pISSN 1738-1495   eISSN 2384-0757
Open Access, Peer-reviewed
    Dement Neurocogn Disord. 2013 Mar;12(1):1-8. Korean.
    Published online Mar 31, 2013.
    https://doi.org/10.12779/dnd.2013.12.1.1
    © 2013 Korean Dementia Association
    Original Article

    Preliminary Study for a Multicenter Study of Alzheimer's Disease Cerebrospinal Fluid Biomarkers

    Sun Ah Park, M.D.,* Jung Hun Kim, M.D.,† Hyeong Jun Kim, M.D.,* Tae Eun Kim, M.D.,* Yoon-Jeong Kim, M.S.,* Dong Hyun Lee, M.D.,* Jeong Ho Park, M.D.,* Won Seok Chae, M.D.,‡ Soo Jae Yim, M.D.,§ Sang Won Seo, M.D.,∥ Duk L. Na, M.D.,∥ and Seong Hye Choi, M.D.
      • *Department of Neurology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
      • †Department of Neurology, Ilsan Hospital, National Health Insurance Corporation, Goyang, Korea.
      • ‡Department of Anesthesiology, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
      • §Department of Orthopedic Surgery, Soonchunhyang University Bucheon Hospital, Bucheon, Korea.
      • ∥Department of Neurology, Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, Korea.
      • Department of Neurology, Inha University School of Medicine, Incheon, Korea.
    • Address for correspondence: Seong Hye Choi, M.D. Department of Neurology, Inha University School of Medicine, 366 Seohae-daero, Jung-gu, Incheon 400-103, Korea. Tel: +82-32-890-3659, Fax: +82-32-890-3864, Email: seonghye@inha.ac.kr
    Received August 13, 2012; Revised February 12, 2013; Accepted February 12, 2013.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    The usefulness of cerebrospinal fluid (CSF) concentrations of amyloid beta protein 1-42 (Aβ42), phosphorylated tau (pTau) and total tau (tTau) have been increasing in Alzheimer's disease (AD). However, the direct adoption of previously reported standard values is not appropriate due to interlaboratory variability. We started this study to set up an accessible system to measure CSF biomarkers in our country with high reproducibility and validity.

    Methods

    Including CSFs from four different institutes the levels of Aβ42, pTau181 and tTau were measured in one lab. The intertest variability and difference in the levels of biomarkers depending on diseases were assessed. Through analysis of receiver operating characteristic cut points and binary logistic regression the cut-off values of Aβ42, pTau and tTau level were obtained, and their validity was evaluated.

    Results

    The intertest consistency was high in measuring CSF biomarkers. The value of Aβ42 was markedly decreased in AD (n= 17) and other dementia (n= 9) compared to normal control (n= 12). The levels of pTau181 and tTau were high in AD, but not in other dementia and normal control. The threshold values of Aβ42, pTau181 and tTau were 290.3 pg/mL, 54.3 pg/mL, and 320.7 pg/mL in differentiating AD from normal control showing high sensitivity and specificity. Especially, the ratios of pTau181/Aβ42 (> 0.16) and tTau/Aβ42 (> 0.76) showed the prime validity.

    Conclusions

    Our data of CSF Aβ42, pTau181, and tTau levels were highly reproducible. PTau181/Aβ42 and tTau/Aβ42 ratios were the greatly helpful in differentiating AD from normal control.

    Keywords
    Alzheimer's disease; Amyloid beta protein; Biomarker; Enzyme-linked immunosorbent assay; Cerebrospinal fluid; Tau

    Tables

    Table 1
    Demographic characteristics of the subjects (mean±SD)

    Table 2
    The coefficient of variance percent (CV%) within a test and intertest correlations

