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Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer’s disease

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Abstract

Background and methods

There is an urgent need for peripheral surrogates of Alzheimer’s disease (AD) that accurately reflect disease state and severity as well as correlate with key features of its neuropathology. The aim of this study was to identify plasma proteins associated with known in vivo markers of disease activity. In an earlier proteomic study of plasma, we discovered a panel of 15 proteins that were differentially expressed in AD and further validated complement factor-H (CFH) and alpha-2-macroglobulin (A2M) as AD-specific plasma biomarkers. In the present study, we extended these findings by testing the associations of these plasma proteins with neuro-imaging measures of disease progression in AD. We combined 1H-magnetic resonance spectroscopy of the hippocampus and MRI-based hippocampal volumetry with proteomic analysis of plasma in early AD and mild cognitive impairment (MCI) to achieve this goal. Using 1H-magnetic resonance spectroscopy, we derived estimates of the hippocampal metabolite ratio N-acetylaspartate/myo-inositol (NAA/mI), a biochemical measure that is associated with cognitive decline in early AD. We also undertook a proteomic analysis of plasma in these individuals using two-dimensional gel electrophoresis (2DGE).

Results

We observed that two plasma proteins previously shown to be differentially expressed in AD, complement factor-H (CFH) and alpha-2-macroglobulin (A2M) showed significant positive correlations with hippocampal NAA/mI ratio in AD.

Conclusions

The association of plasma CFH and A2M with hippocampal NAA/mI in this cohort of AD subjects suggests that these proteins may reflect disease progression in early AD. These findings warrant validation in large population-based datasets.

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References

  1. Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease” (1998) The Ronald and Nancy Reagan Research Institute of the Alzheimer’s Association and the National Institute on Aging Working Group. Neurobiol aging 19(2):109–116

  2. Ackl N, Ising M, Schreiber YA, et al. (2005) Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 384(1–2):23–28

    Article  CAS  PubMed  Google Scholar 

  3. An W, Cai Y, Tang H, et al. (2001) Differentiating Alzheimer’s disease and vascular dementia with regional metabolites comparison by quantitative proton MR spectroscopy. Proc Int Soc Magn Res Med 9:986

    Google Scholar 

  4. Annapoorani P, Dhandapany PS, Sadayappan S, Ramasamy S, Rathinavel A, Selvam GS (2006) Cardiac isoform of alpha-2-macroglobulin – a new biomarker for myocardial infarcted diabetic patients. Atheroscler 186(1):173–176

    Article  CAS  Google Scholar 

  5. Barta L, Dhingra R, Royall, et al. (1997) Improving stereological estimates for the volume of structures identified in three-dimensional arrays of spatial data. J Neurosci Methods 75:111–118

    Article  CAS  PubMed  Google Scholar 

  6. Blennow K, Vanmechelen E, Hampel H (2001) CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer’s disease. Mol Neurobiol 24(1–3):87–97

    Article  CAS  PubMed  Google Scholar 

  7. Blennow K, Hampel H (2003) CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2(10):605–613

    Article  CAS  PubMed  Google Scholar 

  8. Buerger K, Teipel SJ, Zinkowski R, et al. (2002) CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurol 59(4):627–629

    CAS  Google Scholar 

  9. Chu CT, Howard GC, Misra UK, et al. (1994) Alpha-2-macroglobulin: a sensor for proteolysis. Ann NY Acad Sci 737:291–307

    Article  CAS  PubMed  Google Scholar 

  10. Cucullo L, Marchi N, Marroni M, et al. (2003) Blood-brain barrier damage induces release of alpha-2-macroglobulin. Mol Cell Proteomics 2(4):234–241

    CAS  PubMed  Google Scholar 

  11. Cummings JL (2004) Treatment of Alzheimer’s disease: current and future therapeutic approaches. Rev Neurol Dis 1(2):60–69

    PubMed  Google Scholar 

  12. de Leon MJ, Segal S, Tarshish CY, et al. (2002) Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment. Neurosci Lett 333(3):183–186

    Article  CAS  PubMed  Google Scholar 

  13. Delshammar M, Lasson A, Ohlsson K (1989) Proteases and protease inhibitor balance in peritonitis with different causes. Surgery 106(3):555–562

    CAS  PubMed  Google Scholar 

  14. Doraiswamy PM, Charles HC, Krishnan KR (1998) Prediction of cognitive decline in early Alzheimer’s disease. Lancet 352(9141):1678

    Article  CAS  PubMed  Google Scholar 

  15. Edwards AO, Ritter R, Abel KJ, et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308(5720):421–424

    Article  CAS  PubMed  Google Scholar 

  16. Frank RA, Galasko D, Hampel H, et al. (2003) Biological markers for therapeutic trials in Alzheimer’s disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease. Neurobiol Aging 24(4):521–536

    Article  PubMed  Google Scholar 

  17. Hampel H, Burger K, Pruessner JC, et al. (2005) Correlation of cerebrospinal fluid levels of tau protein phosphorylated at threonine 231 with rates of hippocampal atrophy in Alzheimer disease. Arch Neurol 62(5):770–773

    Article  PubMed  Google Scholar 

  18. Holmes C, Lovestone S (2003) Longterm cognitive and functional decline in late onset Alzheimer’s disease: therapeutic implications. Age and ageing 32(2):200–204

    Article  PubMed  Google Scholar 

  19. Hye A, Lynham S, Thambisetty M, et al. (2006) Proteome-based plasma biomarkers for Alzheimer’s disease. Brain 129:3042–3050

    Article  CAS  PubMed  Google Scholar 

  20. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T (2001) MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 357(9262):1069–1075

