Skip to main content

Advertisement

SpringerLink
Log in

Cerebrospinal fluid analysis in Alzheimer’s disease: technical issues and future developments

  • Techniques in Clinical Science
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a leading cause of morbidity, mortality, and a major epidemic worldwide. Although clinical assessment continues to remain the keystone for patient management and clinical trials, such evaluation has important limitations. In this context, cerebrospinal fluid (CSF) biomarkers are important tools to better identify high-risk individuals, to diagnose AD promptly and accurately, especially at the prodromal mild cognitive impairment stage of the disease, and to effectively prognosticate and treat AD patients. Recent advances in functional genomics, proteomics, metabolomics, and bioinformatics will hopefully revolutionize unbiased inquiries into several putative CSF markers of cerebral pathology that may be concisely informative with regard to the various stages of AD progression through years and decades. Moreover, the identification of efficient drug targets and development of optimal therapeutic strategies for AD will increasingly rely on a better understanding and integration of the systems biology paradigm, which will allow predicting the series of events and resulting responses of the biological network triggered by the introduction of new therapeutic compounds. In this scenario, unbiased systems biology-based diagnostic and prognostic models in AD will consist of relevant comprehensive panels of molecules and key branches of the disease-affected cellular neuronal network. Such characteristic and unbiased biomarkers will more accurately and comprehensively reflect pathophysiology from the early asymptomatic and presymptomatic to the final prodromal and symptomatic clinical stages in individual patients (and their individual genetic disease predisposition), ultimately increasing the chances of success of future disease modifying and preventive treatments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368:387–403

    Article  CAS  PubMed  Google Scholar 

  2. Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256:184–185

    Article  CAS  PubMed  Google Scholar 

  3. Walsh DM, Selkoe DJ (2007) A beta oligomers––a decade of discovery. J Neurochem 101:1172–1184

    Article  CAS  PubMed  Google Scholar 

  4. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, He F, Sun X, Thomas RG, Aisen PS, Alzheimer’s Disease Cooperative Study Steering Committee, Siemers E, Sethuraman G, Mohs R, Semagacestat Study Group (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350

    Article  CAS  PubMed  Google Scholar 

  5. Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, Sabbagh M, Honig LS, Porsteinsson AP, Ferris S, Reichert M, Ketter N, Nejadnik B, Guenzler V, Miloslavsky M, Wang D, Lu Y, Lull J, Tudor IC, Liu E, Grundman M, Yuen E, Black R, Brashear HR, Bapineuzumab 301 and 302 Clinical Trial Investigators (2014) Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 370:322–333

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe S, Kieburtz K, Raman R, Sun X, Aisen PS, Siemers E, Liu-Seifert H, Mohs R, Alzheimer’s Disease Cooperative Study Steering Committee, Solanezumab Study Group (2014) Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 370:311–321

    Article  CAS  PubMed  Google Scholar 

  7. Hampel H, Lista S (2012) Alzheimer disease: from inherited to sporadic AD-crossing the biomarker bridge. Nat Rev Neurol 8:598–600

    Article  PubMed  Google Scholar 

  8. Moulder KL, Snider BJ, Mills SL, Buckles VD, Santacruz AM, Bateman RJ, Morris JC (2013) Dominantly Inherited Alzheimer network: facilitating research and clinical trials. Alzheimers Res Ther 5:48

    Article  PubMed Central  PubMed  Google Scholar 

  9. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, Delacourte A, Galasko D, Gauthier S, Jicha G, Meguro K, O’brien J, Pasquier F, Robert P, Rossor M, Salloway S, Stern Y, Visser PJ, Scheltens P (2007) Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 6:734–746

    Article  PubMed  Google Scholar 

  10. Dubois B, Feldman HH, Jacova C, Cummings JL, Dekosky ST, Barberger-Gateau P, Delacourte A, Frisoni G, Fox NC, Galasko D, Gauthier S, Hampel H, Jicha GA, Meguro K, O’Brien J, Pasquier F, Robert P, Rossor M, Salloway S, Sarazin M, de Souza LC, Stern Y, Visser PJ, Scheltens P (2010) Revising the definition of Alzheimer’s disease: a new lexicon. Lancet Neurol 9:1118–1127