    Table 3
    The concentrations of Aβ42, pTau181, tTau in cerebrospinal fluid

    Table 4
    Receiver operating characteristic (ROC) curve parameters

    Table 5
    Brief summary of the previous literatures

    References

      1. Aisen PS, Andrieu S, Sampaio C, Carrillo M, Khachaturian ZS, Dubois B, et al. Report of the task force on designing clinical trials in early (predementia) AD. Neurology 2011;76:280–286.
      1. Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron 2011;69:203–213.
      1. Cummings JL. Biomarkers in Alzheimer's disease drug development. Alzheimers Dement 2011;7:e13–e44.
      1. Mueller SG, Weiner MW, Thal LJ, Petersen RC, Jack CR, Jugust W, et al. Ways toward an early diagnosis in Alzheimer's disease: the Alzheimer's disease Neuroimaging Initiative (ADNI). Alzheimers Dement 2005;1:55–66.
      1. Choi J, Lee HW, Suk K. Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer's disease. J Neurol 2011;258:2181–2185.
      1. Han SH, Jung ES, Sohn JH, Hong HJ, Hong HS, Kim JW, et al. Human serum transthyretin levels correlate inversely with Alzheimer's disease. J Alzheimers Dis 2011;25:77–84.
      1. Kim SM, Song J, Kim S, Han C, Park MH, Koh Y, et al. Identification of peripheral inflammatory markers between normal control and Alzheimer's disease. BMC Neurol 2011;11:51.
      1. Lee KS, Chung JH, Lee KH, Shin MJ, Oh BH, Hong CH. Bioplex analysis of plasma cytokines in Alzheimer's disease and mild cognitive impairment. Immunol Lett 2008;121:105–109.
      1. Lee JW, Namkoong H, Kim HK, Kim S, Hwang DW, Na HR, et al. Fibrinogen gamma-A chain precursor in CSF: a candidate biomarker for Alzheimer's disease. BMC Neurol 2007;7:14.
      1. Holtzman DM. CSF biomarkers for Alzheimer's disease: current utility and potential future use. Neurobiol Aging 2011;32:S4–S9.
      1. Zetterberg H, Blennow K, Hanse E. Amyloid beta and APP as biomarkers for Alzheimer's disease. Exp Gerontol 2010;45:23–29.
      1. Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol Neurobiol 2001;24:87–97.
      1. Buerger K, Zinkowski R, Teipel SJ, Tapiola T, Arai H, Blennow K, et al. Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch Neurol 2002;59:1267–1272.
      1. Shaw LM, Vanderstichele H, Knapik-Czajka M, Clark CM, Aisen PS, Petersen RC, et al. Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 2009;65:403–413.
      1. Welge V, Fiege O, Lewczuk P, Mollenhauer B, Esselmann H, Klafki HW, et al. Combined CSF tau, p-tau181 and amyloid-beta 38/40/42 for diagnosing Alzheimer's disease. J Neural Transm 2009;116:203–212.
      1. Lee EH, Youn YC, Park KY, Min JH, Kwon OS, Lee HO, et al. The effect of acetylcholine esterase inhibitor on cerebrospinal fluid β-amyloid 1-42 and phosphorylated tau protein in Korean Alzheimer's disease patients: Preliminary study. J Korean Neurol Assoc 2008;26:224–230.
      1. 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.
      1. Dubois B, Feldman HH, Jacova C, DeKosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734–746.
      1. Emre M, Aarslan D, Brown R, Burn DJ, Kuyckaerts C, Mizuno Y, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord 2007;22:1689–1707.
      1. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–1872.
      1. 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.
      1. Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1–9.
      1. Roman GC, Tatemichi TK, Erkinjuntti 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;43:250–260.
      1. Bjerke M, Portelius E, Minthon L, Wallin A, Anckarsäter H, Anckarsäter R, et al. Confounding factors influencing amyloid beta concentration in cerebrospinal fluid. Int J Alzheimers Dis 2010;2010:986310.
      1. Bateman RJ, Wen G, Morris JC, Holtzman DM. Fluctuations of CSF amyloid-β levels: Implications for a diagnostic and therapeutic biomarker. Neurology 2007;68:666–669.
