Cerebrospinal Fluid Biomarkers in Alzheimer’s Disease

  • Henrik ZetterbergEmail author
  • Jonathan M. Schott
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Alzheimer’s disease (AD) is a progressive neurodegenerative disease, which typically shows an initial predilection for brain regions involved in episodic memory consolidation before progressing to affect also other cognitive functions. Neuropathologically, the disease is characterised by accumulation of a 42-amino acid-long protein called amyloid β (Aβ42), as well as N-terminally truncated fragments thereof in extracellular senile plaques. In addition to senile plaques, there are intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuroaxonal degeneration and loss. Clinical chemistry tests for these pathologies have been developed and applied to cerebrospinal fluid samples. Here, we review what these markers have taught us about the disease process in AD and how they can be used as diagnostic tests in clinical practice as well as inclusion criteria and outcome measures for clinical trials. We describe both how such analyses are currently performed in clinical chemistry laboratories and the ongoing efforts to standardise analysis between different sites. Finally, we are also providing an overview of new markers in various stages of development and implementation.

Key words

Alzheimer’s disease Biomarkers Cerebrospinal fluid Plasma Tau Amyloid Clinical trials Clinical diagnosis 



Alzheimer’s disease


Familial AD


Creutzfeldt-Jakob disease


Amyloid precursor protein


Soluble APP alpha


Soluble APP beta


Beta-site APP-cleaving enzyme


Central nervous system


Cerebrospinal fluid






Amyloid β-42


Mild cognitive impairment


Neurofilament light


Transforming growth factor-β


Tumour necrosis factor α


Interleukin 1β


C-C chemokine ligand 2


Coefficient of variation


Human immunodeficiency virus


Quality control


Global Consortium for Biomarker Standardization


International Federation of Clinical Chemistry and Laboratory Medicine


Enzyme-linked immunosorbent assay



We gratefully acknowledge the support of the Leonard Wolfson Experimental Neurology Centre. Work in the authors’ laboratories is supported by the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Alzheimer’s Association, Swedish State Support for Clinical Research, Alzheimer’s Research UK and the NIHR Queen Square BRU in dementia. We wish to thank colleagues, patients and their families for generating the extensive literature that was reviewed here.


