Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2002 Nov;73(5):556–560. doi: 10.1136/jnnp.73.5.556

Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study

S Davis 1, A Thomas 1, R Perry 1, A Oakley 1, R Kalaria 1, J O'Brien 1
PMCID: PMC1738142  PMID: 12397151

Abstract

Objectives: Depression is a common psychiatric disorder in late life. Cerebrovascular disease has been postulated as an important aetiological factor in many cases (the "vascular depression" hypothesis). Consistent with this, an inflammatory response, most probably representing ischaemia, has been reported with increases in intercellular adhesion molecule 1 (ICAM-1), in the dorsolateral prefrontal cortex (DLPFC) in postmortem tissue from elderly depressed subjects. As ischaemia is known to cause astrogliosis, this study has further tested the "vascular depression hypothesis" by investigating the distribution of the astrocytic marker glial fibrillary acidic protein (GFAP) in the DLPFC and in the anterior cingulate cortex (ACC).

Methods: Postmortem tissue was obtained from 20 elderly patients with a history of major depressive disorder (MDD) and 20 control subjects. Sections were stained for GFAP using standard immunocytochemistry. Sets of images were obtained from all cortical layers in the DLPFC and ACC with the exception of layer IV in the ACC, and from gyral and deep white matter in both regions. The percentage of the area of each image occupied by GFAP was calculated using true colour image analysis, and mean values obtained for each region examined.

Results: Immunoreactivity for GFAP was low in grey matter (for example, Mean (SEM) 0.76 (0.2)% in DLPFC layer V in depressed subjects), but higher in white matter (for example, 12.02 (2.2)% in DLPFC deep white matter in depressed subjects). Pronounced gliosis was observed within grey matter in a few cases only. GFAP immunoreactivity was significantly higher in layer I of the DLPFC in depressed subjects 15.8 (2.6)% than in controls 9.7 (1.3)% (t=2.2; df=27.5, p=0.04). No difference was detected in any other region.

Conclusions: The data suggest any increase in GFAP in elderly MDD patients is limited to layer 1 of the DLPFC. These results provide some support for the vascular depression hypothesis and further implicate DLPFC abnormalities in depression.