    Article  PubMed  Google Scholar 

  11. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144

    Article  CAS  PubMed  Google Scholar 

  12. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Shen L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative (2013) The Alzheimer’s disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement 9:e111–e194

    Article  PubMed Central  PubMed  Google Scholar 

  13. Lista S, Garaci FG, Ewers M, Teipel S, Zetterberg H, Blennow K, Hampel H (2013) CSF Aβ1-42 combined with neuroimaging biomarkers in the early detection, diagnosis and prediction of Alzheimer’s disease. Alzheimers Dement. doi:10.1016/j.jalz.2013.04.506

    PubMed  Google Scholar 

  14. Risacher SL, Saykin AJ (2013) Neuroimaging and other biomarkers for Alzheimer’s disease: the changing landscape of early detection. Annu Rev Clin Psychol 9:621–648

    Article  PubMed Central  PubMed  Google Scholar 

  15. Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ, Green RC, Harvey D, Jack CR, Jagust W, Liu E, Morris JC, Petersen RC, Saykin AJ, Schmidt ME, Shaw L, Siuciak JA, Soares H, Toga AW, Trojanowski JQ, Alzheimer’s Disease Neuroimaging Initiative (2012) The Alzheimer’s disease neuroimaging initiative: a review of papers published since its inception. Alzheimers Dement 8:S1–S68

    Article  PubMed Central  PubMed  Google Scholar 

  16. Scheff SW, Price DA, Schmitt FA, Mufson EJ (2006) Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol Aging 27:1372–1384

    Article  CAS  PubMed  Google Scholar 

  17. Davidsson P, Blennow K (1998) Neurochemical dissection of synaptic pathology in Alzheimer’s disease. Int Psychogeriatr 10:11–23

    Article  CAS  PubMed  Google Scholar 

  18. Davidsson P, Jahn R, Bergquist J, Ekman R, Blennow K (1996) Synaptotagmin, a synaptic vesicle protein, is present in human cerebrospinal fluid: a new biochemical marker for synaptic pathology in Alzheimer disease? Mol Chem Neuropathol 27:195–210

    Article  CAS  PubMed  Google Scholar 

  19. 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 20:431–437

    Article  CAS  PubMed  Google Scholar 

  20. Thorsell A, Bjerke M, Gobom J, Brunhage E, Vanmechelen E, Andreasen N, Hansson O, Minthon L, Zetterberg H, Blennow K (2010) Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer’s disease. Brain Res 1362:13–22

    Article  CAS  PubMed  Google Scholar 

  21. Zougman A, Pilch B, Podtelejnikov A, Kiehntopf M, Schnabel C, Kumar C, Mann M (2008) Integrated analysis of the cerebrospinal fluid peptidome and proteome. J Proteome Res 7:386–399

    Article  CAS  PubMed  Google Scholar 

  22. Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, Piech T, Patel PP, Chang L, Rivnak AJ, Ferrell EP, Randall JD, Provuncher GK, Walt DR, Duffy DC (2010) Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 28:595–599

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Savage MJ, Kalinina J, Wolfe A, Tugusheva K, Korn R, Cash-Mason T, Maxwell JW, Hatcher NG, Haugabook SJ, Wu G, Howell BJ, Renger JJ, Shughrue PJ, McCampbell A (2014) A sensitive aβ oligomer assay discriminates Alzheimer’s and aged control cerebrospinal fluid. J Neurosci 34:2884–2897

    Article  CAS  PubMed  Google Scholar 

  24. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K, Powell J, St George-Hyslop P, Singleton A, Hardy J, Alzheimer Genetic Analysis Group (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA, van Duijn CM, Thorsteinsdottir U, Kong A, Stefansson K (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Mattsson N, Tabatabaei S, Johansson P, Hansson O, Andreasson U, Månsson JE, Johansson JO, Olsson B, Wallin A, Svensson J, Blennow K, Zetterberg H (2011) Cerebrospinal fluid microglial markers in Alzheimer’s disease: elevated chitotriosidase activity but lack of diagnostic utility. Neuromolecular Med 13:151–159