  1. 1.
    Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat 8(6):429–431PubMedCrossRefGoogle Scholar
  2. 2.
    Blennow K, De Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368(9533):387–403PubMedCrossRefGoogle Scholar
  3. 3.
    Tomlinson BE, Blessed G, Roth M (1970) Observations on the brains of demented old people. J Neurol Sci 11(3):205–242PubMedCrossRefGoogle Scholar
  4. 4.
    Katzman R (1986) Alzheimer’s disease. N Engl J Med 314(15):964–973PubMedCrossRefGoogle Scholar
  5. 5.
    Roth M, Tomlinson BE, Blessed G (1966) Correlation between scores for dementia and counts of ‘senile plaques’ in cerebral grey matter of elderly subjects. Nature 209(5018):109–110PubMedCrossRefGoogle Scholar
  6. 6.
    Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890PubMedCrossRefGoogle Scholar
  7. 7.
    Masters CL, Simms G, Weinman NA, Multhaup G, Mcdonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82(12):4245–4249PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Portelius E, Bogdanovic N, Gustavsson MK et al (2010) Mass spectrometric characterization of brain amyloid beta isoform signatures in familial and sporadic Alzheimer’s disease. Acta Neuropathol 120(2):185–193PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 83(13):4913–4917PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Nukina N, Ihara Y (1986) One of the antigenic determinants of paired helical filaments is related to tau protein. J Biochem 99(5):1541–1544PubMedGoogle Scholar
  11. 11.
    Mandelkow EM, Mandelkow E (2012) Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med 2(7):a006247PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Kang J, Lemaire HG, Unterbeck A et al (1987) The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 325(6106):733–736PubMedCrossRefGoogle Scholar
  13. 13.
    Goldgaber D, Lerman MI, Mcbride OW, Saffiotti U, Gajdusek DC (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science 235(4791):877–880PubMedCrossRefGoogle Scholar
  14. 14.
    Popovitch ER, Wisniewski HM, Barcikowska M et al (1990) Alzheimer neuropathology in non-Down’s syndrome mentally retarded adults. Acta Neuropathol 80(4):362–367PubMedCrossRefGoogle Scholar
  15. 15.
    Van Nostrand WE, Wagner SL, Suzuki M et al (1989) Protease nexin-II, a potent antichymotrypsin, shows identity to amyloid beta-protein precursor. Nature 341(6242):546–549PubMedCrossRefGoogle Scholar
  16. 16.
    Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587(13):2046–2054PubMedCrossRefGoogle Scholar
  17. 17.
    Mullan M, Crawford F, Axelman K et al (1992) A pathogenic mutation for probable Alzheimer’s disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet 1(5):345–347PubMedCrossRefGoogle Scholar
  18. 18.
    Van Duijn CM, Hendriks L, Cruts M, Hardy JA, Hofman A, Van Broeckhoven C (1991) Amyloid precursor protein gene mutation in early-onset alzheimer’s disease. Lancet 337(8747):978Google Scholar
  19. 19.
    Chartier-Harlin MC, Crawford F, Houlden H et al (1991) Early-onset alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353(6347):844–846Google Scholar
  20. 20.
    Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766PubMedGoogle Scholar
  21. 21.
    Chavez-Gutierrez L, Bammens L, Benilova I et al (2012) The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J 31(10):2261–2274PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Walsh DM, Selkoe DJ (2007) A beta oligomers—a decade of discovery. J Neurochem 101(5):1172–1184PubMedCrossRefGoogle Scholar
  23. 23.
    Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185PubMedCrossRefGoogle Scholar
  24. 24.
    Hardy J, Bogdanovic N, Winblad B et al (2014) Pathways to Alzheimer’s disease. J Intern Med 275(3):296–303PubMedCrossRefGoogle Scholar
  25. 25.
    Jonsson T, Atwal JK, Steinberg S et al (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409):96–99PubMedCrossRefGoogle Scholar
  26. 26.
    Blennow K, Wallin A (1992) Clinical heterogeneity of probable Alzheimer’s disease. J Geriatr Psychiatry Neurol 5(2):106–113PubMedCrossRefGoogle Scholar
  27. 27.
    Potter R, Patterson BW, Elbert DL et al. (2013) Increased in vivo amyloid-beta42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med 5(189):189ra177Google Scholar
  28. 28.
    Pedersen NL, Gatz M, Berg S, Johansson B (2004) How heritable is Alzheimer’s disease late in life? Findings from Swedish twins. Ann Neurol 55(2):180–185PubMedCrossRefGoogle Scholar
  29. 29.
    Gatz M, Reynolds CA, Fratiglioni L et al (2006) Role of genes and environments for explaining Alzheimer disease. Arch Gen Psychiatry 63(2):168–174PubMedCrossRefGoogle Scholar
  30. 30.
    Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2(3):a006312PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Lambert JC, Ibrahim-Verbaas CA, Harold D et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Jones L, Holmans PA, Hamshere ML et al (2010) Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS ONE 5(11), e13950PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Guerreiro R, Wojtas A, Bras J et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2):117–127PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Jonsson T, Stefansson H, Steinberg S et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Fjell AM, Mcevoy L, Holland D, Dale AM, Walhovd KB (2013) Brain changes in older adults at very low risk for Alzheimer’s disease. J Neurosci 33(19):8237–8242PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C (2009) Age, neuropathology, and dementia. N Engl J Med 360(22):2302–2309PubMedCrossRefGoogle Scholar
  37. 37.
    Mattsson N, Rosen E, Hansson O et al (2012) Age and diagnostic performance of Alzheimer disease CSF biomarkers. Neurology 78(7):468–476PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Thal DR, Rub U, Orantes M, Braak H (2002) Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800PubMedCrossRefGoogle Scholar
  39. 39.
    Braak H, Zetterberg H, Del Tredici K, Blennow K (2013) Intraneuronal tau aggregation precedes diffuse plaque deposition, but amyloid-beta changes occur before increases of tau in cerebrospinal fluid. Acta Neuropathol 126(5):631–641PubMedCrossRefGoogle Scholar
  40. 40.
    Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71(5):362–381PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Wojtas A, Heggeli KA, Finch N et al (2012) C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic. Am J Neurodegener Dis 1(1):107–118PubMedPubMedCentralGoogle Scholar
  42. 42.
