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tau protein in cerebrospinal fluid

A biochemical marker for axonal degeneration in Alzheimer disease?

  • Original Articles
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Molecular and Chemical Neuropathology

Abstract

Cerebrospinal fluid (CSF) biochemical markers for Alzheimer disease (AD) would be of great value to improve the clinical diagnostic accuracy of the disorder. As abnormally phosphorylated forms of the microtubule-associated protein tau have been consistently found in the brains of AD patients, and since tau can be detected in CSF, two assays based on several well-defined monoclonal tau antibodies were used to study these proteins in CSF. One assay detects most normal and abnormal forms of tau (CSF-tau), while the other is highly specific for phosphorylated tau (CSF-PHFtau). A marked increase in CSF-PHFtau was found in AD (2230±930 pg/mL), as compared with controls (640±230 pg/mL;p<0.0001), vascular dementia, VAD (1610±840 pg/mL;p<0.05), frontal lobe dementia, FLD (1530±1000 pg/mL;p<0.05), Parkinson disease, PD (720±590 pg/mL;p<0.0001), and patients with major depression (230±130 pg/mL;p<0.0001). Parallel results were obtained for CSF-tau. No less than 35/40 (88%) of AD patients had a CSF-PHFtau value higher than the cutoff level of 1140 pg/mL in controls. The present study demonstrates that elevated tau/PHFtau levels are consistently found in CSF of AD patients. However, a considerable overlap is still present with other forms of dementia, both VAD and FLD. CSF-tau and CSF-PHFtau may therefore be useful as a positive biochemical marker, to discriminate AD from normal aging, PD, and depressive pseudodementia. Further studies are needed to clarify the sensitivity and specificity of these assays, including follow-up studies with neuropathological examinations.

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References

  • American Psychiatric Association (1987)Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., American Psychiatric Association, Washington, DC.

    Google Scholar 

  • Bancher, C., Brunner C., Lassman H., Budka H., Jellinger K., Wiche G., Seitelberger F., Grundke-Iqbal I., Iqbal K., and Wisniewski H. M. (1989) Accumulation of abornmally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer disease.Brain Res. 477, 90–99.

    Article  PubMed  CAS  Google Scholar 

  • Bissette G., Smith W. H., Dole K. C., Crain B., Ghanbari H., Miller B., and Nemeroff C. B. (1991) Alterations in Alzheimer’s disease-associated protein in Alzheimer’s disease frontal and temporal cortex.Arch. Gen. Psychiat. 48, 1009–1012.

    PubMed  CAS  Google Scholar 

  • Blennow K., Wallin A., and Gottfries C. G. (1991) Presence of parietal lobe symptomatology distinguishes early and late onset Alzheimer’s disease.Int. J. Geriatr. Psychiat.,6, 147–154.

    Article  Google Scholar 

  • Blennow K. and Wallin A. (1992) Clinical heterogeneity of probable Alzheimer’s disease.J. Geriatr. Psychiatry Neurol. 5, 106–113.

    PubMed  CAS  Google Scholar 

  • Blennow K., Fredman P., Wallin A., Gottfries C. G., Langstrom L., and Svennerholm L. (1993) Protein analyses in cerebrospinal fluid: I. Influence of concentration gradients for proteins on cerebrospinal fluid/serum albumin ratio.Eur. Neurol. 33, 126–128.

    Article  PubMed  CAS  Google Scholar 

  • Bramblett G. T., Trojanowski J. Q., and Lee V. M. Y. (1992) Regions with abundant neurofibrillary pathology in human brain exhibit a selective reduction in levels of binding-competent τ and accumulation of abnormal τ-isoforms (A68 proteins).Lab. Invest. 66, 212–222.

    PubMed  CAS  Google Scholar 

  • Coleman P. D. and Flood D. G. (1987) Neuron numbers and dendrite extent in normal aging and Alzheimer’s disease.Neurobiol. Aging 8, 521–545.

    Article  PubMed  CAS  Google Scholar 

  • Davies C. A., Mann D. M. A., Sumpter P. Q., and Yates P. O. (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease.J. Neurol. Sci. 78, 151–164.

    Article  PubMed  CAS  Google Scholar 

  • Delacourte A., Flament S., Dibe E. M., Hublau P., Sablonniére B., Hémon B., Shérrer V., and Défossez A. (1990) Pathological proteins tau 64 and 69 are specifically expressed in the somatodendritic domain of the degenerating cortical neurons during Alzheimer’s disease.Acta Neuropathol. 80, 111–117.