    Article  CAS  PubMed  Google Scholar 

  27. Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ, Mintun MA, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, D’Angelo G, Malone JP, Townsend RR, Morris JC, Fagan AM, Holtzman DM (2010) YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol Psychiatry 68:903–912

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Barone E, Di Domenico F, Mancuso C, Butterfield DA (2014) The Janus face of the heme oxygenase/biliverdin reductase system in Alzheimer disease: it’s time for reconciliation. Neurobiol Dis 62:144–159

    Article  CAS  PubMed  Google Scholar 

  29. Montine TJ, Beal MF, Cudkowicz ME, O’Donnell H, Margolin RA, McFarland L, Bachrach AF, Zackert WE, Roberts LJ, Morrow JD (1999) Increased CSF F2-isoprostane concentration in probable AD. Neurology 52:562–565

    Article  CAS  PubMed  Google Scholar 

  30. 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):410–413

    Article  CAS  PubMed  Google Scholar 

  31. Montine TJ, Montine KS, McMahan W, Markesbery WR, Quinn JF, Morrow JD (2005) F2-isoprostanes in Alzheimer and other neurodegenerative diseases. Antioxid Redox Signal 7:269–275

    Article  CAS  PubMed  Google Scholar 

  32. de Leon MJ, Mosconi L, Li J, De Santi S, Yao Y, Tsui WH, Pirraglia E, Rich K, Javier E, Brys M, Glodzik L, Switalski R, Saint Louis LA, Pratico D (2007) Longitudinal CSF isoprostane and MRI atrophy in the progression to AD. J Neurol 254:1666–1675

    Article  PubMed  Google Scholar 

  33. Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-Agudelo Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL (2008) Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 71:85–92

    Article  CAS  PubMed  Google Scholar 

  34. Hall S, Öhrfelt A, Constantinescu R, Andreasson U, Surova Y, Bostrom F, Nilsson C, Håkan W, Decraemer H, Någga K, Minthon L, Londos E, Vanmechelen E, Holmberg B, Zetterberg H, Blennow K, Hansson O (2012) Accuracy of a panel of 5 cerebrospinal fluid biomarkers in the differential diagnosis of patients with dementia and/or parkinsonian disorders. Arch Neurol 69:1445–1452

    Article  PubMed  Google Scholar 

  35. Zetterberg H, Petzold M, Magdalinou N (2014) Cerebrospinal fluid alpha-synuclein levels in Parkinson’s disease––changed or unchanged? Eur J Neurol 21:365–367

    Article  CAS  PubMed  Google Scholar 

  36. Noto Y, Shibuya K, Sato Y, Kanai K, Misawa S, Sawai S, Mori M, Uchiyama T, Isose S, Nasu S, Sekiguchi Y, Fujimaki Y, Kasai T, Tokuda T, Nakagawa M, Kuwabara S (2011) Elevated CSF TDP-43 levels in amyotrophic lateral sclerosis: specificity, sensitivity, and a possible prognostic value. Amyotroph Lateral Scler 12:140–143

    Article  CAS  PubMed  Google Scholar 

  37. Geser F, Prvulovic D, O’Dwyer L, Hardiman O, Bede P, Bokde AL, Trojanowski JQ, Hampel H (2011) On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia. Prog Neurobiol 95:649–662

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Biomarkers Definitions Working Group (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  39. Rosén C, Zetterberg H (2013) Cerebrospinal fluid biomarkers for pathological processes in Alzheimer’s disease. Curr Opin Psychiatry 26:276–282

    Article  PubMed  Google Scholar 

  40. Zetterberg H, Blennow K (2013) Cerebrospinal fluid biomarkers for Alzheimer’s disease: more to come? J Alzheimers Dis 33(Suppl 1):S361–S369

    PubMed  Google Scholar 

  41. Cummings J, Zhong K (2014) Biomarker-driven therapeutic management of Alzheimer’s disease: establishing the foundations. Clin Pharmacol Ther 95:67–77

    Article  CAS  PubMed  Google Scholar 

  42. Hampel H, Lista S, Khachaturian ZS (2012) Development of biomarkers to chart all Alzheimer’s disease stages: the royal road to cutting the therapeutic Gordian Knot. Alzheimers Dement 8:312–336

