Molecular and Chemical Neuropathology

, Volume 29, Issue 2–3, pp 237–252 | Cite as

Blood levels of histamine, IL-1β, and TNF-α in patients with mild to moderate alzheimer disease

  • X. Antón AlvarezEmail author
  • Andrés Franco
  • Lucía Fernández-Novoa
  • Ramón Cacabelos


In this study, we have evaluated the levels of blood histamine, serum interleukin-1 beta (IL-1β), and plasma tumor necrosis factor-alpha (TNF-α) in 20 patients with mild to moderate Alzheimer disease (AD; 13 early onset and 7 late-onset AD subjects) and in 20 agematched control subjects (C). AD patients showed higher concentrations of histamine (AD=452.9±237.9 pmol/mL; C=275.3±151.5 pmol/mL;p<0.05) and IL-1β (AD=211.2±31.1 pg/mL; C=183.4±24.4 pg/mL;p<0.01), and lower values of TNF-α (AD=3.59±2.02 pg/mL; C=9.47±2.64 pg/mL;p<0.001) than elderly controls. Increased levels of histamine and decreased levels of TNF-α were observed in both early onset AD (EOAD) and late-onset AD (LOAD) patients, but only EOAD subjects had elevated serum IL-1β values compared with age-matched controls. Age negatively correlated with histamine (r=−0.57;p<0.05) and positively with IL-1β levels (r=0.48;p<0.05) in healthy subjects, but not in AD, whereas a positive correlation between TNF-α scores and age was only found in AD patients (r=0.46;p<0.05). Furthermore, histamine and TNF-α values correlated negatively in AD (r=−0.50,p<0.05). In addition, cognitive impairment increased in patients with lower TNF-α and higher histamine and IL-1β levels, as indicated by the correlations between mental performance scores and histamine (r=−0.37, ns), IL-1β (r=−0.33, ns) and TNF-α levels (r=0.42,p<0.05). Finally, histamine concentrations decreased as depression scores increased in AD (r=−0.63,p<0.01). These data suggest a dysfunction in cytokine and histamine regulation in AD, probably indicating changes associated with inflammatory processes.

Index Entries

Alzheimer disease histamine interleukin-1β, tumor necrosis factor-alpha cognitive performance depression elderly subjects 


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  1. Abraham C. R. (1992) The role of the acute-phase protein α1-antichymotrypsin in brain dysfunction and injury.Res. Immunol. 143, 631–636.PubMedCrossRefGoogle Scholar
  2. Airaksinen M. S., Paetau A., Paljarvi L., Reinkainen K., Riekkinen P., Soumalainen R., and Panula P. (1991) Histamine neurons in human hypothalamus: anatomy in normal and Alzheimer’s disease brains.Neuroscience 44, 465–481.PubMedCrossRefGoogle Scholar
  3. Altstiel L. D. and Sperber K. (1991) Cytokines in Alzheimer’s disease.Prog. Neurol. Psychopharmacol. Biol. Psychiat. 15, 481–495.CrossRefGoogle Scholar
  4. Alvarez X. A., Franco A., Fernández-Novoa L., and Cacabelos R. (1993a) Agerelated changes in serum interleukin-1β and tumor necrosis factor-alpha levels in healthy control subjects.Eur. Neuropsychopharmacol. 3, 414.CrossRefGoogle Scholar
  5. Alvarez X. A., Franco A., Rettori M-C., Kamoun A., Polo E., and Cacabelos R. (1993b) S 9977-2 reduces learning impairment and brain interleukin-1β overproduction in rats with neurotoxic lesions in the nucleus basalis of Meynert.Eur. Neuropsychopharmacol. 3, 425.CrossRefGoogle Scholar
  6. Alvarez X. A., Franco A., Fernández-Novoa L., and Cacabelos R. (1994) Effects of neurotoxic lesions in histaminergic neurons on brain tumor necrosis factor levels.Agents and Actions 41, C70-C72.PubMedCrossRefGoogle Scholar
  7. Alvarez X. A., Zas R., Lagares R., Franco A., Beyer K., Polo E., Garcia M., Guez D., Fernández-Novoa L., and Cacabelos R. (1995a) Effects of S9977-2, a new cognition enhancing drug, on behavior and brain neurotransmitters in rats.Ann. Psychiatry 5, 247–265.Google Scholar
  8. Alvarez X. A., Zas R., Lagares R., Franco A., Maneiro E., Miguel-Hidalgo J. J. Lao J. I., Fernández-Novoa L., Díaz J., and Cacabelos R. (1995b) Neuroimmunomodulatory and neurotrophic activity of anapsos: studies with laboratory animals.Ann. Psychiatry 5, 267–280.Google Scholar
  9. American Psychiatric Association. (1994)Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, DC.Google Scholar
  10. Araujo D. M. (1992) Contrasting effects of specific lymphokines on the survival of hippocampal neurons in culture.Adv. Behav. Biol. 40, 113–122.Google Scholar
  11. Blume A. J. and Vitek M. P. (1989) Focusing on IL1-production of beta-amyloid precursor protein synthesis as an early event in Alzheimer’s disease.Neurobiol. Aging 10, 406–408.PubMedCrossRefGoogle Scholar
  12. Cacabelos R., Wiigawa H., and Ikemura Y. (1986) Neuroendocrine correlates in senile dementia of the Alzheimer type.Prog. Clin. Neurosci. 2, 231–247.Google Scholar
  13. Cacabelos R., Yamatodani A., Niigawa H., Hariguchi S., Tada K., Nishimura T., Wada H., Brandeis L., and Pearson J. (1989) Brain histamine in Alzheimer’s disease.Methods Findings Exp. Clin. Pharmacol. 11, 353–360.Google Scholar
  14. Cacabelos R., Barquero M., García P., Alvarez X. A., and Varela de Seijas E. (1991a) Cerebrospinal fluid interleukin-1beta in Alzheimer’s disease and neurological disorders.Methods Findings Clin. Pharmacol. 13, 455–458.Google Scholar
  15. Cacabelos R., Franco-Maside A., and Alvarez X. A. (1991b) Interleukin-1 in Alzheimer’s disease and multi-infarct dementia: Neuropsychological correlations.Methods Findings Exp. Clin. Pharmacol. 13, 703–708.Google Scholar
  16. Cacabelos R., Alvarez X. A., Franco A., Fernández-Novoa L., Caamaño J., and del Valle-Inclán F. (1992a) Therapeutic effects of CDP choline in Alzheimer’s disease and multi-infarct dementia: Psychometric assessment and immune function.Ann. Psychiatry 3, 233–245.Google Scholar
  17. Cacabelos R., Fernández-Novoa L., Franco-Maside A., and Alvarez X. A. (1992b) Neuroimmune function of brain histamine: Implications for neurotrophic activity and neurotoxicity.Ann. Psychiatry 3, 147–200.Google Scholar