Full Text

The Full Text of this article is available as a PDF (202.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alexopoulos G. S., Meyers B. S., Young R. C., Campbell S., Silbersweig D., Charlson M. 'Vascular depression' hypothesis. Arch Gen Psychiatry. 1997 Oct;54(10):915–922. doi: 10.1001/archpsyc.1997.01830220033006. [DOI] [PubMed] [Google Scholar]
  2. Baxter L. R., Jr, Schwartz J. M., Phelps M. E., Mazziotta J. C., Guze B. H., Selin C. E., Gerner R. H., Sumida R. M. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry. 1989 Mar;46(3):243–250. doi: 10.1001/archpsyc.1989.01810030049007. [DOI] [PubMed] [Google Scholar]
  3. Beekman A. T., Copeland J. R., Prince M. J. Review of community prevalence of depression in later life. Br J Psychiatry. 1999 Apr;174:307–311. doi: 10.1192/bjp.174.4.307. [DOI] [PubMed] [Google Scholar]
  4. Bench C. J., Friston K. J., Brown R. G., Scott L. C., Frackowiak R. S., Dolan R. J. The anatomy of melancholia--focal abnormalities of cerebral blood flow in major depression. Psychol Med. 1992 Aug;22(3):607–615. doi: 10.1017/s003329170003806x. [DOI] [PubMed] [Google Scholar]
  5. Cotter D., Mackay D., Landau S., Kerwin R., Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001 Jun;58(6):545–553. doi: 10.1001/archpsyc.58.6.545. [DOI] [PubMed] [Google Scholar]
  6. Cuevas E. C., Bateman A. C., Wilkins B. S., Johnson P. A., Williams J. H., Lee A. H., Jones D. B., Wright D. H. Microwave antigen retrieval in immunocytochemistry: a study of 80 antibodies. J Clin Pathol. 1994 May;47(5):448–452. doi: 10.1136/jcp.47.5.448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. David J. P., Ghozali F., Fallet-Bianco C., Wattez A., Delaine S., Boniface B., Di Menza C., Delacourte A. Glial reaction in the hippocampal formation is highly correlated with aging in human brain. Neurosci Lett. 1997 Oct 10;235(1-2):53–56. doi: 10.1016/s0304-3940(97)00708-8. [DOI] [PubMed] [Google Scholar]
  8. Drevets W. C., Price J. L., Simpson J. R., Jr, Todd R. D., Reich T., Vannier M., Raichle M. E. Subgenual prefrontal cortex abnormalities in mood disorders. Nature. 1997 Apr 24;386(6627):824–827. doi: 10.1038/386824a0. [DOI] [PubMed] [Google Scholar]
  9. Eng L. F., Ghirnikar R. S. GFAP and astrogliosis. Brain Pathol. 1994 Jul;4(3):229–237. doi: 10.1111/j.1750-3639.1994.tb00838.x. [DOI] [PubMed] [Google Scholar]
  10. Eng L. F. Glial fibrillary acidic protein (GFAP): the major protein of glial intermediate filaments in differentiated astrocytes. J Neuroimmunol. 1985 Jun;8(4-6):203–214. doi: 10.1016/s0165-5728(85)80063-1. [DOI] [PubMed] [Google Scholar]
  11. Everson S. A., Roberts R. E., Goldberg D. E., Kaplan G. A. Depressive symptoms and increased risk of stroke mortality over a 29-year period. Arch Intern Med. 1998 May 25;158(10):1133–1138. doi: 10.1001/archinte.158.10.1133. [DOI] [PubMed] [Google Scholar]
  12. Glassman A. H., Shapiro P. A. Depression and the course of coronary artery disease. Am J Psychiatry. 1998 Jan;155(1):4–11. doi: 10.1176/ajp.155.1.4. [DOI] [PubMed] [Google Scholar]
  13. Greenwald B. S., Kramer-Ginsberg E., Krishnan K. R., Ashtari M., Auerbach C., Patel M. Neuroanatomic localization of magnetic resonance imaging signal hyperintensities in geriatric depression. Stroke. 1998 Mar;29(3):613–617. doi: 10.1161/01.str.29.3.613. [DOI] [PubMed] [Google Scholar]
  14. Greenwald B. S., Kramer-Ginsberg E., Krishnan R. R., Ashtari M., Aupperle P. M., Patel M. MRI signal hyperintensities in geriatric depression. Am J Psychiatry. 1996 Sep;153(9):1212–1215. doi: 10.1176/ajp.153.9.1212. [DOI] [PubMed] [Google Scholar]
  15. Halliday G. M., Cullen K. M., Kril J. J., Harding A. J., Harasty J. Glial fibrillary acidic protein (GFAP) immunohistochemistry in human cortex: a quantitative study using different antisera. Neurosci Lett. 1996 May 3;209(1):29–32. doi: 10.1016/0304-3940(96)12592-1. [DOI] [PubMed] [Google Scholar]
  16. Harris E. C., Barraclough B. Excess mortality of mental disorder. Br J Psychiatry. 1998 Jul;173:11–53. doi: 10.1192/bjp.173.1.11. [DOI] [PubMed] [Google Scholar]