    Article  CAS  PubMed  Google Scholar 

  43. Rosén C, Hansson O, Blennow K, Zetterberg H (2013) Fluid biomarkers in Alzheimer’s disease––current concepts. Mol Neurodegener 8:20

    Article  PubMed Central  PubMed  Google Scholar 

  44. Kang JH, Korecka M, Toledo JB, Trojanowski JQ, Shaw LM (2013) Clinical utility and analytical challenges in measurement of cerebrospinal fluid amyloid-β(1-42) and τ proteins as Alzheimer disease biomarkers. Clin Chem 59:903–916

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Andreasson U, Vanmechelen E, Shaw LM, Zetterberg H, Vanderstichele H (2012) Analytical aspects of molecular Alzheimer’s disease biomarkers. Biomark Med 6:377–389

    Article  CAS  PubMed  Google Scholar 

  46. Mattsson N, Zegers I, Andreasson U, Bjerke M, Blankenstein MA, Bowser R, Carrillo MC, Gobom J, Heath T, Jenkins R, Jeromin A, Kaplow J, Kidd D, Laterza OF, Lockhart A, Lunn MP, Martone RL, Mills K, Pannee J, Ratcliffe M, Shaw LM, Simon AJ, Soares H, Teunissen CE, Verbeek MM, Umek RM, Vanderstichele H, Zetterberg H, Blennow K, Portelius E (2012) Reference measurement procedures for Alzheimer’s disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42. Biomark Med 6:409–417

    Article  CAS  PubMed  Google Scholar 

  47. Wattamwar PR, Mathuranath PS (2010) An overview of biomarkers in Alzheimer’s disease. Ann Indian Acad Neurol 13(Suppl 2):S116–S123

    PubMed Central  PubMed  Google Scholar 

  48. Miller BB, Mandell JW (2005) Multiplex method for measuring biomarkers of Alzheimer disease in cerebrospinal fluid. Clin Chem 51:289–290

    Article  CAS  PubMed  Google Scholar 

  49. Kang JH, Vanderstichele H, Trojanowski JQ, Shaw LM (2012) Simultaneous analysis of cerebrospinal fluid biomarkers using microsphere-based xMAP multiplex technology for early detection of Alzheimer’s disease. Methods 56:484–493

    Article  CAS  PubMed  Google Scholar 

  50. Zetterberg H, Wilson D, Andreasson U, Minthon L, Blennow K, Randall J, Hansson O (2013) Plasma tau levels in Alzheimer’s disease. Alzheimers Res Ther 5:9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Zetterberg H, Mörtberg E, Song L, Chang L, Provuncher GK, Patel PP, Ferrell E, Fournier DR, Kan CW, Campbell TG, Meyer R, Rivnak AJ, Pink BA, Minnehan KA, Piech T, Rissin DM, Duffy DC, Rubertsson S, Wilson DH, Blennow K (2011) Hypoxia due to cardiac arrest induces a time-dependent increase in serum amyloid β levels in humans. PLoS One 6:e28263

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Pannee J, Portelius E, Oppermann M, Atkins A, Hornshaw M, Zegers I, Höjrup P, Minthon L, Hansson O, Zetterberg H, Blennow K, Gobom J (2013) A selected reaction monitoring (SRM)-based method for absolute quantification of Aβ38, Aβ40, and Aβ42 in cerebrospinal fluid of Alzheimer’s disease patients and healthy controls. J Alzheimers Dis 33:1021–1032

    CAS  PubMed  Google Scholar 

  53. Ludwig C, Claassen M, Schmidt A, Aebersold R (2012) Estimation of absolute protein quantities of unlabeled samples by selected reaction monitoring mass spectrometry. Mol Cell Proteomics 11(M111):013987

    PubMed  Google Scholar 

  54. Picotti P, Aebersold R (2012) Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat Methods 9:555–566

    Article  CAS  PubMed  Google Scholar 

  55. Bensimon A, Heck AJ, Aebersold R (2012) Mass spectrometry-based proteomics and network biology. Annu Rev Biochem 81:379–405