  18. Cacabelos R., Fernández-Novoa L., Pérez-Trullén J. M., Franco-Maside A., and Alvarez X. A. (1992c) Serum histamine in Alzheimer’s disease and multi-infarct dementia.Methods Findings Exp. Clin. Pharmacol. 14, 711–715.Google Scholar
  19. Cacabelos R., Alvarez X. A., Franco-Maside A., Fernández-Novoa L., and Caamaño J. (1993) Effect of CDP-choline on cognition and immune function in Alzheimer’s disease and multi-infarct dementia.Ann. NY Acad. Sci. 695, 321–323.PubMedCrossRefGoogle Scholar
  20. Cacabelos R., Alvarez X. A., Fernández-Novoa L., Franco A., Mangues R., Pellicer A., and Nishimura T. (1994a) Brain interleukin-1β in Alzheimer’s disease and vascular dementia.Methods Findings Exp. Clin. Pharmacol. 16, 141–151.Google Scholar
  21. Cacabelos R., Alvarez X. A., Franco-Maside A., Fernández-Novoa L., and Caamano J. (1994b) Serum tumor necrosis factor (TNF) in Alzheimer’s disease and multi-infarct dementia.Methods Findings Exp. Clin. Pharmacol. 16, 29–35.Google Scholar
  22. Cacabelos R., Nordberg A., Caamaño J., Franco-Maside A., Fernández-Novoa L., Gómez M. J., Alvarez X. A., Takeda M., Prous J., Jr., Nishimura T., and Winblad B. (1994c) Molecular strategies for the first generation of antidementia drugs (I). Tacrine and related compounds.Drugs Today 30, 295–337.Google Scholar
  23. Cacabelos R., Caamaño J., Gómez M. J., Fernández-Novoa L., Franco-Maside A., Vinagre D., Novo B., Zas R., and Alvarez X. A. (1995) Treatment of Alz-heimer’s disease with CDP-Choline: Effects on mental performance, brain electrical activity, cerebrovascular parameters and cytokine production.Ann. Psychiatry 5, 295–315.Google Scholar
  24. Carmeliet P., Van Damme J., and Denef C. (1989) Interleukin-1 beta inhibits acetylcholine synthesis in the pituitary corticotropic cell line AtT20.Brain Res. 491, 199–203.PubMedCrossRefGoogle Scholar
  25. Chaplin D. D. and Hogquist K. A. (1992) Interaction between TNF and interleukin-1 inTumor necrosis factors: The Molecules and Their Emerging Role in Medicine (Beutler, B. ed.), Raven, New York, pp. 197–220.Google Scholar
  26. Dickson D. W. and Rogers J. (1992) Neuroimmunology of Alzheimer’s disease: A conference report.Neurobiol. Aging 13, 793–798.PubMedCrossRefGoogle Scholar
  27. Fernández-Novoa L., Alvarez X. A., Franco A., and Cacabelos R. (1993) Histamine induced interleukin-1β changes in the rat hypothalamus.Methods Findings Exp. Clin. Pharmacol. 15, 735–741.Google Scholar
  28. Fernández-Novoa L., Alvarez X. A., Franco-Maside A., Caamaño J., and Cacabelos R. (1994) CDP-Choline-induced blood histamine changes in Alzheimer’s disease.Method Findings Exp. Clin. Pharmacol. 16, 279–284.Google Scholar
  29. Fernández-Novoa L., Franco A., Alvarez X. A., and Cacabelos R. (1995) Effects of histamine and α-fluoromethylhistidine on brain tumor necrosis factor levels in rats.Inflamm. Res. 44, 55–57.PubMedCrossRefGoogle Scholar
  30. Fillit H., Ding W. H., Buee L., Kalman J., Altstiel L., Lawlor B., and Wolf-Klein G. (1991) Elevated circulating tumor necrosis factor levels in Alzheimer’s disease.Neurosci. Lett. 129, 318–320.PubMedCrossRefGoogle Scholar
  31. Folstein M. F., Folstein S. E., and McHug P. R. (1975) Mini-mental state: A practical method for grading the cognitive state of patients for the clinician.J. Psychiat. Res. 12, 189–198.PubMedCrossRefGoogle Scholar
  32. Forloni G., Demicheli F., Giorgi S., Bendotti C., and Angeretti N. (1992) Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1.Mol. Brain Res. 16, 128–134.PubMedCrossRefGoogle Scholar
  33. Gray C. W. and Patel A. J. (1993) Regulation of β-amyloid precursor protein isoform mRNAs by transforming growth factor-β1 and interleukin-1β in astrocytes.Mol. Brain Res. 19, 251–256.PubMedCrossRefGoogle Scholar
  34. Griffin W. S. T., Stanley L. C., Ling C., White L., Macleod V., Perrot L. J., White C. L., and Araoz C. (1989) Brain interleukin 1 and S100 immunoreactivity are elevated in Down’s syndrome and Alzheimer disease.Proc. Natl. Acad. Sci. USA 86, 7611–7615.PubMedCrossRefGoogle Scholar