    Jin SC, Pastor P, Cooper B et al (2012) Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease Ibero-American cohort. Alzheimers Res Ther 4(4):34PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Gottfries CG, Gottfries I, Roos BE (1969) Homovanillic acid and 5-hydroxyindoleacetic acid in the cerebrospinal fluid of patients with senile dementia, presenile dementia and parkinsonism. J Neurochem 16(9):1341–1345PubMedCrossRefGoogle Scholar
  44. 44.
    Gottfries CG, Gottfries I, Roos BE (1970) Homovanillic acid and 5-hydroxyindoleacetic acid in cerebrospinal fluid related to rated mental and motor impairment in senile and presenile dementia. Acta Psychiatr Scand 46(2):99–105PubMedGoogle Scholar
  45. 45.
    Gottfries CG, Kjallquist A, Ponten U, Roos BE, Sundbarg G (1974) Cerebrospinal fluid pH and monoamine and glucolytic metabolites in Alzheimer’s disease. Br J Psychiatry 124:280–287PubMedCrossRefGoogle Scholar
  46. 46.
    Glenner GG, Wong CW (1984) Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 122(3):1131–1135PubMedCrossRefGoogle Scholar
  47. 47.
    Haass C, Schlossmacher MG, Hung AY et al (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359(6393):322–325PubMedCrossRefGoogle Scholar
  48. 48.
    Portelius E, Price E, Brinkmalm G et al (2011) A novel pathway for amyloid precursor protein processing. Neurobiol Aging 32(6):1090–1098PubMedCrossRefGoogle Scholar
  49. 49.
    Motter R, Vigo-Pelfrey C, Kholodenko D et al (1995) Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 38(4):643–648PubMedCrossRefGoogle Scholar
  50. 50.
    Rosen C, Hansson O, Blennow K, Zetterberg H (2013) Fluid biomarkers in Alzheimer’s disease—current concepts. Mol Neurodegener 8:20PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Strozyk D, Blennow K, White LR, Launer LJ (2003) CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60(4):652–656PubMedCrossRefGoogle Scholar
  52. 52.
    Fagan AM, Mintun MA, Mach RH et al (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59(3):512–519PubMedCrossRefGoogle Scholar
  53. 53.
    Forsberg A, Engler H, Almkvist O et al (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29(10):1456–1465PubMedCrossRefGoogle Scholar
  54. 54.
    Seppala TT, Nerg O, Koivisto AM et al (2012) CSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings. Neurology 78(20):1568–1575PubMedCrossRefGoogle Scholar
  55. 55.
    Andreasen N, Minthon L, Vanmechelen E et al (1999) Cerebrospinal fluid tau and Abeta42 as predictors of development of Alzheimer’s disease in patients with mild cognitive impairment. Neurosci Lett 273(1):5–8PubMedCrossRefGoogle Scholar
  56. 56.
    Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L (2006) Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 5(3):228–234PubMedCrossRefGoogle Scholar
  57. 57.
    Shaw LM, Vanderstichele H, Knapik-Czajka M et al (2009) Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann Neurol 65(4):403–413PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Visser PJ, Verhey F, Knol DL et al (2009) Prevalence and prognostic value of CSF markers of Alzheimer’s disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol 8(7):619–627PubMedCrossRefGoogle Scholar
  59. 59.
    Buchhave P, Minthon L, Zetterberg H, Wallin AK, Blennow K, Hansson O (2012) Cerebrospinal fluid levels of beta-amyloid 1-42, but not of tau, are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry 69(1):98–106PubMedCrossRefGoogle Scholar
  60. 60.
    Skoog I, Davidsson P, Aevarsson O, Vanderstichele H, Vanmechelen E, Blennow K (2003) Cerebrospinal fluid beta-amyloid 42 is reduced before the onset of sporadic dementia: a population-based study in 85-year-olds. Dement Geriatr Cogn Disord 15(3):169–176PubMedCrossRefGoogle Scholar
  61. 61.
    Fagan AM, Head D, Shah AR et al (2009) Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly. Ann Neurol 65(2):176–183PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Gustafson DR, Skoog I, Rosengren L, Zetterberg H, Blennow K (2007) Cerebrospinal fluid beta-amyloid 1-42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry 78(5):461–464PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Dubois B, Feldman HH, Jacova C et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13(6):614–629PubMedCrossRefGoogle Scholar
  64. 64.
    Sjogren M, Gisslen M, Vanmechelen E, Blennow K (2001) Low cerebrospinal fluid beta-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment. Neurosci Lett 314(1–2):33–36PubMedCrossRefGoogle Scholar
  65. 65.
    Mattsson N, Axelsson M, Haghighi S et al (2009) Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis. Mult Scler 15(4):448–454PubMedCrossRefGoogle Scholar
  66. 66.
    Gisslen M, Krut J, Andreasson U et al (2009) Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 9:63PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Mattsson N, Bremell D, Anckarsater R et al (2010) Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism. BMC Neurol 10:51PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Schoonenboom NS, Mulder C, Van Kamp GJ et al (2005) Amyloid beta 38, 40, and 42 species in cerebrospinal fluid: more of the same? Ann Neurol 58(1):139–142PubMedCrossRefGoogle Scholar
  69. 69.
    Portelius E, Zetterberg H, Andreasson U et al (2006) An Alzheimer’s disease-specific beta-amyloid fragment signature in cerebrospinal fluid. Neurosci Lett 409(3):215–219PubMedCrossRefGoogle Scholar
  70. 70.
    Mattsson N, Portelius E, Rolstad S et al (2012) Longitudinal cerebrospinal fluid biomarkers over four years in mild cognitive impairment. J Alzheimers Dis 30(4):767–778PubMedGoogle Scholar
  71. 71.
    Vandermeeren M, Mercken M, Vanmechelen E et al (1993) Detection of tau proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzyme-linked immunosorbent assay. J Neurochem 61(5):1828–1834PubMedCrossRefGoogle Scholar
  72. 72.
    Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26(3):231–245PubMedCrossRefGoogle Scholar
  73. 73.
    Wang L, Fagan AM, Shah AR et al (2012) Cerebrospinal fluid proteins predict longitudinal hippocampal degeneration in early-stage dementia of the Alzheimer type. Alzheimer Dis Assoc Disord 26(4):314–321PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Glodzik L, Mosconi L, Tsui W et al (2012) Alzheimer’s disease markers, hypertension, and gray matter damage in normal elderly. Neurobiol Aging 33(7):1215–1227PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Trojanowski JQ, Schuck T, Schmidt ML, Lee VM (1989) Distribution of tau proteins in the normal human central and peripheral nervous system. J Histochem Cytochem 37(2):209–215PubMedCrossRefGoogle Scholar
  76. 76.
    Hesse C, Rosengren L, Andreasen N et al (2001) Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 297(3):187–190PubMedCrossRefGoogle Scholar
  77. 77.
    Zetterberg H, Hietala MA, Jonsson M et al (2006) Neurochemical aftermath of amateur boxing. Arch Neurol 63(9):1277–1280PubMedCrossRefGoogle Scholar
  78. 78.
    Wallin AK, Blennow K, Zetterberg H, Londos E, Minthon L, Hansson O (2010) CSF biomarkers predict a more malignant outcome in Alzheimer disease. Neurology 74(19):1531–1537PubMedCrossRefGoogle Scholar
  79. 79.
    Sanchez-Juan P, Sanchez-Valle R, Green A et al (2007) Influence of timing on CSF tests value for Creutzfeldt-Jakob disease diagnosis. J Neurol 254(7):901–906PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Saman S, Kim W, Raya M et al (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287(6):3842–3849PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Maia LF, Kaeser SA, Reichwald J et al. (2013) Changes in amyloid-beta and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med 5(194):194re192Google Scholar
  82. 82.
    Meredith JE Jr, Sankaranarayanan S, Guss V et al (2013) Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer’s Disease. PLoS ONE 8(10), e76523PubMedCrossRefGoogle Scholar
  83. 83.
    Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6(3):131–144PubMedCrossRefGoogle Scholar
  84. 84.
    Uryu K, Chen XH, Martinez D et al (2007) Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans. Exp Neurol 208(2):185–192PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Wischik CM, Novak M, Thogersen HC et al (1988) Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 85(12):4506–4510PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Hampel H, Buerger K, Zinkowski R et al (2004) Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 61(1):95–102PubMedCrossRefGoogle Scholar
  87. 87.
    Buerger K, Ewers M, Pirttila T et al (2006) CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer’s disease. Brain 129(Pt 11):3035–3041PubMedCrossRefGoogle Scholar
  88. 88.
    Riemenschneider M, Wagenpfeil S, Vanderstichele H et al (2003) Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Mol Psychiatry 8(3):343–347PubMedCrossRefGoogle Scholar
  89. 89.
    Skillback T, Rosen C, Asztely F, Mattsson N, Blennow K, Zetterberg H (2014) Diagnostic performance of cerebrospinal fluid total tau and phosphorylated tau in Creutzfeldt-Jakob disease: results from the Swedish Mortality Registry. JAMA Neurol 71(4):476–483PubMedCrossRefGoogle Scholar
  90. 90.
    Mattsson N, Savman K, Osterlundh G, Blennow K, Zetterberg H (2009) Converging molecular pathways in human neural development and degeneration. Neurosci Res 66(3):330–332PubMedCrossRefGoogle Scholar
  91. 91.
    Grahn A, Hagberg L, Nilsson S, Blennow K, Zetterberg H, Studahl M (2013) Cerebrospinal fluid biomarkers in patients with varicella-zoster virus CNS infections. J Neurol 260(7):1813–1821PubMedCrossRefGoogle Scholar
  92. 92.
    Kondziella D, Zetterberg H (2008) Hyperphosphorylation of tau protein in superficial CNS siderosis. J Neurol Sci 273(1–2):130–132PubMedCrossRefGoogle Scholar
  93. 93.
    Ikeda T, Noto D, Noguchi-Shinohara M et al (2010) CSF tau protein is a useful marker for effective treatment of superficial siderosis of the central nervous system: two case reports. Clin Neurol Neurosurg 112(1):62–64PubMedCrossRefGoogle Scholar
  94. 94.
    Williams CT, Barnes BM, Richter M, Buck CL (2012) Hibernation and circadian rhythms of body temperature in free-living Arctic ground squirrels. Physiol Biochem Zool 85(4):397–404PubMedCrossRefGoogle Scholar
  95. 95.
    Hartig W, Stieler J, Boerema AS et al (2007) Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons—implications for Alzheimer’s disease. Eur J Neurosci 25(1):69–80PubMedCrossRefGoogle Scholar
  96. 96.
    Whittington RA, Bretteville A, Dickler MF, Planel E (2013) Anesthesia and tau pathology. Prog Neuropsychopharmacol Biol Psychiatry 47:147–155PubMedCrossRefGoogle Scholar
  97. 97.
    Johansson P, Mattsson N, Hansson O et al (2011) Cerebrospinal fluid biomarkers for Alzheimer’s disease: diagnostic performance in a homogeneous mono-center population. J Alzheimers Dis 24(3):537–546PubMedGoogle Scholar
  98. 98.
    Mattsson N, Zetterberg H, Hansson O et al (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302(4):385–393PubMedCrossRefGoogle Scholar
  99. 99.
    Baumann TP, Duyar H, Sollberger M et al (2010) CSF-tau and CSF-Abeta(1-42) in posterior cortical atrophy. Dement Geriatr Cogn Disord 29(6):530–533PubMedCrossRefGoogle Scholar
  100. 100.
    Seguin J, Formaglio M, Perret-Liaudet A et al (2011) CSF biomarkers in posterior cortical atrophy. Neurology 76(21):1782–1788PubMedCrossRefGoogle Scholar
  101. 101.
    Bibl M, Mollenhauer B, Lewczuk P et al (2011) Cerebrospinal fluid tau, p-tau 181 and amyloid-beta38/40/42 in frontotemporal dementias and primary progressive aphasias. Dement Geriatr Cogn Disord 31(1):37–44PubMedCrossRefGoogle Scholar
  102. 102.
    Borroni B, Premi E, Agosti C et al (2011) CSF Alzheimer’s disease-like pattern in corticobasal syndrome: evidence for a distinct disorder. J Neurol Neurosurg Psychiatry 82(8):834–838PubMedCrossRefGoogle Scholar
  103. 103.
    Toledo JB, Xie SX, Trojanowski JQ, Shaw LM (2013) Longitudinal change in CSF tau and Abeta biomarkers for up to 48 months in ADNI. Acta Neuropathol 126(5):659–670PubMedCrossRefGoogle Scholar
  104. 104.
    Mattsson N, Insel P, Nosheny R et al (2013) CSF protein biomarkers predicting longitudinal reduction of CSF beta-amyloid42 in cognitively healthy elders. Transl Psychiatry 3, e293PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Moghekar A, Li S, Lu Y et al (2013) CSF biomarker changes precede symptom onset of mild cognitive impairment. Neurology 81(20):1753–1758PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Zetterberg H, Pedersen M, Lind K et al (2007) Intra-individual stability of CSF biomarkers for Alzheimer’s disease over two years. J Alzheimers Dis 12(3):255–260PubMedGoogle Scholar
  107. 107.
    Blennow K, Zetterberg H, Minthon L et al (2007) Longitudinal stability of CSF biomarkers in Alzheimer’s disease. Neurosci Lett 419(1):18–22PubMedCrossRefGoogle Scholar
  108. 108.
    Mattsson N, Rajendran L, Zetterberg H et al (2012) BACE1 inhibition induces a specific cerebrospinal fluid beta-amyloid pattern that identifies drug effects in the central nervous system. PLoS ONE 7(2), e31084PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Lannfelt L, Blennow K, Zetterberg H et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7(9):779–786PubMedCrossRefGoogle Scholar
