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Validation of amyloid-β peptides in CSF diagnosis of neurodegenerative dementias

Molecular Psychiatry volume 12, pages 671–680 (2007)Cite this article

Abstract

Biomarkers for differential diagnosis of the three most frequent degenerative forms of dementia, Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementias (FTD), are currently under intensive investigation, but disease-specific biomarkers for FTD and DLB are still lacking. We analyzed 303 cerebrospinal fluid (CSF) samples of 71 AD, 32 DLB and 36 FTD patients in comparison to 93 various other dementias (OD), 20 peripheral neurologic disease (PND) controls, 25 neurodegenerative disorders without dementia (ND) and 26 depressive cognitive complainers (DCC) for distinct CSF amyloid-β (Aβ) peptide patterns, using the quantitative Aβ-SDS-PAGE/immunoblot. Additionally, the novel electrochemiluminescence technique (MSD) was used to validate the measures on Aβ1-38. The main outcome measures were a striking decrease of Aβ1-42 in AD (P=7.4 × 10−19), and most interestingly a pronounced decrease of Aβ1-38 in FTD (P=9.6 × 10−7). Moreover, a novel peptide that most probably represents an oxidized α-helical form of Aβ1-40 (Aβ1-40ox) displayed a highly significant increase in DLB (P=3.7 × 10−3) as compared to non-demented disease controls. The overall diagnostic accuracy of percentage Aβ peptide abundances (Aβ1-X%) was clearly superior to absolute CSF Aβ levels. Aβ1-42% and Aβ1-38% enabled contrasts of 85% or beyond to distinguish AD and FTD, respectively, from all other investigated subjects. Aβ1-40ox% yielded a diagnostic sensitivity and specificity of 88 and 73% for the detection of DLB among all other investigated patients. We found a strong correlation between Aβ1-38 levels as measured by the Aβ-SDS-PAGE/immunoblot and MSD, respectively. CSF Aβ peptides may reflect disease-specific impact of distinct neurodegenerative processes on Aβ peptide metabolism and represent a potential diagnostic biomarker for AD, FTD and DLB.

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References

  1. Glenner GG, Wong CW . Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–890.

    Article  CAS  Google Scholar 

  2. Jendroska K, Kashiwagi M, Sassoon J, Daniel SE . Amyloid beta-peptide and its relationship with dementia in Lewy body disease. J Neural Transm Suppl 1997; 51: 137–144.

    Article  CAS  Google Scholar 

  3. Arnold SE, Han LY, Clark CM, Grossman M, Trojanowski JQ . Quantitative neurohistological features of frontotemporal degeneration. J Struct Biol 2000; 130: 271–279.

    Article  Google Scholar 

  4. Wiltfang J, Esselmann H, Bibl M, Smirnov A, Otto M, Paul S et al. Highly conserved and disease-specific patterns of carboxyterminally truncated Abeta peptides 1-37/38/39 in addition to 1-40/42 in Alzheimer's disease and patients with chronic neuroinflammation. J Neurochem 2002; 81: 481–496.

    Article  CAS  Google Scholar 

  5. Bibl M, Mollenhauer B, Esselmann H, Lewczuk P, Klafki HW, Sparbier K et al. CSF amyloid-β-peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia. Brain 2006a; 129: 1177–1187.

    Article  Google Scholar 

  6. Mollenhauer B, Bibl M, Esselmann H, Steinacker P, Ciesielcyk B, Neubert K et al. Slective reduction of amyloid beta42 discriminates Alzheimer's from Huntington's disease: indication for distinct pathological events in amyloid beta peptide aggregation. J Neurol Neurosurg Psychiatry 2006; 77: 1201–1203.

    Article  CAS  Google Scholar 

  7. World Medical Organisation. Declaration of Helsinki. Br Med J 1996; 313: 1448–1449.

    Google Scholar 

  8. Bibl M, Esselmann H, Otto M, Lewczuk P, Cepek L, Rüther E et al. Cerebrospinal fluid (CSF) amyloid beta (Aβ) peptide patterns in Alzheimer's disease (AD) patients and non-demented controls depend on sample pre-treatment: indication of carrier-mediated epitope masking of Aβ peptides. Electrophoresis 2004; 25: 2912–2918.

    Article  CAS  Google Scholar 

  9. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM . Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 1984; 34: 939–944.

    Article  CAS  Google Scholar 

  10. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 1113–1124.

    Article  CAS  Google Scholar 

  11. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S et al. Frontotemporal lobar degeneration. A consensus on clinical diagnostic criteria. Neurology 1998; 51: 1546–1554.

    Article  CAS  Google Scholar 

  12. Roman GC, Tatemichi TK, Erkinjutti T, Cummings JL, Masdeu JC, Garcia JH et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993; 43: 243–245.

