Skip to main content

Advertisement

SpringerLink
Log in

Cerebrospinal Fluid Microglial Markers in Alzheimer’s Disease: Elevated Chitotriosidase Activity but Lack of Diagnostic Utility

  • Original Paper
  • Published:
NeuroMolecular Medicine Aims and scope Submit manuscript

Abstract

Activated microglial cells, which are the resident macrophages of the central nervous system, surround amyloid β-plaques in Alzheimer’s disease (AD) brains. Inflammation including microglial activation may contribute in AD pathogenesis, and biomarkers for this process may thus be of value to study AD pathogenesis and might facilitate development of therapies targeting these cells. We therefore examined cerebrospinal fluid (CSF) biomarkers in patients with AD, other dementias, mild cognitive impairment and in healthy controls. Samples were analyzed for markers with known association to macrophage activity, including chitotriosidase, YKL-40 (CHI3L1, HC gp-39) and chemokine CC motif ligand 2 (CCL2, MCP1). Patients with AD had higher chitotriosidase activity than controls and patients with stable mild cognitive impairment, consistent with the presence of activated microglial cells in AD brains, but with large overlaps between groups. CCL2 and YKL-40 concentrations did not differ among groups. Microglial markers are unlikely to be useful for AD diagnosis, but might be useful for identification of distinct subgroups of patients, and for the development and implementation of drugs targeting microglial pathology.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Aerts, J. M., van Breemen, M. J., Bussink, A. P., Ghauharali, K., Sprenger, R., Boot, R. G., et al. (2008). Biomarkers for lysosomal storage disorders: Identification and application as exemplified by chitotriosidase in Gaucher disease. Acta Paediatrica. Supplement, 97, 7–14.

    Article  PubMed  Google Scholar 

  • American Psychiatric Association. (1987). Diagnostic and statistical manual of mental disorders, third edition, revised. Arlington, VA, USA: American Psychiatric Association.

    Google Scholar 

  • Amor, S., Puentes, F., Baker, D., & van der Valk, P. (2010). Inflammation in neurodegenerative diseases. Immunology, 129, 154–169.

    Article  PubMed  CAS  Google Scholar 

  • Banati, R. B., Newcombe, J., Gunn, R. N., Cagnin, A., Turkheimer, F., Heppner, F., et al. (2000). The peripheral benzodiazepine binding site in the brain in multiple sclerosis: Quantitative in vivo imaging of microglia as a measure of disease activity. Brain, 123(Pt 11), 2321–2337.

    Article  PubMed  Google Scholar 

  • Bjerke, M., Portelius, E., Minthon, L., Wallin, A., Anckarsater, H., Anckarsater, R., et al. (2010). Confounding factors influencing amyloid Beta concentration in cerebrospinal fluid. International Journal of Alzheimer’s Disease.

  • Blasko, I., Lederer, W., Oberbauer, H., Walch, T., Kemmler, G., Hinterhuber, H., et al. (2006). Measurement of thirteen biological markers in CSF of patients with Alzheimer’s disease and other dementias. Dementia and Geriatric Cognitive Disorders, 21, 9–15.

    Article  PubMed  Google Scholar 

  • Blennow, K., de Leon, M. J., & Zetterberg, H. (2006). Alzheimer’s disease. Lancet, 368, 387–403.

    Article  PubMed  CAS  Google Scholar 

  • Boot, R. G., Renkema, G. H., Verhoek, M., Strijland, A., Bliek, J., de Meulemeester, T. M., et al. (1998). The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem, 273, 25680–25685.

    Article  PubMed  CAS  Google Scholar 

  • Boot, R. G., Verhoek, M., de Fost, M., Hollak, C. E., Maas, M., Bleijlevens, B., et al. (2004). Marked elevation of the chemokine CCL18/PARC in Gaucher disease: A novel surrogate marker for assessing therapeutic intervention. Blood, 103, 33–39.

    Article  PubMed  CAS  Google Scholar 

  • Craig-Schapiro, R., Perrin, R. J., Roe, C. M., Xiong, C., Carter, D., Cairns, N. J., et al. (2010). YKL-40: A novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biological Psychiatry, 68, 903–912.

    Article  PubMed  CAS  Google Scholar 

  • Deshmane, S. L., Kremlev, S., Amini, S., & Sawaya, B. E. (2009). Monocyte chemoattractant protein-1 (MCP-1): An overview. Journal of Interferon and Cytokine Research, 29, 313–326.

    Article  PubMed  CAS  Google Scholar 

  • Di Rosa, M., Dell’Ombra, N., Zambito, A. M., Malaguarnera, M., Nicoletti, F., & Malaguarnera, L. (2006). Chitotriosidase and inflammatory mediator levels in Alzheimer’s disease and cerebrovascular dementia. European Journal of Neuroscience, 23, 2648–2656.

    Article  PubMed  Google Scholar 

  • Dubois, B., Feldman, H. H., Jacova, C., Cummings, J. L., Dekosky, S. T., Barberger-Gateau, P., et al. (2010). Revising the definition of Alzheimer’s disease: A new lexicon. Lancet Neurology, 9, 1118–1127.