  110. 110.
    May PC, Dean RA, Lowe SL et al (2011) Robust central reduction of amyloid-beta in humans with an orally available, non-peptidic beta-secretase inhibitor. J Neurosci 31(46):16507–16516PubMedCrossRefGoogle Scholar
  111. 111.
    Portelius E, Dean RA, Gustavsson MK et al (2010) A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimers Res Ther 2(2):7PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Gilman S, Koller M, Black RS et al (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64(9):1553–1562PubMedCrossRefGoogle Scholar
  113. 113.
    Blennow K, Zetterberg H, Rinne JO et al (2012) Effect of immunotherapy with bapineuzumab on cerebrospinal fluid biomarker levels in patients with mild to moderate Alzheimer disease. Arch Neurol 69(8):1002–1010PubMedCrossRefGoogle Scholar
  114. 114.
    Schott JM, Warren JD (2012) Alzheimer’s disease: mimics and chameleons. Pract Neurol 12(6):358–366PubMedCrossRefGoogle Scholar
  115. 115.
    Shim YS, Roe CM, Buckles VD, Morris JC (2013) Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics. J Alzheimers Dis 35(4):799–811PubMedPubMedCentralGoogle Scholar
  116. 116.
    Andreasson U, Portelius E, Andersson ME, Blennow K, Zetterberg H (2007) Aspects of beta-amyloid as a biomarker for Alzheimer’s disease. Biomark Med 1(1):59–78PubMedCrossRefGoogle Scholar
  117. 117.
    Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59(9):1381–1389PubMedCrossRefGoogle Scholar
  118. 118.
    Holsinger RM, Lee JS, Boyd A, Masters CL, Collins SJ (2006) CSF BACE1 activity is increased in CJD and Alzheimer disease versus other dementias. Neurology 67(4):710–712PubMedCrossRefGoogle Scholar
  119. 119.
    Holsinger RM, Mclean CA, Collins SJ, Masters CL, Evin G (2004) Increased beta-Secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Ann Neurol 55(6):898–899PubMedCrossRefGoogle Scholar
  120. 120.
    Zetterberg H, Andreasson U, Hansson O et al (2008) Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol 65(8):1102–1107PubMedCrossRefGoogle Scholar
  121. 121.
    Mulder SD, Van Der Flier WM, Verheijen JH et al (2010) BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology. J Alzheimers Dis 20(1):253–260PubMedGoogle Scholar
  122. 122.
    Zhong Z, Ewers M, Teipel S et al (2007) Levels of beta-secretase (BACE1) in cerebrospinal fluid as a predictor of risk in mild cognitive impairment. Arch Gen Psychiatry 64(6):718–726PubMedCrossRefGoogle Scholar
  123. 123.
    Rosen C, Andreasson U, Mattsson N et al (2012) Cerebrospinal fluid profiles of amyloid beta-related biomarkers in Alzheimer’s disease. Neuromolecular Med 14(1):65–73PubMedCrossRefGoogle Scholar
  124. 124.
    Olsson A, Hoglund K, Sjogren M et al (2003) Measurement of alpha- and beta-secretase cleaved amyloid precursor protein in cerebrospinal fluid from Alzheimer patients. Exp Neurol 183(1):74–80PubMedCrossRefGoogle Scholar
  125. 125.
    Perneczky R, Tsolakidou A, Arnold A et al (2011) CSF soluble amyloid precursor proteins in the diagnosis of incipient Alzheimer disease. Neurology 77(1):35–38PubMedCrossRefGoogle Scholar
  126. 126.
    Lewczuk P, Kamrowski-Kruck H, Peters O et al (2010) Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer’s disease: a multicenter study. Mol Psychiatry 15(2):138–145PubMedCrossRefGoogle Scholar
  127. 127.
    Lewczuk P, Popp J, Lelental N et al (2012) Cerebrospinal fluid soluble amyloid-beta protein precursor as a potential novel biomarkers of Alzheimer’s disease. J Alzheimers Dis 28(1):119–125PubMedGoogle Scholar
  128. 128.
    Gabelle A, Roche S, Geny C et al (2010) Correlations between soluble alpha/beta forms of amyloid precursor protein and Abeta38, 40, and 42 in human cerebrospinal fluid. Brain Res 1357:175–183PubMedCrossRefGoogle Scholar
  129. 129.
    Castellani RJ, Smith MA (2011) Compounding artefacts with uncertainty, and an amyloid cascade hypothesis that is ‘too big to fail’. J Pathol 224(2):147–152PubMedCrossRefGoogle Scholar
  130. 130.
    Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416(6880):535–539PubMedCrossRefGoogle Scholar
  131. 131.
    Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938–11950PubMedCrossRefGoogle Scholar
  132. 132.
    Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108(14):5819–5824PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    De Felice FG, Wu D, Lambert MP et al (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9):1334–1347PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Bruggink KA, Jongbloed W, Biemans EA et al (2013) Amyloid-beta oligomer detection by ELISA in cerebrospinal fluid and brain tissue. Anal Biochem 433(2):112–120PubMedCrossRefGoogle Scholar
  135. 135.
    Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14(8):837–842PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Gao CM, Yam AY, Wang X et al (2010) Abeta40 oligomers identified as a potential biomarker for the diagnosis of Alzheimer’s disease. PLoS ONE 5(12), e15725PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Fukumoto H, Tokuda T, Kasai T et al (2010) High-molecular-weight {beta}-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J 24(8):2716–2726PubMedCrossRefGoogle Scholar
  138. 138.
    Georganopoulou DG, Chang L, Nam JM et al (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc Natl Acad Sci U S A 102(7):2273–2276PubMedPubMedCentralCrossRefGoogle Scholar
  139. 139.
    Pitschke M, Prior R, Haupt M, Riesner D (1998) Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy. Nat Med 4(7):832–834PubMedCrossRefGoogle Scholar
  140. 140.
    Holtta M, Hansson O, Andreasson U et al (2013) Evaluating amyloid-beta oligomers in cerebrospinal fluid as a biomarker for Alzheimer’s disease. PLoS ONE 8(6), e66381PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Handoko M, Grant M, Kuskowski M et al (2013) Correlation of specific amyloid-beta oligomers with tau in cerebrospinal fluid from cognitively normal older adults. JAMA Neurol 70(5):594–599PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Santos AN, Torkler S, Nowak D et al (2007) Detection of amyloid-beta oligomers in human cerebrospinal fluid by flow cytometry and fluorescence resonance energy transfer. J Alzheimers Dis 11(1):117–125PubMedGoogle Scholar
  143. 143.