    Article  Google Scholar 

  13. Gibb WR, Lees AJ . The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J Neurol Neurosurg Psychiatry 1988; 51: 745–752.

    Article  CAS  Google Scholar 

  14. Ishikawa M . Clinical guidelines for idiopathic normal pressure hydrocephalus. Neurol Med Chir 2004; 44: 222–223.

    Article  Google Scholar 

  15. Litvan I . Progressive supranuclear palsy and corticobasal degeneration. Bailliere's Clin Neurol 1997; 6: 167–185.

    CAS  Google Scholar 

  16. World Health Organization. Human Transmissible Spongiform Encephalopathy. Weekly Epidemiological Record 1998; 73: 361–365.

    Google Scholar 

  17. Oslin D, Aktinsson RM, Smith DM, Hendrie H . Alcohol related dementia: proposed clinical criteria. Int J Geriatr Psychiatry 1998; 13: 203–212.

    Article  CAS  Google Scholar 

  18. Mehta PD, Pirttila T . Increased cerebrospinal fluid A beta38/A beta42 ratio in Alzheimer's disease. Neurodegener Dis 2005; 2: 242–245.

    Article  CAS  Google Scholar 

  19. Blennow K . Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 2004; 1: 213–225.

    Article  Google Scholar 

  20. Wiltfang J, Lewczuk P, Riederer P, Grunblatt E, Hock C, Scheltens P et al. Consensus paper of the WFSBP Task Force on Biological Markers of Dementia: the role of CSF and blood analysis in the early and differential diagnosis of dementia. World J Biol Psychiatry 2005; 6: 69–84.

    Article  CAS  Google Scholar 

  21. Hulstaert F, Blennow K, Ivanoiu A, Schoonderwald HC, Riemenschneider M, De Deyn PP et al. Improved discrimination of AD-patients using β-amyloid (1-42) and tau levels in CSF. Neurology 1999; 52: 1555–1562.

    Article  CAS  Google Scholar 

  22. Mollenhauer B, Cepek L, Bibl M, Wiltfang J, Schulz-Schaeffer WJ, Ciesielczyk B et al. Tau protein, beta-amyloid (1-42) and S100B protein in cerebrospinal fluid of patients with Dementia with Lewy Bodies. Dement Geriatr Cogn Disord 2005; 19: 164–170.

    Article  CAS  Google Scholar 

  23. Grossman M, Farmer J, Light S, Work M, Moore P, Van Deerlin V et al. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease. Ann Neurol 2005; 57: 721–729.

    Article  Google Scholar 

  24. Wiltfang J, Esselmann H, Smirnov A, Bibl M, Cepek L, Steinacker P et al. Beta-amyloid peptides in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Ann Neurol 2003; 54: 263–267.

    Article  CAS  Google Scholar 

  25. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Andreasen N, Sjögren M et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer's disease – a comparative study. Arch Gen Psychiatry 2004; 61: 95–102.

    Article  CAS  Google Scholar 

  26. Motter R, Vigo-Pelfrey C, Kholodenko D, Barbour R, Johnson-Wood K, Galasko D et al. Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol 1995; 38: 643–648.

    Article  CAS  Google Scholar 

  27. Koudinov AR, Koudinova NV, Kumar A, Beavis RC, Ghiso J . Biochemical characterization of Alzheimer's soluble amyloid beta protein in human cerebrospinal fluid: association with density lipoproteins. Biochem Biophys Res Commun 1996; 223: 592–597.

    Article  CAS  Google Scholar 

  28. Podlisny MB, Ostaszewski BL, Squazzo SL, Koo EH, Rydell RE, Teplow DB et al. Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J Biol Chem 1995; 270: 9564–9570.

    Article  CAS  Google Scholar 

  29. Pitschke M, Prior R, Haupt M, Riesner D . Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer's patients by fluorescence correlation spectroscopy. Nat Med 1998; 4: 832–834.

    Article  CAS  Google Scholar 

  30. Sjögren M, Davidsson P, Tullberg M, Minthon L, Wallin A, Wikkelso C et al. Both total and phosphorylated tau are increased in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2001; 70: 624–630.

    Article  Google Scholar 

  31. Sjögren M, Rosgren L, Minthon L, Davidson P, Blennow K, Wallin A . Cytoskeleton proteins in CSF distinguish frontotemporal dementia from AD. Neurology 2000; 54: 1960–1964.

    Article  Google Scholar 

  32. Riemenschneider M, Wagenpfeil S, Diehl J, Lautenschlager N, Theml T, Heldmann B et al. Tau and Aβ42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002; 58: 1622–1628.

    Article  CAS  Google Scholar 

  33. Galasko D, Marder K . Picking away at frontotemporal dementia. Neurology 2002; 58: 1585–1586.

    Article  Google Scholar 

  34. Andersen C, Jensen M, Lannfelt L, Lindau M, Wahlund LO . Amyloid Aβ40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia. Neuroreport 2000; 11: 287–290.