  17. Hickie I., Scott E. Late-onset depressive disorders: a preventable variant of cerebrovascular disease? Psychol Med. 1998 Sep;28(5):1007–1013. doi: 10.1017/s0033291797006090. [DOI] [PubMed] [Google Scholar]
  18. Johnston-Wilson N. L., Sims C. D., Hofmann J. P., Anderson L., Shore A. D., Torrey E. F., Yolken R. H. Disease-specific alterations in frontal cortex brain proteins in schizophrenia, bipolar disorder, and major depressive disorder. The Stanley Neuropathology Consortium. Mol Psychiatry. 2000 Mar;5(2):142–149. doi: 10.1038/sj.mp.4000696. [DOI] [PubMed] [Google Scholar]
  19. Jonas B. S., Franks P., Ingram D. D. Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Fam Med. 1997 Jan-Feb;6(1):43–49. doi: 10.1001/archfami.6.1.43. [DOI] [PubMed] [Google Scholar]
  20. Leifer D., Kowall N. W. Immunohistochemical patterns of selective cellular vulnerability in human cerebral ischemia. J Neurol Sci. 1993 Nov;119(2):217–228. doi: 10.1016/0022-510x(93)90137-n. [DOI] [PubMed] [Google Scholar]
  21. Miguel-Hidalgo J. J., Baucom C., Dilley G., Overholser J. C., Meltzer H. Y., Stockmeier C. A., Rajkowska G. Glial fibrillary acidic protein immunoreactivity in the prefrontal cortex distinguishes younger from older adults in major depressive disorder. Biol Psychiatry. 2000 Oct 15;48(8):861–873. doi: 10.1016/s0006-3223(00)00999-9. [DOI] [PubMed] [Google Scholar]
  22. Murray C. J., Lopez A. D. Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet. 1997 May 17;349(9063):1436–1442. doi: 10.1016/S0140-6736(96)07495-8. [DOI] [PubMed] [Google Scholar]
  23. Nichols N. R., Day J. R., Laping N. J., Johnson S. A., Finch C. E. GFAP mRNA increases with age in rat and human brain. Neurobiol Aging. 1993 Sep-Oct;14(5):421–429. doi: 10.1016/0197-4580(93)90100-p. [DOI] [PubMed] [Google Scholar]
  24. O'Brien J., Desmond P., Ames D., Schweitzer I., Harrigan S., Tress B. A magnetic resonance imaging study of white matter lesions in depression and Alzheimer's disease. Br J Psychiatry. 1996 Apr;168(4):477–485. doi: 10.1192/bjp.168.4.477. [DOI] [PubMed] [Google Scholar]
  25. Ongür D., Drevets W. C., Price J. L. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13290–13295. doi: 10.1073/pnas.95.22.13290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Petito C. K., Halaby I. A. Relationship between ischemia and ischemic neuronal necrosis to astrocyte expression of glial fibrillary acidic protein. Int J Dev Neurosci. 1993 Apr;11(2):239–247. doi: 10.1016/0736-5748(93)90082-o. [DOI] [PubMed] [Google Scholar]
  27. Rabins P. V., Pearlson G. D., Aylward E., Kumar A. J., Dowell K. Cortical magnetic resonance imaging changes in elderly inpatients with major depression. Am J Psychiatry. 1991 May;148(5):617–620. doi: 10.1176/ajp.148.5.617. [DOI] [PubMed] [Google Scholar]
  28. Rajkowska G., Miguel-Hidalgo J. J., Wei J., Dilley G., Pittman S. D., Meltzer H. Y., Overholser J. C., Roth B. L., Stockmeier C. A. Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression. Biol Psychiatry. 1999 May 1;45(9):1085–1098. doi: 10.1016/s0006-3223(99)00041-4. [DOI] [PubMed] [Google Scholar]
  29. Thomas A. J., Ferrier I. N., Kalaria R. N., Perry R. H., Brown A., O'Brien J. T. A neuropathological study of vascular factors in late-life depression. J Neurol Neurosurg Psychiatry. 2001 Jan;70(1):83–87. doi: 10.1136/jnnp.70.1.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Thomas A. J., Ferrier I. N., Kalaria R. N., Woodward S. A., Ballard C., Oakley A., Perry R. H., O'Brien J. T. Elevation in late-life depression of intercellular adhesion molecule-1 expression in the dorsolateral prefrontal cortex. Am J Psychiatry. 2000 Oct;157(10):1682–1684. doi: 10.1176/appi.ajp.157.10.1682. [DOI] [PubMed] [Google Scholar]
  31. Unger J. W. Glial reaction in aging and Alzheimer's disease. Microsc Res Tech. 1998 Oct 1;43(1):24–28. doi: 10.1002/(SICI)1097-0029(19981001)43:1<24::AID-JEMT4>3.0.CO;2-P. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES