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Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections

Journal of Neurology volume 260, pages 620–626 (2013)Cite this article

Abstract

The cerebrospinal fluid (CSF) biomarker profile in Alzheimer's disease (AD) is characterized by decreased beta amyloid (Aβ1-42), increased total and hyperphosphorylated tau (t-tau and p-tau, respectively), which is a useful diagnostic tool and gives insight in the pathogenesis of AD. It is of importance to study how these biomarkers react in other CNS diseases; therefore, we decided to analyse amyloid and tau biomarkers in different CNS infections. We also included analysis of soluble amyloid precursor proteins (sAPPα and -β). CSF Aβ1-42, sAPPα and -β, t-tau and p-tau were analysed in bacterial meningitis (n = 12), Lyme neuroborreliosis (n = 13), herpes simplex virus type 1 (HSV-1) encephalitis (n = 10), HIV-associated dementia (HAD) (n = 21), AD (n = 21) and healthy controls (n = 42). Concurrent with AD, Aβ1-42 was decreased in all groups except neuroborreliosis compared to controls. HSV-1 encephalitis, bacterial meningitis and HAD showed lower concentrations of sAPPα and -β compared to AD. T-tau was increased in AD and HSV-1 encephalitis compared to all other groups. P-tau was higher in AD and HSV-1 encephalitis compared to bacterial meningitis, HAD and control. Decreased CSF Aβ1-42, sAPPα and -β in various CNS infections imply an effect of neuroinflammation on amyloid metabolism which is similar in regard to AD concerning Aβ1-42, but differs concerning sAPPα and -β. These results clearly indicate different pathologic pathways in AD and infectious CNS disease and may provide help in the differential biomarker diagnostics. Increased p-tau in HSV-1 encephalitis probably reflect acute neuronal damage and necrosis.

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References

  1. Blennow K, de Leon MJ, Zetterberg H (2006) Alzheimer’s disease. Lancet 368(9533):387–403. doi:10.1016/S0140-6736(06)69113-7

    PubMed  Article  CAS  Google Scholar 

  2. Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6(3):131–144. doi:10.1038/nrneurol.2010.4

    PubMed  Article  CAS  Google Scholar 

  3. Hampel H, Blennow K, Shaw LM, Hoessler YC, Zetterberg H, Trojanowski JQ (2010) Total and phosphorylated tau protein as biological markers of Alzheimer’s disease. Exp Gerontol 45(1):30–40. doi:10.1016/j.exger.2009.10.010

    PubMed  Article  CAS  Google Scholar 

  4. Zetterberg H, Blennow K, Hanse E (2010) Amyloid beta and APP as biomarkers for Alzheimer’s disease. Exp Gerontol 45(1):23–29. doi:10.1016/j.exger.2009.08.002

    PubMed  Article  CAS  Google Scholar 

  5. Strozyk D, Blennow K, White LR, Launer LJ (2003) CSF Abeta 42 levels correlate with amyloid-neuropathology in a population-based autopsy study. Neurology 60(4):652–656

    PubMed  Article  CAS  Google Scholar 

  6. Forsberg A, Engler H, Almkvist O, Blomquist G, Hagman G, Wall A, Ringheim A, Langstrom B, Nordberg A (2008) PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiol Aging 29(10):1456–1465. doi:10.1016/j.neurobiolaging.2007.03.029

    PubMed  Article  CAS  Google Scholar 

  7. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, DeKosky ST, Morris JC, Holtzman DM (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59(3):512–519. doi:10.1002/ana.20730

    PubMed  Article  CAS  Google Scholar 

  8. Mattsson N, Axelsson M, Haghighi S, Malmestrom C, Wu G, Anckarsater R, Sankaranarayanan S, Andreasson U, Fredrikson S, Gundersen A, Johnsen L, Fladby T, Tarkowski A, Trysberg E, Wallin A, Anckarsater H, Lycke J, Andersen O, Simon AJ, Blennow K, Zetterberg H (2009) Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis. Mult Scler 15(4):448–454. doi:10.1177/1352458508100031

    PubMed  Article  CAS  Google Scholar 

  9. Sjogren M, Gisslen M, Vanmechelen E, Blennow K (2001) Low cerebrospinal fluid beta-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment. Neurosci Lett 314(1–2):33–36. pii:S0304394001022856

    PubMed  Article  CAS  Google Scholar 

  10. Gisslen M, Krut J, Andreasson U, Blennow K, Cinque P, Brew BJ, Spudich S, Hagberg L, Rosengren L, Price RW, Zetterberg H (2009) Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 9:63. doi:10.1186/1471-2377-9-63

    PubMed  Article  Google Scholar 

  11. Mattsson N, Bremell D, Anckarsater R, Blennow K, Anckarsater H, Zetterberg H, Hagberg L (2010) Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism. BMC Neurol 10(1):51. doi:10.1186/1471-2377-10-51