  35. Hachinski V. C., Lassen N. A., and Marshall J. (1974) Multi-infarct dementia: A cause of mental deterioration in the elderly.Lancet ii, 207.CrossRefGoogle Scholar
  36. Hamilton M. A. (1960) A rating scale for depression.J. Neurol. Neurosurg. Psychiat. 23, 56–62.PubMedCrossRefGoogle Scholar
  37. Harris H., Goldgaber W., Hla D., Maciag T., and Gajdusek C. (1989) Interleukin-1 regulates synthesis of amyloid beta protein precursor mRNA in human endothelial cells.Proc. Natl. Acad. Sci. USA 86, 7606–7610.PubMedCrossRefGoogle Scholar
  38. Heinonen O., Syrjänen S., Soininen H., Talasniemi S., Kasdi M., Mäntyjärvi R., Syrjanen K., and Riekkinen P. (1993) Circulating immune complexes in sera from patients with Alzheimer’s disease, multi-infarct dementia and Down’s syndrome.Neurosci. Lett. 149, 67–70.PubMedCrossRefGoogle Scholar
  39. Hermus A. R. and Sweep C. G. (1990) Cytokines and the hypothalamic-pituitary-adrenal axis.J. Steroid Biochem. Mol. Biol. 37, 867–871.PubMedCrossRefGoogle Scholar
  40. Holliday J. and Gruol D. L. (1993) Cytokine stimulation increases intracellular calcium and alters the response to quisqualtate in cultured cortical astrocytes.Brain Res. 621, 233–241.PubMedCrossRefGoogle Scholar
  41. Hotermans G., Bury T., and Radermecker M. F. (1991) Effects of histamine on tumor necrosis factor production by human monocytes.Int. Arch. Allerg. Appl. Immunol. 95, 278–281.Google Scholar
  42. Huberman M., Shalit F., Roth-Deri I., Gutman B., BrodieC., Kott E., and Sredni B. (1994) Correlation of cytokine secretion by mononuclear cells of Alzheimer patients and their disease state.J. Neuroimmunol. 52, 147–152.PubMedCrossRefGoogle Scholar
  43. Karlsson J.-Q., Blennow K., Janson I., Blomgren K., Karlsson I., Regland B., Wallin A., and Gottfries C. G. (1995) Increased proteolitic activity in lymphocytes from patients with early onset Alzheimer’s disease.Alzheimer's Res. 1 (Suppl 1) 35.Google Scholar
  44. Martinez M., Frank A., and Hernanz A. (1993) Relationship of interleukin-1 beta and beta 2-macroglobulin with neuropeptides in cerebrospinal fluid of patients with dementia of the Alzheimer’s type.J. Neuroimmunol. 48, 235–240.PubMedCrossRefGoogle Scholar
  45. Massey W. A., Randall T. C., Kagey-Sobotka A., Warner J. A., MacDonald S. M., Gillis S., Allison A. C., and Lichtenstein L. M. (1989) Recombinant human IL-1-alpha and-1β potentiate IgE-mediated histamine release from human basophils.J. Immunol. 143, 1875–1880.PubMedGoogle Scholar
  46. Mazurkiewich-Kwilecki I. M. and Nsonwah S. (1989) Changes in the regional brain histamine and histidine levels in postmortem brains of Alzheimer patients.Can. J. Physiol. Pharmacol. 67, 75–78.Google Scholar
  47. McGeer P. L., Itagaki S., Akiyama H., and McGeer E. G. (1988) Immune system response in Alzheimer’s disease, inCurrent Communications in Molecular Biology. The Molecular Biology of Alzheimer’s Disease (Finch C. E. and Davis P., eds.), CHS, New York, pp. 45–50.Google Scholar
  48. McGeer P. L., Kawamata T., Walker D. G., Akiyama H., Tooyama I., and McGeer E. G. (1993) Microglia in degenerative neurological disease.Glia 7, 84–92.PubMedCrossRefGoogle Scholar
  49. McKhann G., Drachman D., Folstein M., Katzman R., Price D., and Stadlan E. M. (1984) Clinical diagnosis of Alzheimer’s disease: Report of NINCDSADRDA Work Group.Neurology 34, 939–944.PubMedGoogle Scholar
  50. Nakamura S., Takemura M., Ohnishi K., Suenaga T., Nishimura M., Akiguchi I., Kimura J., and Kimura T. (1993) Loss of large neurons and occurrence of neurofibrillary tangles in the tuberomammillary nucleus of patients with Alzheimer’s disease.Neurosci. Lett. 151, 196–199.PubMedCrossRefGoogle Scholar
  51. Pirttila T., Mehta P. D., Frey H., and Wisniewski H. M. (1994) α1-Antichymotrypsin and IL-1β are not increased in CSF or serum in Alzheimer’s disease.Neurobiol. Aging 15, 313–317.PubMedCrossRefGoogle Scholar