    Article  CAS  PubMed  Google Scholar 

  21. Jokiranta TS (2006) C3b and factor H: key components of the complement system. Exp Rev Clin Immunol 2(5):775–786

    Article  CAS  Google Scholar 

  22. Kanoh Y, Ohtani N, Mashiko T, Ohtani S, Nishikawa T, Egawa S, Baba S, Ohtani H (2001) Levels of alpha-2-macroglobulin can predict bone metastases in prostate cancer. Anticancer Res 21(1B):551–556

    CAS  PubMed  Google Scholar 

  23. Kantarci K, Reynolds G, Petersen RC, et al. (2003) Proton MR spectroscopy in mild cognitive impairment and Alzheimer disease: comparison of 1.5 and 3 T. Am J Neuroradiol 24(5):843–849

    PubMed  Google Scholar 

  24. Kantarci K, Smith GE, Ivnik RJ, et al. (2002) 1H magnetic resonance spectroscopy, cognitive function, and apolipoprotein E genotype in normal aging, mild cognitive impairment and Alzheimer’s disease. J Int Neuropsychol Soc 8(7):934–942

    Article  CAS  PubMed  Google Scholar 

  25. Koster MN, Dermaut B, Cruts M, et al. (2000) The alpha-2-macroglobulin gene in AD: a population-based study and meta-analysis. Neurology 55(5):678–684

    CAS  PubMed  Google Scholar 

  26. Ly DH, Lockhart DJ, Lerner RA, et al. (2000) Mitotic misregulation and human aging. Science 287(5462):2486–2492

    Article  CAS  PubMed  Google Scholar 

  27. Martinez-Bisbal MC, Arana E, Marti-Bonmati L, et al. (2004) Cognitive impairment: classification by 1H magnetic resonance spectroscopy. Eur J Neurol 11(3):187–193

    Article  CAS  PubMed  Google Scholar 

  28. Petersen RC, Smith GE, Ivnik RJ, et al. (1994) Memory function in very early Alzheimer’s disease. Neurology 44(5):867–872

    CAS  PubMed  Google Scholar 

  29. Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679

    Article  CAS  PubMed  Google Scholar 

  30. Robertson DM, van Amelsvoort T, Daly E, et al. (2001) Effects of estrogen replacement therapy on human brain aging: an in vivo 1H MRS study. Neurology 57(11):2114–2117

    CAS  PubMed  Google Scholar 

  31. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, et al. (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41(4):355–367

    Article  CAS  PubMed  Google Scholar 

  32. Rose SE, de Zubicaray GI, Wang D, et al. (1999) A 1H MRS study of probable Alzheimer’s disease and normal aging: implications for longitudinal monitoring of dementia progression. Magn Reson Imaging 17(2):291–299

    Article  CAS  PubMed  Google Scholar 

  33. Rothermundt M, Arolt V, Peters M, Gutbrodt H, Fenker J, Kersting A, Kirchner H (2001) Inflammatory markers in major depression and melancholia. J Affect Disord 63(1–3):93–102

    Article  CAS  PubMed  Google Scholar 

  34. Saunders AJ, Bertram L, Mullin K, et al. (2003) Genetic association of Alzheimer’s disease with multiple polymorphisms in alpha-2-macroglobulin. Hum Mol Gen 12(21):2765–2776

    Article  CAS  PubMed  Google Scholar 

  35. Saunders AJ, Tanzi RE (2003) Welcome to the complex disease world. Alpha-2-macroglobulin and Alzheimer’s disease. Exp Neurol 184(1):50–53

    Article  CAS  PubMed  Google Scholar 

  36. Shonk TK, Moats RA, Gifford P, et al. (1995) Probable Alzheimer disease: diagnosis with proton MR spectroscopy. Radiology 195(1):65–72

    CAS  PubMed  Google Scholar 

  37. Simmons A, Arridge SR, Barker GJ, et al. (1996) Simulation of MRI cluster plots and application to neurological segmentation. Magn Reson Im 14(1):73–92

    Article  CAS  Google Scholar 

  38. Simmons A, Smail M, Moore E, et al. (1998) Serial precision of metabolite peak area ratios and water referenced metabolite peak areas in proton MR spectroscopy of the human brain. Magn Reson Im 16(3):319–30

    Article  CAS  Google Scholar 

  39. Strohmeyer R, Ramirez M, Cole GJ, et al. (2002) Association of factor H of the alternative pathway of complement with agrin and complement receptor 3 in the Alzheimer’s disease brain. J Neuroimmunol 131(1–2):135–146

    Article  CAS  PubMed  Google Scholar 

  40. van Amelsvoort E, Daly D, Robertson J, et al. (2001) Structural brain abnormalities associated with deletion at chromosome 22q11 Quantitative neuroimaging study of adults with velocardio-facial syndrome. Br J Psychiatry 178:412–419

    Article  CAS  PubMed  Google Scholar 

  41. Waldman AD, Rai GS (2003) The relationship between cognitive impairment and in vivo metabolite ratios in patients with clinical Alzheimer’s disease and vascular dementia: a proton magnetic resonance spectroscopy study. Neuroradiology 45(8):507–512

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Simon Lovestone PhD, MRC, Psych.

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Thambisetty, M., Hye, A., Foy, C. et al. Proteome-based identification of plasma proteins associated with hippocampal metabolism in early Alzheimer’s disease. J Neurol 255, 1712–1720 (2008). https://doi.org/10.1007/s00415-008-0006-8

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  • DOI: https://doi.org/10.1007/s00415-008-0006-8

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