    Article  CAS  Google Scholar 

  35. Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J et al. A novel presenilin 1 mutation associated with Pick's disease but not β-amyloid plaques. Ann Neurol 2004; 55: 617–626.

    Article  CAS  Google Scholar 

  36. Andreasen N, Minthon L, Davidsson P, Vanmechelen E, Vanderstichele H, Winblad B et al. Evaluation of CSF-tau and CSF-Aβ42 as diagnostic markers for Alzheimer disease in clinical practice. 2001; 58: 373–379.

  37. Bibl M, Mollenhauer B, Esselmann H, Lewczuk P, Trenkwalder C, Brechlin P et al. CSF diagnosis of Alzheimer's disease and dementias with Lewy bodies. J Neural Transm 2006b; 113: 1771–1778.

    Article  CAS  Google Scholar 

  38. Dong J, Atwood CS, Anderson VE, Siedlak SL, Smith MA, Perry G et al. Metal binding and oxidation of amyloid-beta within isolated senile plaque cores: Raman microscopic evidence. Biochemistry 2003; 42: 2768–2773.

    Article  CAS  Google Scholar 

  39. Yoshimoto M, Iwai A, Kang D, Otero DA, Xia Y, Saitoh T . NACP, the precursor of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci USA 1995; 92: 9141–9145.

    Article  CAS  Google Scholar 

  40. Giacomelli CE, Norde W . Conformational changes in the amyloid β peptide (1-40) adsorbed on solid surfaces. Macromol Biosci 2005; 5: 401–407.

    Article  CAS  Google Scholar 

  41. Klimov DK, Thirumalai D . Dissecting the assembly of Aβ16-22 amyloid peptides into antiparallel β sheets. Structure 2003; 11: 295–307.

    Article  CAS  Google Scholar 

  42. Kirkitadze MD, Condron MM, Teplow DB . Identification and characterization of key kinetic intermediates in amyloid β-protein fibrillogenesis. J Mol Biol 2001; 312: 1103–1119.

    Article  CAS  Google Scholar 

  43. Butterfield DA . Amyloid β-peptide (1-42)-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences. Curr Med Chem 2003; 10: 2651–2659.

    Article  CAS  Google Scholar 

  44. Barnham KJ, Ciccotosto GD, Tickler AK, Ali FE, Smith DG, Williamson MA et al. Neurotoxic, redox-competent Alzheimer's β-Amyloid is released from lipid membrane by methionine oxidation. J Biol Chem 2003; 278: 42959–42965.

    Article  CAS  Google Scholar 

  45. Lewczuk P, Esselmann H, Otto M, Maler JM, Henkel AW, Henkel MK et al. Neurochemical diagnosis of Alzheimer's dementia by CSF Abeta 42, Abeta42/ Abeta40 ratio and total tau. Neurobiol Aging 2004; 25: 273–281.

    Article  CAS  Google Scholar 

  46. Schoonenboom NS, Mulder C, Van Kamp GJ, Mehta SP, Scheltens P, Blankenstein MA et al. Amyloid β 38, 40 and 42 species in cerebrospinal fluid: more of the same? Ann Neurol 2005; 58: 139–142.

    Article  CAS  Google Scholar 

  47. Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212–216.

    Article  CAS  Google Scholar 

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Acknowledgements

MB, PL, HE, SW, JK, MO and JW were supported by grants from the German Federal Ministry of Education and Research (Competence Net Dementia, grant O1 GI 0420); MB was supported by the Research Program, Faculty of Medicine, Georg-August-Universität Göttingen; JK, JW and PL were supported by grants from the German Federal Ministry of Education and Research CJK (01 GI 0301) and HBPP-NGFN2 (01 GR 0447). MO was supported by grants from the German Federal Ministry of Education (German CJD therapy study FK 01KO0506), EU (anteprion 019090) and Landesstiftung Baden Württemberg).

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  1. M Bibl and B Mollenhauer: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, University of Goettingen, Goettingen, Germany

    M Bibl, S Wolf, G Stiens & E Rüther

  2. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA

    B Mollenhauer

  3. Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany

    P Lewczuk, H Esselmann, J Kornhuber & J Wiltfang

  4. University of Goettingen, Paracelsus-Elena Klinik, Kassel, Germany

    C Trenkwalder

  5. Department of Neurology, University of Ulm, Ulm, Germany

    M Otto

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Correspondence to M Bibl or J Wiltfang.

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Bibl, M., Mollenhauer, B., Lewczuk, P. et al. Validation of amyloid-β peptides in CSF diagnosis of neurodegenerative dementias. Mol Psychiatry 12, 671–680 (2007). https://doi.org/10.1038/sj.mp.4001967

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