    Article  CAS  PubMed  Google Scholar 

  56. Sabidó E, Selevsek N, Aebersold R (2012) Mass spectrometry-based proteomics for systems biology. Curr Opin Biotechnol 23:591–597

    Article  PubMed  Google Scholar 

  57. Noorbakhsh F, Overall CM, Power C (2009) Deciphering complex mechanisms in neurodegenerative diseases: the advent of systems biology. Trends Neurosci 32:88–100

    Article  CAS  PubMed  Google Scholar 

  58. Tyers M, Mann M (2003) From genomics to proteomics. Nature 422:193–197

    Article  CAS  PubMed  Google Scholar 

  59. Hamacher M, Meyer HE (2005) HUPO Brain Proteome Project: aims and needs in proteomics. Expert Rev Proteomics 2:1–3

    Article  PubMed  Google Scholar 

  60. Aebersold R, Mann M (2003) Mass spectrometry-based proteomics. Nature 422:198–207

    Article  CAS  PubMed  Google Scholar 

  61. Portelius E, Gustavsson MK, Zetterberg H, Andreasson U, Blennow K (2012) Evaluation of the performance of novel Aβ isoforms as theragnostic markers in Alzheimer’s disease: from the cell to the patient. Neurodegener Dis 10:138–140

    Article  CAS  PubMed  Google Scholar 

  62. Portelius E, Price E, Brinkmalm G, Stiteler M, Olsson M, Persson R, Westman-Brinkmalm A, Zetterberg H, Simon AJ, Blennow K (2011) A novel pathway for amyloid precursor protein processing. Neurobiol Aging 32:1090–1098

    Article  CAS  PubMed  Google Scholar 

  63. Perrin RJ, Craig-Schapiro R, Malone JP, Shah AR, Gilmore P, Davis AE, Roe CM, Peskind ER, Li G, Galasko DR, Clark CM, Quinn JF, Kaye JA, Morris JC, Holtzman DM, Townsend RR, Fagan AM (2011) Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer’s disease. PLoS One 6:e16032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Craig-Schapiro R, Kuhn M, Xiong C, Pickering EH, Liu J, Misko TP, Perrin RJ, Bales KR, Soares H, Fagan AM, Holtzman DM (2011) Multiplexed immunoassay panel identifies novel CSF biomarkers for Alzheimer’s disease diagnosis and prognosis. PLoS One 6:e18850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Portelius E, Dean RA, Gustavsson MK, Andreasson U, Zetterberg H, Siemers E, Blennow K (2010) A novel Abeta isoform pattern in CSF reflects gamma-secretase inhibition in Alzheimer disease. Alzheimers Res Ther 2:7

    Article  PubMed Central  PubMed  Google Scholar 

  66. Albertini V, Bruno A, Paterlini A, Lista S, Benussi L, Cereda C, Binetti G, Ghidoni R (2010) Optimization protocol for amyloid-β peptides detection in human cerebrospinal fluid using SELDI TOF MS. Proteomics Clin Appl 4:352–357

    Article  CAS  PubMed  Google Scholar 

  67. Portelius E, Brinkmalm G, Tran AJ, Zetterberg H, Westman-Brinkmalm A, Blennow K (2009) Identification of novel APP/Abeta isoforms in human cerebrospinal fluid. Neurodegener Dis 6:87–94

    Article  CAS  PubMed  Google Scholar 

  68. Simonsen AH, McGuire J, Podust VN, Davies H, Minthon L, Skoog I, Andreasen N, Wallin A, Waldemar G, Blennow K (2008) Identification of a novel panel of cerebrospinal fluid biomarkers for Alzheimer’s disease. Neurobiol Aging 29:961–968

    Article  CAS  PubMed  Google Scholar 

  69. Simonsen AH, McGuire J, Hansson O, Zetterberg H, Podust VN, Davies HA, Waldemar G, Minthon L, Blennow K (2007) Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment. Arch Neurol 64:366–370

    Article  PubMed  Google Scholar 

  70. Simonsen AH, McGuire J, Podust VN, Hagnelius NO, Nilsson TK, Kapaki E, Vassilopoulos D, Waldemar G (2007) 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 24:434–440