    Article  PubMed  CAS  Google Scholar 

  • Dewar D., Graham D. I., Teasdale G. M., and McCulloch J. (1994) Cerebral ischemia induces alterations in tau and ubiquitin proteins.Dementia 5, 168–173.

    PubMed  CAS  Google Scholar 

  • Folstein M., Folstein S., and McHugh P. (1975) “Mini-Mental State” A practical method for grading the cognitive state of patients for the clinician.J. Psychiatr. Res. 12, 189–198.

    Article  PubMed  CAS  Google Scholar 

  • Garver T. D., Harris K. A., Lehman R. A. W., Lee V. M. Y., Trojanowski J. Q., and Billingsley M. L. (1994) τ phosphorylation in human, primate, and rat brain: evidence that a pool of τ is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro.J. Neurochem. 63, 2279–2287.

    Article  PubMed  CAS  Google Scholar 

  • Ghanbari H. A., Kozuk T., Miller B. E., and Riesing S. (1990) A sandwich enzyme immunoassay for detecting and measuring Alzheimer’s disease-associated proteins in human brain tissue.J. Clin. Lab. Anal. 4, 189–192.

    Article  PubMed  CAS  Google Scholar 

  • Goedert M., Wischik C. M., Crowther R. A., Walker J. E., and Klug A. (1988) Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau.Proc. Natl. Acad. Sci. USA 85, 4051–4055.

    Article  PubMed  CAS  Google Scholar 

  • Goedert M., Spillantini M., and Jakes R. (1991) Localization of the Alz-50 epitope in recombinant human microtubule-associated protein tau.Neurosci. Lett. 126, 149–154.

    Article  PubMed  CAS  Google Scholar 

  • Goedert M. (1993) Tau protein and the neurofibrillary pathology of Alzheimer’s disease.Trends Neurosci. 16, 460–465.

    Article  PubMed  CAS  Google Scholar 

  • Goedert M., Jakes R., Crowther A., Cohen P., Vanmechelen E., Vandermeeren M., and Cras P. (1994) Epitope mapping of monoclonal antibodies to the paired helical filaments of Alzheimer’s disease: identification of phosphorylation sites in tau protein.Biochem. J. 301, 871–877.

    PubMed  CAS  Google Scholar 

  • Greenberg S. G. and Davies P. (1990) A preparation of Alzheimer paired helical filaments that displays distinct → proteins by polyacrylamide gel electrophoresis.Proc. Natl. Acad. Sci. USA 87, 5827–5831.

    Article  PubMed  CAS  Google Scholar 

  • Grundke-Iqbal I., Iqbal K., Tung Y. C., Quinlan M., Wisniewski H. M., and Binder L. I. (1986) Abnormal phosphorylation of the microtubule-associated protein → (tau) in Alzheimer cytoskeletal pathology.Proc. Natl. Acad. Sci. USA 83, 4913–4917.

    Article  PubMed  CAS  Google Scholar 

  • Gustafson L. (1987) Frontal lobe degeneration of non-Alzheimer type. 2. Clinical picture and differential diagnosis.Arch. Gerontol. Geriatr. 6, 209–223.

    Article  PubMed  CAS  Google Scholar 

  • Hamos J. E., DeGennaro L. J., and Drachman D. A. (1989) Synaptic loss in Alzheimer’s disease and other dementias.Neurology 39, 355–361.

    PubMed  CAS  Google Scholar 

  • Harrington C. R., Mukeatova-Ladinska E. B., Hills R., Edwards P. C., de Garcini E. M., Novak M., and Wischik C. M. (1991) Measurement of distinct immunochemical presentations of tau protein in Alzheimer disease.Proc. Natl. Acad. Sci. USA 88, 5842–5846.

    Article  PubMed  CAS  Google Scholar 

  • Harrington C. R., Perry R. H., Perry E. K., Hurt J., McKeith I. G., Roth M., and Wischik C. M. (1994) Senile dementia of Lewy Body-type and Alzheimer type are biochemically distinct in terms of paired helical filaments and hyperphosphorylated tau protein.Dementia 5, 215–218.