    PubMed  Article  Google Scholar 

  12. Studahl M, Bergstrom T, Hagberg L (1998) Acute viral encephalitis in adults–a prospective study. Scand J Infect Dis 30(3):215–220

    PubMed  Article  CAS  Google Scholar 

  13. Aurelius E, Johansson B, Skoldenberg B, Staland A, Forsgren M (1991) Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid. Lancet 337(8735):189–192. pii:0140-6736(91)92155-U

    PubMed  Article  CAS  Google Scholar 

  14. Association AP (1987) Diagnostic and statistical manual of mental disorders. 3rd ed, revised edn. American Psychiatric Association, Arlington

  15. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) 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 34(7):939–944

    PubMed  Article  CAS  Google Scholar 

  16. Zetterberg M, Landgren S, Andersson ME, Palmer MS, Gustafson DR, Skoog I, Minthon L, Thelle DS, Wallin A, Bogdanovic N, Andreasen N, Blennow K, Zetterberg H (2008) Association of complement factor H Y402H gene polymorphism with Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 147B(6):720–726. doi:10.1002/ajmg.b.30668

    PubMed  Article  CAS  Google Scholar 

  17. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, Clifford DB, Cinque P, Epstein LG, Goodkin K, Gisslen M, Grant I, Heaton RK, Joseph J, Marder K, Marra CM, McArthur JC, Nunn M, Price RW, Pulliam L, Robertson KR, Sacktor N, Valcour V, Wojna VE (2007) Updated research nosology for HIV-associated neurocognitive disorders. Neurology 69(18):1789–1799. doi:10.1212/01.WNL.0000287431.88658.8b

    PubMed  Article  CAS  Google Scholar 

  18. American Academy of Neurology AIDS Task Force (1991) Nomenclature and research case definitions for neurologic manifestations of human immunodeficiency virus-type 1 (HIV-1) infection. Report of a Working Group of the American Academy of Neurology AIDS Task Force. Neurology 41(6):778–785

  19. National Center for Infectious Diseases Division of HIV/AIDS, CDC (1992) 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 41(RR-17):1–19

    Google Scholar 

  20. Vanmechelen E (2000) Quantification of tau phosphorylated at threonine 181 in human cerebrospinal fluid: a sandwich ELISA with a synthetic phosphopeptide for standardization. Neurosci Lett 285(1):49

    PubMed  Article  CAS  Google Scholar 

  21. Blennow K, Wallin A, Agren H, Spenger C, Siegfried J, Vanmechelen E (1995) Tau protein in cerebrospinal fluid: a biochemical marker for axonal degeneration in Alzheimer disease? Mol Chem Neuropathol 26(3):231–245. doi:10.1007/BF02815140

    PubMed  Article  CAS  Google Scholar 

  22. Vanderstichele HBK, D’Heuvaert N, Buyse M, Wallin A et al (1998) Development of a specific diagnostic test for measurement of amyloid (1–42) beta in CSF. In: Yoshida M (ed) Fisher A HI. Progress in Alzheimer’s and Parkinson’s Diseases. Plenum Press, New York, pp 773–778

    Google Scholar 

  23. Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB (2007) Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation. Neurosci Lett 429(2–3):95–100. doi:10.1016/j.neulet.2007.09.077

    PubMed  Article  CAS  Google Scholar 

  24. Piacentini R, Civitelli L, Ripoli C, Marcocci ME, De Chiara G, Garaci E, Azzena GB, Palamara AT, Grassi C (2010) HSV-1 promotes Ca(2+)-mediated APP phosphorylation and Abeta accumulation in rat cortical neurons. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2010.06.009

    PubMed  Google Scholar 

  25. Shipley SJ, Parkin ET, Itzhaki RF, Dobson CB (2005) Herpes simplex virus interferes with amyloid precursor protein processing. BMC Microbiol 5:48. doi:10.1186/1471-2180-5-48

    PubMed  Article  Google Scholar 

  26. Livrea P, Trojano M, Simone IL, Zimatore GB, Pisicchio L, Logroscino G, Cibelli G (1984) Heterogeneous models for blood-cerebrospinal fluid barrier permeability to serum proteins in normal and abnormal cerebrospinal fluid/serum protein concentration gradients. J Neurol Sci 64(3):245–258

    PubMed  Article  CAS  Google Scholar 

  27. Bjerke M, Portelius E, Minthon L, Wallin A, Anckarsater H, Anckarsater R, Andreasen N, Zetterberg H, Andreasson U, Blennow K (2010) Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. Int J Alzheimer’s Dis 2010:11. doi:10.4061/2010/986310

    Google Scholar 

  28. Nau R, Gerber J, Bunkowski S, Bruck W (2004) Axonal injury, a neglected cause of CNS damage in bacterial meningitis. Neurology 62(3):509–511

    PubMed  Article  Google Scholar 

  29. Pachner AR, Steiner I (2007) Lyme neuroborreliosis: infection, immunity, and inflammation. Lancet Neurol 6(6):544–552. doi:10.1016/S1474-4422(07)70128-X