    Article  PubMed  Google Scholar 

  • Erkinjuntti, T., Inzitari, D., Pantoni, L., Wallin, A., Scheltens, P., Rockwood, K., et al. (2000). Research criteria for subcortical vascular dementia in clinical trials. Journal of Neural Transmission. Supplementum, 59, 23–30.

    PubMed  CAS  Google Scholar 

  • Forsberg, A., Engler, H., Almkvist, O., Blomquist, G., Hagman, G., Wall, A., et al. (2008). PET imaging of amyloid deposition in patients with mild cognitive impairment. Neurobiology of Aging, 29, 1456–1465.

    Article  PubMed  CAS  Google Scholar 

  • Galasko, D., & Montine, T. J. (2010). Biomarkers of oxidative damage and inflammation in Alzheimer’s disease. Biomarkers in Medicine, 4, 27–36.

    Article  PubMed  CAS  Google Scholar 

  • Galimberti, D., Schoonenboom, N., Scarpini, E., & Scheltens, P. (2003). Chemokines in serum and cerebrospinal fluid of Alzheimer’s disease patients. Annals of Neurology, 53, 547–548.

    Article  PubMed  Google Scholar 

  • Hakala, B. E., White, C., & Recklies, A. D. (1993). Human cartilage gp-39, a major secretory product of articular chondrocytes and synovial cells, is a mammalian member of a chitinase protein family. Journal of Biological Chemistry, 268, 25803–25810.

    PubMed  CAS  Google Scholar 

  • Hansson, O., Zetterberg, H., Buchhave, P., Londos, E., Blennow, K., & Minthon, L. (2006). Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: A follow-up study. Lancet Neurology, 5, 228–234.

    Article  PubMed  CAS  Google Scholar 

  • Hollak, C. E., van Weely, S., van Oers, M. H., & Aerts, J. M. (1994). Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. Journal of Clinical Investigation, 93, 1288–1292.

    Article  PubMed  CAS  Google Scholar 

  • Johansson, P., Mattsson, N., Hansson, O., Wallin, A., Johansson, J. O., Andreasson, U., et al. (2011). Cerebrospinal fluid biomarkers for Alzheimer’s disease: Diagnostic performance in a homogeneous mono-center population. Journal of Alzheimer’s Disease.

  • Lucin, K. M., & Wyss-Coray, T. (2009). Immune activation in brain aging and neurodegeneration: Too much or too little? Neuron, 64, 110–122.

    Article  PubMed  CAS  Google Scholar 

  • Lue, L. F., Rydel, R., Brigham, E. F., Yang, L. B., Hampel, H., Murphy, G. M., Jr., et al. (2001). Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro. Glia, 35, 72–79.

    Article  PubMed  CAS  Google Scholar 

  • Luo, X. G., Ding, J. Q., & Chen, S. D. (2010). Microglia in the aging brain: Relevance to neurodegeneration. Molecular Neurodegeneration, 5, 12.

    Article  PubMed  Google Scholar 

  • Mattsson, N., Blennow, K., & Zetterberg, H. (2010a). Inter-laboratory variation in cerebrospinal fluid biomarkers for Alzheimer’s disease: United we stand, divided we fall. Clinical Chemistry and Laboratory Medicine, 48, 603–607.

    Article  PubMed  CAS  Google Scholar 

  • Mattsson, N., Johansson, P., Hansson, O., Wallin, A., Johansson, J. O., Andreasson, U., et al. (2010b). Converging pathways of chromogranin and amyloid metabolism in the brain. Journal of Alzheimers Disease, 20, 1039–1049.

    CAS  Google Scholar 

  • Mattsson, N., Zetterberg, H., Hansson, O., Andreasen, N., Parnetti, L., Jonsson, M., et al. (2009). CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA, 302, 385–393.

    Article  PubMed  CAS  Google Scholar 

  • McKeith, I. G. (2006). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the Consortium on DLB International Workshop. Journal of Alzheimers Disease, 9, 417–423.

    Google Scholar 

  • McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (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, 939–944.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Okello, A., Koivunen, J., Edison, P., Archer, H. A., Turkheimer, F. E., Nagren, K., et al. (2009). Conversion of amyloid positive and negative MCI to AD over 3 years: An 11C-PIB PET study. Neurology, 73, 754–760.

    Article  PubMed  CAS  Google Scholar 

  • Olson, L., & Humpel, C. (2010). Growth factors and cytokines/chemokines as surrogate biomarkers in cerebrospinal fluid and blood for diagnosing Alzheimer’s disease and mild cognitive impairment. Experimental Gerontology, 45, 41–46.

    Article  PubMed  CAS  Google Scholar 

  • Perry, V. H., Nicoll, J. A., & Holmes, C. (2010). Microglia in neurodegenerative disease. Nature Reviews Neurology, 6, 193–201.

    Article  PubMed  Google Scholar 

  • Petersen, R. C. (2004). Mild cognitive impairment as a diagnostic entity. Journal of Internal Medicine, 256, 183–194.

    Article  PubMed  CAS  Google Scholar 

  • Piras, I., Melis, A., Ghiani, M. E., Falchi, A., Luiselli, D., Moral, P., et al. (2007). Human CHIT1 gene distribution: New data from Mediterranean and European populations. Journal of Human Genetics, 52, 110–116.