    PubMed  CAS  Google Scholar 

  • Hyman B. T., van Hoesen G. W., Wolozin B. L., Davies P., Kromer L. J., and Damosio A. R. (1988) Alz-50 antibody recognizes Alzheimer-related neuronal changes.Ann. Neurol. 23, 371–379.

    Article  PubMed  CAS  Google Scholar 

  • Ihara Y., Nukina N., Miura R., and Ogawara M. (1986) Phosphorylated tauprotein is integrated into paired helical filaments in Alzheimer’s disease.J. Biochem. 99, 1807–1810.

    PubMed  CAS  Google Scholar 

  • International Federation of Clinical Chemistry (IFCC) (1987) Approved recommentation on the theory of reference values, Part 5. Statistical treatment of collected reference values. Determination of reference limits.Clin. Chim. Acta 170, 13–32.

    Article  Google Scholar 

  • Katzman R. (1986) Alzheimer’s disease.N. Engl. J. Med. 314, 964–973.

    Article  PubMed  CAS  Google Scholar 

  • Khatoon S., Grundke-Iqbal I., and Iqbal K. (1992) Brain levels of microtubule-associated protein → are elevated in Alzheimer’s disease: a radioimmunoslot-blot assay for nanograms of the protein.J. Neurochem. 59, 750–753.

    Article  PubMed  CAS  Google Scholar 

  • Langston J. W., Widner H., Goetz C. G., Brooks D., Fahn S., Freeman T., and Watts R. (1992) Core assessment program for intracerebral transplantations (CAPIT).Mov. Disord. 7, 2–13.

    Article  PubMed  CAS  Google Scholar 

  • Lishman W. A. (1987)Organic Psychiatry: the Psychological Consequences of Cerebral Disorder. 2nd ed. Chicago, Year Book Medical Publishers.

    Google Scholar 

  • Matsuo E., Shin R.-W., Billingsley M. L., Van de Voorde A., O’Connor M., Trojanowski J., and Lee V.-M. (1994) Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau.Neuron 13, 989–1002.

    Article  PubMed  CAS  Google Scholar 

  • McKhann G., Drachman D., Folstein M., Katzman R., Price D., and 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 

  • Mehta P. H., Thal L., and Wisniewski H. M., et al. (1985) Paired helical filaments antigen in CSF. (letter)Lancet II 35.

  • Mercken M., Vandermeeren M., Lübke U., Six J., Boons J., van der Voorde A., Martin J. J., and Gheuens J. (1992) Monoclonal antibodies with selective specificity for Alzheimer tau are directed against phosphatase-sensitive epitopes.Acta Neuropathol. 84, 265–272.

    Article  PubMed  CAS  Google Scholar 

  • Mori H., Kondo J., and Ihara Y. (1987) Ubiquitin is a component of paired helical filaments in Alzheimer’s disease.Science 235, 1641–1644.

    Article  PubMed  CAS  Google Scholar 

  • Morishima-Kawashima M., Hasegawa M., Takio K., Suzuki M., Yoshida H., Titani K., and Ihara Y. (1995) Proline-directed and non-proline-directed phosphorylation of PHF-tau.J. Biol. Chem. 270, 823–829.

    Article  PubMed  CAS  Google Scholar 

  • Mukaetova-Ladinska E. B., Harrington C. R., Hills R., O’Sullivan A., Roth M., and Wischik C. M. (1992) Regional distribution of paired helical filaments and normal tau proteins in aging and in Alzheimer’s disease with and without temporal lobe involvement.Dementia 3, 61–69.

    Google Scholar 

  • Oyama F., Shimada H., Oyama R., Titani K., and Ihara Y. (1991) Differential expression of β amyloid protein precursor (APP) and tau mRNA in the aged human brain: individual variability and correlation between APP-751 and four-repeat tau.J. Neuropathol. Exp. Neurol. 50, 560–578.

    Article  PubMed  CAS  Google Scholar 

  • Perry G., Friedman R., Shaw G., and Chau V. (1987) Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains.Proc. Natl. Acad. Sci. USA 84, 3033–3036.

    Article  PubMed  CAS  Google Scholar 

  • Scheltens P., Vermersch P., and Leys D. (1993) Hétérogénéité de la maladie d’Alzheimer.Rev. Neurol. (Paris) 149, 14–25.