      1. Verwey NA, van der Flier WM, Blennow K, Clark C, Sokolow S, De Deyn PP, et al. A wordwide multicenter comparison of assays for cerebrospinal fluid biomarkers in Alzheimer's disease. Ann Clin Biochem 2009;46:235–240.
      1. Schoonenboom NS, Reesink FE, Verwey NA, Kester MI, Teunissen CE, van de Ven PM, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 2012;78:47–54.
      1. Kemppainen NM, Aalto S, Karrasch M, Nagren K, Savisto N, Oikonen V, et al. Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer's disease. Ann Neurol 2008;63:112–118.
      1. 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.
      1. Sunderland T, Linker G, Mirza N, Putnam KT, Friedman DL, Kimmel LH, et al. Decreased beta-amyloid 1-42 and increased tau levels in cerebrospinalfluid of patients with Alzheimer disease. JAMA 2003;289:2094–2103.
      1. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 2006;59:512–519.
      1. Fagan AM, Mintun MA, Shah AR, Aldea P, Roe CM, Mach RH, et al. Cerebrospinal fluid tau and ptau(181) increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer's disease. EMBO Mol Med 2009;1:371–380.
      1. Weigand SD, Vemuri P, Wiste HJ, Senjem ML, Pankratz VS, Aisen PS, et al. Transforming cerebrospinal fluid Aβ42 measures into calculated Pittsburgh compound B units of brain Aβ amyloid. Alzheimers Dement 2011;7:133–141.
      1. Englund H, Degerman Gunnarsson M, Brundin RM, Hedlund M, Kilander L, Lannfelt L, et al. Oligomerization partially explains the lowering of Abeta42 in Alzheimer's disease cerebrospinal fluid. Neurodegener Dis 2009;6:139–147.
      1. Hampel H, Buerger K, Zinkowski R, Teipel SJ, Goernitz A, Andreasen N, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry 2004;61:95–102.
      1. Hu YY, He SS, Wang X, Duan QH, Grundke-Iqbal I, Iqbal K, et al. Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients: an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. Am J Pathol 2002;160:1269–1278.
      1. Vemuri P, Wiste HJ, Weigand SD, Shaw LM, Trojanowski JQ, Weiner MW, et al. MRI and CSF biomarkers in normal, MCI, and AD subjects: predicting future clinical change. Neurology 2009;73:294–301.
      1. Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Trojanowski JQ, Shaw LM, et al. Serial MRI and CSF biomarkers in normal aging, MCI, and AD. Neurology 2010;75:143–151.
      1. Montine TJ, Shi M, Quinn JF, Peskind ER, Craft S, Ginghina C, et al. CSF Aβ(42) and tau in Parkinson's disease with cognitive impairment. Mov Disord 2010;25:2682–2685.
      1. Rowe CC, Ng S, Ackermann U, Gong SJ, Pike K, Savage G, et al. Imaging beta-amyloid burden in aging and dementia. Neurology 2007;68:1718–1725.
      1. Lee JH, Kim SH, Kim GH, Seo SW, Park HK, Oh SJ, et al. Identification of pure subcortical vascular dementia using 11C-Pittsburgh compound B. Neurology 2011;77:18–25.
      1. Galasko D, Clark C, Chang L, Miller B, Green RC, Motter R, et at. Assessment of CSF levels of tau protein in mildly demented patients with Alzheimer's disease. Neurology 1997;48:632–635.
      1. Hulstaert F, Blennow K, Ivanoiu A, Schoonderwaldt HC, Riemenschneider M, DeDeyn PP, et al. Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF. Neurology 1999;52:1555–1562.
      1. Andreasen N, Minthon L, Clarberg A, Davidsson P, Gottfries J, Vanmechelen E, et al. Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 1999;53:1488–1494.
      1. Riemenschneider M, Wagenpfeil S, Diehl J, Lautenschlager N, Theml T, Heldmann B, et al. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622–1628.
    Cited by
    Crossref 8
    Google Scholar 
    Metrics
    Share
    Tables
    slide
    slide
    slide
    slide
    slide

    1 / 5

    PERMALINK