    PubMed  Article  Google Scholar 

  30. Lovestone S, Reynolds CH (1997) The phosphorylation of tau: a critical stage in neurodevelopment and neurodegenerative processes. Neuroscience 78(2):309–324. pii:S0306452296005775

    PubMed  Article  CAS  Google Scholar 

  31. Zambrano A, Solis L, Salvadores N, Cortes M, Lerchundi R, Otth C (2008) Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1. J Alzheimers Dis 14(3):259–269

    PubMed  CAS  Google Scholar 

  32. Itzhaki RF, Wozniak MA (2008) Herpes simplex virus type 1 in Alzheimer’s disease: the enemy within. J Alzheimers Dis 13(4):393–405

    PubMed  CAS  Google Scholar 

  33. Honjo K, van Reekum R, Verhoeff NP (2009) Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease? Alzheimers Dement 5(4):348–360. doi:10.1016/j.jalz.2008.12.001

    PubMed  Article  Google Scholar 

  34. Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA (1997) Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease. Lancet 349(9047):241–244. doi:10.1016/S0140-6736(96)10149-5

    PubMed  Article  CAS  Google Scholar 

  35. Riemenschneider M, Wagenpfeil S, Vanderstichele H, Otto M, Wiltfang J, Kretzschmar H, Vanmechelen E, Forstl H, Kurz A (2003) Phospho-tau/total tau ratio in cerebrospinal fluid discriminates Creutzfeldt-Jakob disease from other dementias. Mol Psychiatry 8(3):343–347. doi:10.1038/sj.mp.4001220

    PubMed  Article  CAS  Google Scholar 

  36. Hesse C, Rosengren L, Andreasen N, Davidsson P, Vanderstichele H, Vanmechelen E, Blennow K (2001) Transient increase in total tau but not phospho-tau in human cerebrospinal fluid after acute stroke. Neurosci Lett 297(3):187–190. pii:S0304394000016979

    PubMed  Article  CAS  Google Scholar 

  37. Clifford DB, Fagan AM, Holtzman DM, Morris JC, Teshome M, Shah AR, Kauwe JS (2009) CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease. Neurology 73(23):1982–1987. doi:10.1212/WNL.0b013e3181c5b445

    PubMed  Article  CAS  Google Scholar 

  38. Brew BJ, Pemberton L, Blennow K, Wallin A, Hagberg L (2005) CSF amyloid beta42 and tau levels correlate with AIDS dementia complex. Neurology 65(9):1490–1492. doi:10.1212/01.wnl.0000183293.95787.b7

    PubMed  Article  CAS  Google Scholar 

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Acknowledgments

The study was supported by Sahlgrenska Academy at the University of Gothenburg (ALFGBG-11067), Swedish Research Council (project 2007–7092), Göteborg Medical Society.

Conflicts of interest

Dr. Krut declare that he has no conflicts of interest. Dr. Zetterberg declare that he has no conflicts of interest. Dr. Blennow declare that he has no conflicts of interest. Dr. Cinque declare that she has no conflicts of interest. Dr. Hagberg declare that he has no conflicts of interest. Dr. Price has received research grant support from Merck and Company for an investigator-initiated study and a speaking honorarium from Abbott Laboratories. Dr. Studahl received research funding from Sanofi Pasteur MSD. Dr. Gisslén declare that he has no conflicts of interest.

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All human studies must state that they have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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Affiliations

  1. Department of Infectious Diseases, University of Gothenburg, Gothenburg, Sweden

    Jan Jessen Krut, Lars Hagberg, Marie Studahl & Magnus Gisslén

  2. Department of Clinical Neuroscience, University of Gothenburg, Gothenburg, Sweden

    Henrik Zetterberg & Kaj Blennow

  3. Clinic of Infectious Diseases, San Raffaele Hospital, Milan, Italy

    Paola Cinque

  4. Department of Neurology, San Francisco General Hospital, University of California, San Francisco, CA, USA

    Richard W. Price

  5. Department of Infectious Diseases, Sahlgrenska University Hospital, Smörslottsgatan 1, 41678, Göteborg, Sweden

    Jan Jessen Krut

Authors
  1. Jan Jessen Krut
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  2. Henrik Zetterberg
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  3. Kaj Blennow
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  4. Paola Cinque
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  5. Lars Hagberg
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  7. Marie Studahl
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  8. Magnus Gisslén
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Correspondence to Jan Jessen Krut.

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Krut, J.J., Zetterberg, H., Blennow, K. et al. Cerebrospinal fluid Alzheimer's biomarker profiles in CNS infections. J Neurol 260, 620–626 (2013). https://doi.org/10.1007/s00415-012-6688-y

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  • DOI: https://doi.org/10.1007/s00415-012-6688-y

Keywords

  • Bacterial infections
  • Central nervous system
  • Herpes encephalitis
  • HIV-associated dementia (MesH term AIDS dementia complex)
  • Amyloid
  • Tau protein