6):1386-97
19892786
Proteomics. 2006 Apr;6(7):2305-13
16552785
Anal Chem. 2004 Jul 15;76(14):4193-201
15253663
Neurobiol Aging. 2004 Sep;25(8):1001-7
15212824
Neurology. 2008 May 6;70(19 Pt 2):1827-35
18458217
Neurosci Lett. 1991 Sep 16;130(2):165-8
1686639
Neurosci Lett. 2005 Nov 4;388(1):49-53
16039064
J Neuropathol Exp Neurol. 2002 Dec;61(12):1069-77
12484569
Am J Pathol. 2000 Feb;156(2):489-99
10666378
Arch Neurol. 2009 May;66(5):638-45
19433664
Biochim Biophys Acta. 2008 Jun;1778(6):1429-35
18420026
Cell Mol Life Sci. 2009 Oct;66(19):3095-101
19644733
J Alzheimers Dis. 2005 Apr;7(2):125-33; discussion 173-80
15851850
Eur J Neurosci. 1998 Mar;10(3):1084-94
9753176
Dement Geriatr Cogn Disord. 2007;24(6):434-40
17971664
Proteomics. 2003 Aug;3(8):1486-94
12923774
J Immunol. 2003 Apr 1;170(7):3850-8
12646653
J Alzheimers Dis. 2007 May;11(2):229-40
17522447
J Neural Transm (Vienna). 2006 Nov;113(11):1763-9
16736242
J Neurosci. 2010 Apr 7;30(14):4981-9
20371818
J Neurosci. 2007 Jun 27;27(26):7006-10
17596449
J Neurochem. 2009 Jan;108(2):350-60
19046403
J Immunol. 2008 Oct 1;181(7):5167-73
18802121
Curr Med Chem Cardiovasc Hematol Agents. 2004 Jul;2(3):239-48
15320789
Brain Res. 2009 Apr 10;1265:158-70
19368810
J Cell Sci. 2005 Oct 15;118(Pt 20):4785-95
16219686
Proc Natl Acad Sci U S A. 2007 Apr 10;104(15):6412-7
17404210
Brain Res Mol Brain Res. 2003 Oct 21;118(1-2):140-6
14559363
J Lipid Res. 2001 Jul;42(7):1143-51
11441143
Mol Cell Proteomics. 2005 Dec;4(12):2000-9
16199891
Neurology. 1993 Nov;43(11):2412-4
8232972
Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2681-6
18272491
J Biochem. 1992 May;111(5):573-8
1386357
Arch Neurol. 2006 Jan;63(1):38-46
16401735
Neurobiol Dis. 2009 Oct;36(1):42-50
19607917
J Comp Neurol. 2005 Apr 25;485(1):1-10
15776443
Nat Genet. 2009 Oct;41(10):1094-9
19734903
J Neurochem. 2005 Dec;95(5):1351-62
16219026
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3275-80
9501253
J Neurochem. 2008 Aug;106(4):1841-54
18624913
Lancet. 1997 Sep 13;350(9080):784
9298004
Histochemistry. 1990;94(4):427-33
2228738
Biochem Biophys Res Commun. 1999 May 10;258(2):241-6
10329371
PLoS One. 2008 Aug 06;3(8):e2899
18682830
J Biol Chem. 2003 Dec 12;278(50):50578-87
14514689
Intern Med. 1995 Jun;34(6):481-4
7549128
J Biol Chem. 1968 Aug 10;243(15):4095-103
4175239
Arch Neurol. 2007 Mar;64(3):343-9
17210801
J Clin Neurosci. 2005 Sep;12(7):754-7
16153848
Acta Histochem Cytochem. 2007 Aug 30;40(4):113-21
17898875
Biochem J. 2004 Jun 15;380(Pt 3):651-9
15015934
Ann Neurol. 1995 Oct;38(4):643-8
7574461
Exp Gerontol. 2004 Jan;39(1):101-13
14724070
Anal Chem. 2003 Mar 15;75(6):1300-6
12659189
J Neural Transm (Vienna). 1998;105(1):39-51
9588759