    CAS  Google Scholar 

  • Sjögren T., Sjögren H., and Lindgren Å. (1952) Morbus Alzheimer and morbus Pick: A genetic, clinical and patho-anatomical study.Acta Psych. Neurol. Scand. (Suppl. 82) 66–115.

    Google Scholar 

  • Szendrei G., Lee V.-M., and Otvos L. (1993) Recognition of the minimal epitope of monoclonol antibody Tau-1 depends upon the presence of a phosphate group but not its localization.J. Neurosci. Res. 34, 243–249.

    Article  PubMed  CAS  Google Scholar 

  • Thompson E. J. (1988)The CSF Proteins: A Biomedical Approach. Elsevier, Amsterdam, pp. 9–26.

    Google Scholar 

  • Tibbling G., Link H., and Öhman S. (1977) Principles of albumin and IgG analysis in neurological disorders. I. Establishment of reference values.Scand. J. Clin. Lab. Invest. 37, 385–390.

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson B. E., Blessed G., and Roth M. (1968) Observations of the brans of non-demented old people.J. Neurol. Sci. 7, 331–356.

    Article  PubMed  CAS  Google Scholar 

  • Tomlinson B. E., Blessed G., and Roth M. (1968) Observations of the brains of demented old people.J. Neurol. Sci. 11, 205–242.

    Article  Google Scholar 

  • Tomlinson B. E. and Corsellis J. A. N. (1984)Ageing and the dementias, inGreenfield’s Neuropathology (Hume Adams J., Corsellis J. A. N., and Duchen L. W., eds., Edward Arnold, London, pp. 951–1025.

    Google Scholar 

  • Vandermeeren M., Mercken M., Vanmechelen E., Six J., Van de Voorde A., Martin J. J., and Cras P. (1993) Detection of → proteins in normal and Alzheimer’s disease cerebrospinal fluid with a sensitive sandwich enzymelinked immunosorbent assay.J. Neurochem. 61, 1828–1834.

    Article  PubMed  CAS  Google Scholar 

  • Wallin A., Gottfries C. G., Karlsson I., and Svennerholm L. (1989) Decreased myelin lipids in Alzheimer’s disease and vascular dementia.Acta Neurol. Scand. 80, 319–323.

    Article  PubMed  CAS  Google Scholar 

  • Wallin A. and Blennow K. (1991) The pathogenetic basis of vascular dementia.Alzheimer Dis. Assoc. Disord. 5, 91–102.

    Article  PubMed  CAS  Google Scholar 

  • Wallin A., Blennow K., and Scheltens P. (1994) Research criteria for clinical diagnosis of “pure” Alzheimer’s disease.Drugs Today 30, 265–273.

    Google Scholar 

  • Wang G. P., Iqbal K., Bucht G., Winblad B., Wisniewski H. M., and Grundke-Iqbal I. (1991) Alzheimer’s disease: paired helical filament immunoreactivity in cerebrospinal fluid.Acta Neuropathol. (Berl.) 82, 6–12.

    Article  CAS  Google Scholar 

  • Wisniewski K., George A. J., Moretz R. C., and Wisniewski H. M. (1979) Alzheimer neurofibrillary tangles in diseases other than senile and presenile dementia.Ann. Neurol. 5, 288–294.

    Article  PubMed  CAS  Google Scholar 

  • Wolozin B. and Davies P. (1987) Alzheimer-related neuronal protein A68: specificity and distribution.Ann. Neurol. 22, 521–526.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Neuroscience Unit of Neurochemistry, University of Göteborg, Mölndal Hospital, S-431 80, Mölndal, Sweden

    K. Blennow

  2. Unit of Psychiatry, University of Göteborg, Mölndal Hospital, S-431 80, Mölndal, Sweden

    A. Wallin & H. Ågren

  3. Department of Neurosurgery, University of Bern, Switzerland

    C. Spenger

  4. Klinik im Park, Zürich, Switzerland

    J. Siegfried

  5. Innogenetics N.V., Ghent, Belgium

    E. Vanmechelen

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  1. K. Blennow
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  2. A. Wallin
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  3. H. Ågren
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  4. C. Spenger
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  6. E. Vanmechelen
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Blennow, K., Wallin, A., Ågren, H. et al. tau protein in cerebrospinal fluid. Molecular and Chemical Neuropathology 26, 231–245 (1995). https://doi.org/10.1007/BF02815140

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