    Article  CAS  PubMed  Google Scholar 

  71. Finehout EJ, Franck Z, Choe LH, Relkin N, Lee KH (2007) Cerebrospinal fluid proteomic biomarkers for Alzheimer’s disease. Ann Neurol 61:120–129

    Article  CAS  PubMed  Google Scholar 

  72. Portelius E, Tran AJ, Andreasson U, Persson R, Brinkmalm G, Zetterberg H, Blennow K, Westman-Brinkmalm A (2007) Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 6:4433–4439

    Article  CAS  PubMed  Google Scholar 

  73. Hu Y, Hosseini A, Kauwe JS, Gross J, Cairns NJ, Goate AM, Fagan AM, Townsend RR, Holtzman DM (2007) Identification and validation of novel CSF biomarkers for early stages of Alzheimer’s disease. Proteomics Clin Appl 1:1373–1384

    Article  CAS  PubMed  Google Scholar 

  74. Portelius E, Zetterberg H, Andreasson U, Brinkmalm G, Andreasen N, Wallin A, Westman-Brinkmalm A, Blennow K (2006) An Alzheimer’s disease-specific beta-amyloid fragment signature in cerebrospinal fluid. Neurosci Lett 409:215–219

    Article  CAS  PubMed  Google Scholar 

  75. Portelius E, Westman-Brinkmalm A, Zetterberg H, Blennow K (2006) Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. J Proteome Res 5:1010–1016

    Article  CAS  PubMed  Google Scholar 

  76. Abdi F, Quinn JF, Jankovic J, McIntosh M, Leverenz JB, Peskind E, Nixon R, Nutt J, Chung K, Zabetian C, Samii A, Lin M, Hattan S, Pan C, Wang Y, Jin J, Zhu D, Li GJ, Liu Y, Waichunas D, Montine TJ, Zhang J (2006) Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J Alzheimers Dis 9:293–348

    CAS  PubMed  Google Scholar 

  77. Selle H, Lamerz J, Buerger K, Dessauer A, Hager K, Hampel H, Karl J, Kellmann M, Lannfelt L, Louhija J, Riepe M, Rollinger W, Tumani H, Schrader M, Zucht HD (2005) Identification of novel biomarker candidates by differential peptidomics analysis of cerebrospinal fluid in Alzheimer’s disease. Comb Chem High Throughput Screen 8:801–806

    Article  CAS  PubMed  Google Scholar 

  78. Zhang J, Goodlett DR, Quinn JF, Peskind E, Kaye JA, Zhou Y, Pan C, Yi E, Eng J, Wang Q, Aebersold RH, Montine TJ (2005) Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease. J Alzheimers Dis 7:125–133

    CAS  PubMed  Google Scholar 

  79. Carrette O, Demalte I, Scherl A, Yalkinoglu O, Corthals G, Burkhard P, Hochstrasser DF, Sanchez JC (2003) A panel of cerebrospinal fluid potential biomarkers for the diagnosis of Alzheimer’s disease. Proteomics 3:1486–1494

    Article  CAS  PubMed  Google Scholar 

  80. Puchades M, Hansson SF, Nilsson CL, Andreasen N, Blennow K, Davidsson P (2003) Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer’s disease. Brain Res Mol Brain Res 118:140–146

    Article  CAS  PubMed  Google Scholar 

  81. Davidsson P, Westman-Brinkmalm A, Nilsson CL, Lindbjer M, Paulson L, Andreasen N, Sjögren M, Blennow K (2002) Proteome analysis of cerebrospinal fluid proteins in Alzheimer patients. NeuroReport 13:611–615

    Article  CAS  PubMed  Google Scholar 

  82. Pan S, Zhu D, Quinn JF, Peskind ER, Montine TJ, Lin B, Goodlett DR, Taylor G, Eng J, Zhang J (2007) A combined dataset of human cerebrospinal fluid proteins identified by multi-dimensional chromatography and tandem mass spectrometry. Proteomics 7:469–473

    Article  CAS  PubMed  Google Scholar 

  83. Rifai N, Gillette MA, Carr SA (2006) Protein biomarker discovery and validation: the long and uncertain path to clinical utility. Nat Biotechnol 24:971–983