    Blennow K, Wallin A, Fredman P, Karlsson I, Gottfries CG, Svennerholm L (1990) Blood-brain barrier disturbance in patients with Alzheimer’s disease is related to vascular factors. Acta Neurol Scand 81(4):323–326PubMedCrossRefGoogle Scholar
  144. 144.
    Wallin A, Blennow K, Rosengren L (1999) Cerebrospinal fluid markers of pathogenetic processes in vascular dementia, with special reference to the subcortical subtype. Alzheimer Dis Assoc Disord 13(Suppl 3):S102–S105PubMedGoogle Scholar
  145. 145.
    Tumani H, Nolker G, Reiber H (1995) Relevance of cerebrospinal fluid variables for early diagnosis of neuroborreliosis. Neurology 45(9):1663–1670PubMedCrossRefGoogle Scholar
  146. 146.
    Chalbot S, Zetterberg H, Blennow K, Fladby T, Grundke-Iqbal I, Iqbal K (2010) Cerebrospinal fluid secretory Ca2+-dependent phospholipase A2 activity: a biomarker of blood-cerebrospinal fluid barrier permeability. Neurosci Lett 478(3):179–183PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Zetterberg H, Andreasson U, Blennow K (2009) CSF antithrombin III and disruption of the blood-brain barrier. J Clin Oncol 27(13):2302–2303PubMedCrossRefGoogle Scholar
  148. 148.
    Lee JM, Blennow K, Andreasen N et al (2008) The brain injury biomarker VLP-1 is increased in the cerebrospinal fluid of Alzheimer disease patients. Clin Chem 54(10):1617–1623PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Paterson RW, Bartlett JW, Blennow K et al (2014) Cerebrospinal fluid markers including trefoil factor 3 are associated with neurodegeneration in amyloid-positive individuals. Transl Psychiatry 4, e419PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Rosengren LE, Karlsson JE, Sjogren M, Blennow K, Wallin A (1999) Neurofilament protein levels in CSF are increased in dementia. Neurology 52(5):1090–1093PubMedCrossRefGoogle Scholar
  151. 151.
    Agren-Wilsson A, Lekman A, Sjoberg W et al (2007) CSF biomarkers in the evaluation of idiopathic normal pressure hydrocephalus. Acta Neurol Scand 116(5):333–339PubMedCrossRefGoogle Scholar
  152. 152.
    Wallin A, Sjogren M (2001) Cerebrospinal fluid cytoskeleton proteins in patients with subcortical white-matter dementia. Mech Ageing Dev 122(16):1937–1949PubMedCrossRefGoogle Scholar
  153. 153.
    De Jong D, Jansen RW, Pijnenburg YA et al (2007) CSF neurofilament proteins in the differential diagnosis of dementia. J Neurol Neurosurg Psychiatry 78(9):936–938PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Landqvist Waldo M, Frizell Santillo A, Passant U et al (2013) Cerebrospinal fluid neurofilament light chain protein levels in subtypes of frontotemporal dementia. BMC Neurol 13:54PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Gisslen M, Hagberg L, Brew BJ, Cinque P, Price RW, Rosengren L (2007) Elevated cerebrospinal fluid neurofilament light protein concentrations predict the development of AIDS dementia complex. J Infect Dis 195(12):1774–1778PubMedCrossRefGoogle Scholar
  156. 156.
    Skillbäck T, Zetterberg H, Blennow K, Mattsson N (2013) CSF biomarkers for Alzheimer’s disease and subcortical axonal damage in 5542 clinical samples. Alzheimers Res Ther 5(5):47PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Tortelli R, Ruggieri M, Cortese R et al (2012) Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 19(12):1561–1567PubMedCrossRefGoogle Scholar
  158. 158.
    Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelso C (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67(5):2013–2018PubMedCrossRefGoogle Scholar
  159. 159.
    Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N (2010) A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68(10):930–941PubMedCrossRefGoogle Scholar
  160. 160.
    Comi C, Carecchio M, Chiocchetti A et al (2010) Osteopontin is increased in the cerebrospinal fluid of patients with Alzheimer’s disease and its levels correlate with cognitive decline. J Alzheimers Dis 19(4):1143–1148PubMedGoogle Scholar
  161. 161.
    Naude PJ, Nyakas C, Eiden LE et al (2012) Lipocalin 2: novel component of proinflammatory signaling in Alzheimer’s disease. FASEB J 26(7):2811–2823PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Rosen C, Mattsson N, Johansson PM et al (2011) Discriminatory analysis of biochip-derived protein patterns in CSF and plasma in neurodegenerative diseases. Front Aging Neurosci 3:1PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Blennow K, Wallin A, Fredman P, Gottfries CG, Karlsson I, Svennerholm L (1990) Intrathecal synthesis of immunoglobulins in patients with Alzheimer’s disease. Eur Neuropsychopharmacol 1(1):79–81PubMedCrossRefGoogle Scholar
  164. 164.
    Rossor MN, Fox NC, Mummery CJ, Schott JM, Warren JD (2010) The diagnosis of young-onset dementia. Lancet Neurol 9(8):793–806PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Morrow JD, Roberts LJ (1997) The isoprostanes: unique bioactive products of lipid peroxidation. Prog Lipid Res 36(1):1–21PubMedCrossRefGoogle Scholar
  166. 166.
    Brys M, Pirraglia E, Rich K et al (2009) Prediction and longitudinal study of CSF biomarkers in mild cognitive impairment. Neurobiol Aging 30(5):682–690PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    De Leon MJ, Desanti S, Zinkowski R et al (2006) Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol Aging 27(3):394–401PubMedCrossRefGoogle Scholar
  168. 168.
    Grossman M, Farmer J, Leight S et al (2005) Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer’s disease. Ann Neurol 57(5):721–729PubMedCrossRefGoogle Scholar
  169. 169.
    Montine TJ, Beal MF, Cudkowicz ME et al (1999) Increased CSF F2-isoprostane concentration in probable AD. Neurology 52(3):562–565PubMedCrossRefGoogle Scholar
  170. 170.
    Montine TJ, Markesbery WR, Morrow JD, Roberts LJ 2nd (1998) Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer’s disease. Ann Neurol 44(3):410–413PubMedCrossRefGoogle Scholar
  171. 171.
    Ringman JM, Younkin SG, Pratico D et al (2008) Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71(2):85–92PubMedCrossRefGoogle Scholar
  172. 172.
    Duits FH, Kester MI, Scheffer PG et al (2013) Increase in cerebrospinal fluid F2-isoprostanes is related to cognitive decline in APOE epsilon4 carriers. J Alzheimers Dis 36(3):563–570PubMedGoogle Scholar
  173. 173.
    Gackowski D, Rozalski R, Siomek A et al (2008) Oxidative stress and oxidative DNA damage is characteristic for mixed Alzheimer disease/vascular dementia. J Neurol Sci 266(1–2):57–62PubMedCrossRefGoogle Scholar
  174. 174.
    Podlesniy P, Figueiro-Silva J, Llado A et al (2013) Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol 74(5):655–668PubMedCrossRefGoogle Scholar