  52. Rada P., Mark G. P., Vitek M. P., Mangano R. M., Blume A. J., Beer B., and Hoebel B. G. (1991) Interleukin-1β decreases acetylcholine measured by microdialysis in the hippocampus of freely moving rats.Brain Res. 550, 287–290.PubMedCrossRefGoogle Scholar
  53. Reisberg B., Ferris S. H., and De Leon M. J. (1985) Senile dementia of the Alzheimer type: Diagnosis and differential diagnostic features with special reference to functional assessment staging, inSenile Dementia of the Alzheimer-Type (Traber J. and Gispen W. H., eds.), Springer-Verlag, Berlin, pp. 18–37.Google Scholar
  54. Rothwell N. J. and Relton J. K. (1993) Involvement of cytokines in acute neurodegeneration in the CNS.Neurosci. Behav. Rev. 17, 217–227.Google Scholar
  55. Rozemuller J. M., Stam F. C., and Eikelenboom P. (1990) Acute phase proteins are present in amorphous plaques in the cerebral but not in the cerebellar cortex of patients with Alzheimer’s disease.Neurosci. Lett. 119, 75–78.PubMedCrossRefGoogle Scholar
  56. Sawada M., Hara N., and Maeno T. (1992) Reduction of the acetylcholine-induced K+ current in identified Aplysia neurons by human interleukin-1 and interleukin-2.Cell. Mol. Neurobiol. 12, 439–445.PubMedCrossRefGoogle Scholar
  57. Shalit F., Sredni B., Stern L., Kott E., and Huberman M. (1994) Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer’s patients.Neurosci. Lett. 174, 130–132.PubMedCrossRefGoogle Scholar
  58. Strauss S., Bauer J., Ganter U., Jonas U., Berger M., and Volk B. (1992) Detection of interleukin-6 and α2-macroglobulin immunoreactivity in cortex and hippocampus of Alzheimer’s disease patients.Lab. Invest. 66, 223–230.PubMedGoogle Scholar
  59. Subramanian N. and Bray M. A. (1987) Interleukin 1 releases histamine from human basophils and mast cells in vitro.J. Immunol. 138, 271–275.PubMedGoogle Scholar
  60. Sunderland T., Alterman I. S., Young D., Hill J. L., Tariot P. N., Newhouse P. A., Mueller E. A., Mellow A. M., and Cohen R. M. (1988) A new scale for the assessment of depressed mood in demented patients.Am. J. Psychiatr. 8, 955–959.Google Scholar
  61. Tazi A., Dantzer R., Crestani F., and Le Moal M. (1988) Interleukin-1 induces conditioned taste aversion in rats: a possible explanation for its pituitary-adrenal stimulating activity.Brain Res. 473, 369–371.PubMedCrossRefGoogle Scholar
  62. Van Gool D., De Strooper B., Van Leuven F., TriauE., and Dom R. (1993) α2-macro-globulin expression in Neuritic-type plaques in patients with Alzheimer’s disease.Neurobiol. Aging 14, 233–237.PubMedCrossRefGoogle Scholar
  63. Vannier E., Miller L. C., and Dinarello C. A. (1991) Histamine suppresses gene expression and synthesis of tumor necrosis factor-alpha via H2 receptors.J. Exp. Med. 174, 281–284.PubMedCrossRefGoogle Scholar
  64. Wood P. L. (1994) Microglia: A possible cellular target for pharmacological approaches to neurodegenerative disorders.Drug News & Perspectives 7, 138–157.Google Scholar
  65. Wood J. A., Wood P. L., Ryan R., Graff-Radford N. R., Pilapil C., Robitaille Y., and Quirion R. (1993) Cytokine indices in Alzheimer’s temporal cortex: no changes in mature IL-1β or IL-1RA but increases in the associated acute phase proteins IL-6, α2-macroglobulin and C-reactive protein.Brain Res. 629, 245–252.PubMedCrossRefGoogle Scholar
  66. Yamatodani A., Fukuda H., and Wada H. (1985) High-performance liquid chromatographic determination of plasma and brain histamine without previous purification of biological samples: cation-exchange chromatography coupled with post-column derivatization fluorometry.J. Chromatogr. 344, 115–123.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 1996

Authors and Affiliations

  • X. Antón Alvarez
    • 1
    Email author
  • Andrés Franco
    • 1
  • Lucía Fernández-Novoa
    • 1
  • Ramón Cacabelos
    • 1
  1. 1.Santa Marta de BabíoEuroEspes Research CenterBergondoSpain

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