    Article  PubMed  Google Scholar 

  • Renkema, G. H., Boot, R. G., Au, F. L., Donker-Koopman, W. E., Strijland, A., Muijsers, A. O., et al. (1998). Chitotriosidase, a chitinase, and the 39-kDa human cartilage glycoprotein, a chitin-binding lectin, are homologues of family 18 glycosyl hydrolases secreted by human macrophages. European Journal of Biochemistry, 251, 504–509.

    Article  PubMed  CAS  Google Scholar 

  • Roman, G. C., Tatemichi, T. K., Erkinjuntti, T., Cummings, J. L., Masdeu, J. C., Garcia, J. H., et al. (1993). Vascular dementia: Diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology, 43, 250–260.

    PubMed  CAS  Google Scholar 

  • Schiffmann, R., Heyes, M. P., Aerts, J. M., Dambrosia, J. M., Patterson, M. C., DeGraba, T., et al. (1997). Prospective study of neurological responses to treatment with macrophage-targeted glucocerebrosidase in patients with type 3 Gaucher’s disease. Annals of Neurology, 42, 613–621.

    Article  PubMed  CAS  Google Scholar 

  • Semple, B. D., Kossmann, T., & Morganti-Kossmann, M. C. (2010). Role of chemokines in CNS health and pathology: A focus on the CCL2/CCR2 and CXCL8/CXCR2 networks. Journal of Cerebral Blood Flow and Metabolism, 30, 459–473.

    Article  PubMed  CAS  Google Scholar 

  • Sotgiu, S., Barone, R., Arru, G., Fois, M. L., Pugliatti, M., Sanna, A., et al. (2006). Intrathecal chitotriosidase and the outcome of multiple sclerosis. Multiple Sclerosis, 12, 551–557.

    Article  PubMed  CAS  Google Scholar 

  • Sotgiu, S., Piras, M. R., Barone, R., Arru, G., Fois, M. L., Rosati, G., et al. (2007). Chitotriosidase and Alzheimer’s disease. Current Alzheimer Research, 4, 295–296.

    Article  PubMed  CAS  Google Scholar 

  • Swardfager, W., Lanctot, K., Rothenburg, L., Wong, A., Cappell, J., & Herrmann, N. (2010). A meta-analysis of cytokines in Alzheimer’s disease. Biological Psychiatry, 68, 930–941.

    Article  PubMed  CAS  Google Scholar 

  • van Eijk, M., Voorn-Brouwer, T., Scheij, S. S., Verhoeven, A. J., Boot, R. G., & Aerts, J. M. (2010). Curdlan-mediated regulation of human phagocyte-specific chitotriosidase. FEBS Letters, 584, 3165–3169.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Åsa Källén, Monica Christiansson, Sara Hullberg, Dzemila Secic, Eva Johansson, Mona Palmér and Rita Persson for excellent technical assistance. This study was funded by grants from the Swedish Research Council, the Sahlgrenska University Hospital, the Sahlgrenska Academy, the Lundbeck Foundation, Stiftelsen för Gamla tjänarinnor, Pfannenstills stiftelse, Thuréus stiftelse, the Swedish Association of Persons with Neurological Disabilities, Alzheimer’s Association and the Royal Swedish Academy of Sciences., the Dementia Foundation (Sweden), Uppsala Universitet (Medicinska fakultetens stiftelse för psykiatrisk och neurologisk forskning) and the Swedish Brain Foundation.

Conflict of interests

KB has served in a scientific advisory board for Innogenetics. HZ has served in a scientific advisory board for GlaxoSmithKline. NM has served in a scientific advisory board for Actelion Inc. The other authors have no conflicts of interest.

Author information

Authors and Affiliations

  1. Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, S-431 80, Mölndal, Sweden

    Niklas Mattsson, Shahrzad Tabatabaei, Ulf Andreasson, Jan-Eric Månsson, Bob Olsson, Anders Wallin, Kaj Blennow & Henrik Zetterberg

  2. Department of Neuropsychiatry, Skaraborg Hospital, Falköping and Skövde, Sweden

    Per Johansson

  3. Department of Endocrinology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Per Johansson, Jan-Ove Johansson & Johan Svensson

  4. Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden

    Oskar Hansson

Authors
  1. Niklas Mattsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shahrzad Tabatabaei
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Per Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Oskar Hansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ulf Andreasson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan-Eric Månsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jan-Ove Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Bob Olsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anders Wallin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Johan Svensson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kaj Blennow
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Henrik Zetterberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Niklas Mattsson.

Additional information

Niklas Mattsson, Shahrzad Tabatabaei, and Per Johansson are contributed equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mattsson, N., Tabatabaei, S., Johansson, P. et al. Cerebrospinal Fluid Microglial Markers in Alzheimer’s Disease: Elevated Chitotriosidase Activity but Lack of Diagnostic Utility. Neuromol Med 13, 151–159 (2011). https://doi.org/10.1007/s12017-011-8147-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12017-011-8147-9

Keywords

Search

Navigation