  175. 175.
    Renkema GH, Boot RG, Au FL et al (1998) Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. Eur J Biochem 251(1–2):504–509PubMedCrossRefGoogle Scholar
  176. 176.
    Hollak CE, Van Weely S, Van Oers MH, Aerts JM (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 93(3):1288–1292PubMedPubMedCentralCrossRefGoogle Scholar
  177. 177.
    Watabe-Rudolph M, Song Z, Lausser L et al (2012) Chitinase enzyme activity in CSF is a powerful biomarker of Alzheimer disease. Neurology 78(8):569–577PubMedCrossRefGoogle Scholar
  178. 178.
    Hakala BE, White C, Recklies AD (1993) Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. J Biol Chem 268(34):25803–25810PubMedGoogle Scholar
  179. 179.
    Craig-Schapiro R, Perrin RJ, Roe CM et al (2010) YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol Psychiatry 68(10):903–912PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Olsson B, Hertze J, Lautner R et al (2013) Microglial markers are elevated in the prodromal phase of Alzheimer’s disease and vascular dementia. J Alzheimers Dis 33(1):45–53PubMedGoogle Scholar
  181. 181.
    Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE (2009) Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol 19(3):392–398PubMedCrossRefGoogle Scholar
  182. 182.
    Westin K, Buchhave P, Nielsen H, Minthon L, Janciauskiene S, Hansson O (2012) CCL2 is associated with a faster rate of cognitive decline during early stages of Alzheimer’s disease. PLoS ONE 7(1), e30525PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Correa JD, Starling D, Teixeira AL, Caramelli P, Silva TA (2011) Chemokines in CSF of Alzheimer’s disease patients. Arq Neuropsiquiatr 69(3):455–459PubMedCrossRefGoogle Scholar
  184. 184.
    Galimberti D, Schoonenboom N, Scheltens P et al (2006) Intrathecal chemokine levels in Alzheimer disease and frontotemporal lobar degeneration. Neurology 66(1):146–147PubMedCrossRefGoogle Scholar
  185. 185.
    Galimberti D, Schoonenboom N, Scheltens P et al (2006) Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease. Arch Neurol 63(4):538–543PubMedCrossRefGoogle Scholar
  186. 186.
    Mattsson N, Tabatabaei S, Johansson P et al (2011) Cerebrospinal fluid microglial markers in Alzheimer’s disease: elevated chitotriosidase activity but lack of diagnostic utility. Neuromolecular Med 13(2):151–159PubMedCrossRefGoogle Scholar
  187. 187.
    Blasko I, Lederer W, Oberbauer H et al (2006) Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dement Geriatr Cogn Disord 21(1):9–15PubMedCrossRefGoogle Scholar
  188. 188.
    Yin GN, Jeon H, Lee S, Lee HW, Cho JY, Suk K (2009) Role of soluble CD14 in cerebrospinal fluid as a regulator of glial functions. J Neurosci Res 87(11):2578–2590PubMedCrossRefGoogle Scholar
  189. 189.
    Engelborghs S, De Brabander M, De Cree J et al (1999) Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 34(6):523–530PubMedCrossRefGoogle Scholar
  190. 190.
    Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580PubMedCrossRefGoogle Scholar
  191. 191.
    Davidsson P, Puchades M, Blennow K (1999) Identification of synaptic vesicle, pre- and postsynaptic proteins in human cerebrospinal fluid using liquid-phase isoelectric focusing. Electrophoresis 20(3):431–437PubMedCrossRefGoogle Scholar
  192. 192.
    Thorsell A, Bjerke M, Gobom J et al (2010) Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer’s disease. Brain Res 1362:13–22PubMedCrossRefGoogle Scholar
  193. 193.
    Kvartsberg H, Portelius E, Andreasson U et al (2015) Characterization of the postsynaptic protein neurogranin in paired cerebrospinal fluid and plasma samples from Alzheimer’s disease patients and healthy controls. Alzheimers Res Ther 7(1):40PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Kvartsberg H, Duits FH, Ingelsson M et al (2015) Cerebrospinal fluid levels of the synaptic protein neurogranin correlates with cognitive decline in prodromal Alzheimer’s disease. Alzheimers Dement 11(10):1180–1190PubMedCrossRefGoogle Scholar
  195. 195.
    De Vos A, Jacobs D, Struyfs H et al (2015) C-terminal neurogranin is increased in cerebrospinal fluid but unchanged in plasma in Alzheimer’s disease. Alzheimers Dement 11(12):1461–1469PubMedCrossRefGoogle Scholar
  196. 196.
    Chang L, Rissin DM, Fournier DR et al (2012) Single molecule enzyme-linked immunosorbent assays: theoretical considerations. J Immunol Methods 378(1–2):102–115PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Hartung HP, Steinman L, Goodin DS et al (2013) Interleukin 17F level and interferon beta response in patients with multiple sclerosis. JAMA Neurol 70(8):1017–1021PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    Mollenhauer B, El-Agnaf OM, Marcus K, Trenkwalder C, Schlossmacher MG (2010) Quantification of alpha-synuclein in cerebrospinal fluid as a biomarker candidate: review of the literature and considerations for future studies. Biomark Med 4(5):683–699PubMedCrossRefGoogle Scholar
  199. 199.
    Guo JL, Covell DJ, Daniels JP et al (2013) Distinct alpha-synuclein strains differentially promote tau inclusions in neurons. Cell 154(1):103–117PubMedCrossRefGoogle Scholar
  200. 200.
    Pletnikova O, West N, Lee MK et al (2005) Abeta deposition is associated with enhanced cortical alpha-synuclein lesions in Lewy body diseases. Neurobiol Aging 26(8):1183–1192PubMedCrossRefGoogle Scholar
  201. 201.
    Hall S, Ohrfelt A, Constantinescu R et al (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 69(11):1445–1452PubMedCrossRefGoogle Scholar
  202. 202.
    Mollenhauer B, Locascio JJ, Schulz-Schaeffer W, Sixel-Doring F, Trenkwalder C, Schlossmacher MG (2011) alpha-Synuclein and tau concentrations in cerebrospinal fluid of patients presenting with parkinsonism: a cohort study. Lancet Neurol 10(3):230–240PubMedCrossRefGoogle Scholar
  203. 203.
    Tateno F, Sakakibara R, Kawai T, Kishi M, Murano T (2012) Alpha-synuclein in the cerebrospinal fluid differentiates synucleinopathies (Parkinson Disease, dementia with Lewy bodies, multiple system atrophy) from Alzheimer disease. Alzheimer Dis Assoc Disord 26(3):213–216PubMedCrossRefGoogle Scholar
  204. 204.
    Wennstrom M, Surova Y, Hall S et al (2013) Low CSF levels of both alpha-synuclein and the alpha-synuclein cleaving enzyme neurosin in patients with synucleinopathy. PLoS ONE 8(1), e53250PubMedPubMedCentralCrossRefGoogle Scholar
  205. 205.
    Ohrfelt A, Grognet P, Andreasen N et al (2009) Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders-a marker of synapse loss? Neurosci Lett 450(3):332–335PubMedCrossRefGoogle Scholar
