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

Sun Ah Park; Jung Hun Kim; Hyeong Jun Kim; Tae Eun Kim; Yoon-Jeong Kim; Dong Hyun Lee; Jeong Ho Park; Won Seok Chae; Soo Jae Yim; Sang Won Seo; Duk L. Na; Seong Hye Choi

doi:10.12779/dnd.2013.12.1.1

Journal List > Dement Neurocogn Disord > v.12(1) > 1120809

Go to TopGo to Top Go to BottomGo to Bottom

TOOLS

Park, Kim, Kim, Kim, Kim, Lee, Park, Chae, Yim, Seo, Na, and Choi: Preliminary Study for a Multicenter Study of Alzheimer's Disease Cerebrospinal Fluid Biomarkers

Original Article

Dementia and Neurocognitive Disorders

Dementia and Neurocognitive Disorders 2013; 12(1): 1-8.

Published online: 31 March 2013

DOI: https://doi.org/10.12779/dnd.2013.12.1.1

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.^∥, 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, seonghye@inha.ac.kr

Received 13 August 2012 Revised 12 February 2013 Accepted 12 February 2013

(open-access):

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

Figures and Tables

Table 1

Demographic characteristics of the subjects (mean±SD)

^*p<0.05.

AD, Alzheimer's disease; CDR, clinical dementia rating; D, dementia; F, female; M, male; MMSE, mini-mental state examination; NC, normal control; SD, standard deviation; SOB, sum of box.

Table 2

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

Mean±standard deviation.

CV%, coefficient of variance percent.

Table 3

The concentrations of Aβ42, pTau181, tTau in cerebrospinal fluid

^*p<0.05.

AD, Alzheimer's disease; CI, confidence interval; D, dementia; M, mean; NC, normal control; SD, standard deviation.

Table 4

Receiver operating characteristic (ROC) curve parameters

ROC, receiver operating characteristic; AUC, area under the curve.

Table 5

Brief summary of the previous literatures

^*Unit of results. However in case of ratio, there is no unit.

AD, Alzheimer's disease; CBD, corticobasal ganglionic degeneration; CI, cognitive impairment; CON, control; CJD, Creutzfeldt Jacob disease; D. dementia; DLB, diffuse Lewy body dementia; EOAD, early-onset AD; FTD, frontotemporal dementia; LOAD, late-onset AD; MCI, mild cognitive impairment; PSP, progressive supranuclear palsy; SMI, subjective memory impairment; SVD, subcortical vascular dementia; PD, Parkinson's disease; PSY, psychiatric disorder.

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.

2. Golde TE, Schneider LS, Koo EH. Anti-aβ therapeutics in Alzheimer's disease: the need for a paradigm shift. Neuron. 2011. 69:203–213.

3. Cummings JL. Biomarkers in Alzheimer's disease drug development. Alzheimers Dement. 2011. 7:e13–e44.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. Holtzman DM. CSF biomarkers for Alzheimer's disease: current utility and potential future use. Neurobiol Aging. 2011. 32:S4–S9.

11. Zetterberg H, Blennow K, Hanse E. Amyloid beta and APP as biomarkers for Alzheimer's disease. Exp Gerontol. 2010. 45:23–29.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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.

34. 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. 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.

45. 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.

TOOLS

Similar articles