    Article  CAS  PubMed  Google Scholar 

  84. Fagan AM, Perrin RJ (2012) Upcoming candidate cerebrospinal fluid biomarkers of Alzheimer’s disease. Biomark Med 6:455–476

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  85. Dumas ME, Davidovic L (2013) Metabolic phenotyping and systems biology approaches to understanding neurological disorders. F1000Prime Rep 5:18

    Article  PubMed Central  PubMed  Google Scholar 

  86. Veenstra TD (2012) Metabolomics: the final frontier? Genome Med 4:40

    Article  PubMed Central  PubMed  Google Scholar 

  87. Nicholson JK, Holmes E, Kinross JM, Darzi AW, Takats Z, Lindon JC (2012) Metabolic phenotyping in clinical and surgical environments. Nature 491:384–392

    Article  CAS  PubMed  Google Scholar 

  88. Mandal R, Guo AC, Chaudhary KK, Liu P, Yallou FS, Dong E, Aziat F, Wishart DS (2012) Multi-platform characterization of the human cerebrospinal fluid metabolome: a comprehensive and quantitative update. Genome Med 4:38

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Trushina E, Mielke MM (2013) Recent advances in the application of metabolomics to Alzheimer’s disease. Biochim Biophys Acta. doi:10.1016/j.bbadis.2013.06.014

    PubMed Central  PubMed  Google Scholar 

  90. Trushina E, Dutta T, Persson XM, Mielke MM, Petersen RC (2013) Identification of altered metabolic pathways in plasma and CSF in mild cognitive impairment and Alzheimer’s disease using metabolomics. PLoS One 8:e63644

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  91. Kaddurah-Daouk R, Zhu H, Sharma S, Bogdanov M, Rozen SG, Matson W, Oki NO, Motsinger-Reif AA, Churchill E, Lei Z, Appleby D, Kling MA, Trojanowski JQ, Doraiswamy PM, Arnold SE, Pharmacometabolomics Research Network (2013) Alterations in metabolic pathways and networks in Alzheimer’s disease. Transl Psychiatry 3:e244

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Czech C, Berndt P, Busch K, Schmitz O, Wiemer J, Most V, Hampel H, Kastler J, Senn H (2012) Metabolite profiling of Alzheimer’s disease cerebrospinal fluid. PLoS One 7:e31501

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  93. Kaddurah-Daouk R, Rozen S, Matson W, Han X, Hulette CM, Burke JR, Doraiswamy PM, Welsh-Bohmer KA (2011) Metabolomic changes in autopsy-confirmed Alzheimer’s disease. Alzheimers Dement 7:309–317

    Article  PubMed Central  PubMed  Google Scholar 

  94. Wenk MR (2010) Lipidomics: new tools and applications. Cell 143:888–895

    Article  CAS  PubMed  Google Scholar 

  95. Astarita G, Piomelli D (2011) Towards a whole-body systems [multi-organ] lipidomics in Alzheimer’s disease. Prostaglandins Leukot Essent Fatty Acids 85:197–203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

HH and SL are supported by the AXA Research Fund (AXA RF) and the Fondation pour la Recherche sur Alzheimer (FRA), Paris, France. H. Z. and K. B. are supported by Grants from the Swedish Research Council.

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Département de Neurologie, Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Pavillon François Lhermitte, Hôpital de la Salpêtrière, Université Pierre et Marie Curie, 47 Boulevard de l’Hôpital, 75013, Paris, France

    Simone Lista, Bruno Dubois & Harald Hampel

  2. AXA Research Fund and Pierre and Marie Curie University (UPMC) Chair, Paris, France

    Simone Lista & Harald Hampel

  3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    Henrik Zetterberg & Kaj Blennow

  4. University College London Institute of Neurology, Queen Square, London, UK

    Henrik Zetterberg

Authors
  1. Simone Lista
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henrik Zetterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno Dubois
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kaj Blennow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Harald Hampel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Simone Lista.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lista, S., Zetterberg, H., Dubois, B. et al. Cerebrospinal fluid analysis in Alzheimer’s disease: technical issues and future developments. J Neurol 261, 1234–1243 (2014). https://doi.org/10.1007/s00415-014-7366-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-014-7366-z

Keywords

Search

Navigation