  206. 206.
    Barbour R, Kling K, Anderson JP et al (2008) Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5(2):55–59PubMedCrossRefGoogle Scholar
  207. 207.
    Hong Z, Shi M, Chung KA et al (2010) DJ-1 and alpha-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease. Brain 133(Pt 3):713–726PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Irizarry MC (2004) Biomarkers of Alzheimer disease in plasma. NeuroRx 1(2):226–234PubMedPubMedCentralCrossRefGoogle Scholar
  209. 209.
    Doecke JD, Laws SM, Faux NG et al (2012) Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 69(10):1318–1325PubMedCrossRefGoogle Scholar
  210. 210.
    Ray S, Britschgi M, Herbert C et al (2007) Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nat Med 13(11):1359–1362PubMedCrossRefGoogle Scholar
  211. 211.
    Bjorkqvist M, Ohlsson M, Minthon L, Hansson O (2012) Evaluation of a previously suggested plasma biomarker panel to identify Alzheimer’s disease. PLoS ONE 7(1), e29868PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Soares HD, Chen Y, Sabbagh M, Roher A, Schrijvers E, Breteler M (2009) Identifying early markers of Alzheimer’s disease using quantitative multiplex proteomic immunoassay panels. Ann N Y Acad Sci 1180:56–67PubMedCrossRefGoogle Scholar
  213. 213.
    Hampel H, Lista S, Teipel SJ et al (2014) Perspective on future role of biological markers in clinical therapy trials of Alzheimer’s disease: a long-range point of view beyond 2020. Biochem Pharmacol 88(4):426–449PubMedCrossRefGoogle Scholar
  214. 214.
    Isaac M, Vamvakas S, Abadie E, Jonsson B, Gispen C, Pani L (2011) Qualification opinion of novel methodologies in the predementia stage of Alzheimer’s disease: cerebro-spinal-fluid related biomarkers for drugs affecting amyloid burden—regulatory considerations by European Medicines Agency focusing in improving benefit/risk in regulatory trials. Eur Neuropsychopharmacol 21(11):781–788PubMedCrossRefGoogle Scholar
  215. 215.
    Salloway S, Sperling R, Gilman S et al (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73(24):2061–2070PubMedPubMedCentralCrossRefGoogle Scholar
  216. 216.
    Seubert P, Vigo-Pelfrey C, Esch F et al (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359(6393):325–327PubMedCrossRefGoogle Scholar
  217. 217.
    Siemers ER, Friedrich S, Dean RA et al (2010) Safety and changes in plasma and cerebrospinal fluid amyloid beta after a single administration of an amyloid beta monoclonal antibody in subjects with Alzheimer disease. Clin Neuropharmacol 33(2):67–73PubMedCrossRefGoogle Scholar
  218. 218.
    Seubert P, Barbour R, Khan K et al (2008) Antibody capture of soluble Abeta does not reduce cortical Abeta amyloidosis in the PDAPP mouse. Neurodegener Dis 5(2):65–71PubMedCrossRefGoogle Scholar
  219. 219.
    Salloway S, Sperling R, Fox NC et al (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):322–333PubMedPubMedCentralCrossRefGoogle Scholar
  220. 220.
    Doody RS, Thomas RG, Farlow M et al (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370(4):311–321PubMedCrossRefGoogle Scholar
  221. 221.
    Hampel H, Frank R, Broich K et al (2010) Biomarkers for Alzheimer’s disease: academic, industry and regulatory perspectives. Nat Rev Drug Discov 9(7):560–574PubMedCrossRefGoogle Scholar
  222. 222.
    Mattsson N, Zegers I, Andreasson U et al (2012) Reference measurement procedures for Alzheimer’s disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid beta42. Biomark Med 6(4):409–417PubMedCrossRefGoogle Scholar
  223. 223.
    Duits FH, Teunissen CE, Bouwman FH et al (2014) The cerebrospinal fluid “Alzheimer profile”: Easily said, but what does it mean? Alzheimers Dement 10(6):713–723.e2PubMedCrossRefGoogle Scholar
  224. 224.
    Mattsson N, Andreasson U, Persson S et al (2011) The Alzheimer’s Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement 7(4):386–395, e386PubMedPubMedCentralCrossRefGoogle Scholar
  225. 225.
    Mattsson N, Andreasson U, Persson S et al (2013) CSF biomarker variability in the Alzheimer’s Association quality control program. Alzheimers Dement 9(3):251–261PubMedPubMedCentralCrossRefGoogle Scholar
  226. 226.
    Perret-Liaudet A, Pelpel M, Tholance Y et al (2012) Risk of Alzheimer’s disease biological misdiagnosis linked to cerebrospinal collection tubes. J Alzheimers Dis 31(1):13–20PubMedGoogle Scholar
  227. 227.
    Toombs J, Paterson RW, Lunn MP et al (2013) Identification of an important potential confound in CSF AD studies: aliquot volume. Clin Chem Lab Med 51(12):2311–2317PubMedCrossRefGoogle Scholar
  228. 228.
    Toombs J, Paterson RW, Schott JM, Zetterberg H (2014) Amyloid-beta 42 adsorption following serial tube transfer. Alzheimers Res Ther 6(1):5PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Bjerke M, Portelius E, Minthon L et al (2010) Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Int J Alzheimers Dis 2010Google Scholar
  230. 230.
    Carrillo MC, Blennow K, Soares H et al (2013) Global standardization measurement of cerebral spinal fluid for Alzheimer’s disease: An update from the Alzheimer’s Association Global Biomarkers Consortium. Alzheimers Dement 9(2):137–140PubMedCrossRefGoogle Scholar
  231. 231.
    Pannee J, Portelius E, Oppermann M et al (2013) A selected reaction monitoring (SRM)-based method for absolute quantification of Abeta38, Abeta40, and Abeta42 in cerebrospinal fluid of Alzheimer’s disease patients and healthy controls. J Alzheimers Dis 33(4):1021–1032PubMedGoogle Scholar
  232. 232.
    Leinenbach A, Pannee J, Dulffer T et al (2014) Mass spectrometry-based candidate reference measurement procedure for quantification of amyloid-beta in cerebrospinal fluid. Clin Chem 60(7):987–994PubMedCrossRefGoogle Scholar
  233. 233.
    Korecka M, Waligorska T, Figurski M et al (2014) Qualification of a surrogate matrix-based absolute quantification method for amyloid-beta(4)(2) in human cerebrospinal fluid using 2D UPLC-tandem mass spectrometry. J Alzheimers Dis 41(2):441–451PubMedPubMedCentralGoogle Scholar

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© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Department of Psychiatry and NeurochemistryThe Sahlgrenska Academy at the University of GothenburgGöteborgSweden
  2. 2.Department of Molecular NeuroscienceUCL Institute of NeurologyQueen Square, LondonUK
  3. 3.Dementia Research CentreUCL Institute of NeurologyQueen Square, LondonUK

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